85 results on '"Andrew J Lawrence"'
Search Results
2. Pattern and Rate of Cognitive Decline in Cerebral Small Vessel Disease: A Prospective Study.
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Andrew J Lawrence, Rebecca L Brookes, Eva A Zeestraten, Thomas R Barrick, Robin G Morris, and Hugh S Markus
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Medicine ,Science - Abstract
ObjectivesCognitive impairment, predominantly affecting processing speed and executive function, is an important consequence of cerebral small vessel disease (SVD). To date, few longitudinal studies of cognition in SVD have been conducted. We determined the pattern and rate of cognitive decline in SVD and used the results to determine sample size calculations for clinical trials of interventions reducing cognitive decline.Methods121 patients with MRI confirmed lacunar stroke and leukoaraiosis were enrolled into the prospective St George's Cognition And Neuroimaging in Stroke (SCANS) study. Patients attended one baseline and three annual cognitive assessments providing 36 month follow-up data. Neuropsychological assessment comprised a battery of tests assessing working memory, long-term (episodic) memory, processing speed and executive function. We calculated annualized change in cognition for the 98 patients who completed at least two time-points.ResultsTask performance was heterogeneous, but significant cognitive decline was found for the executive function index (pConclusionsThe pattern of cognitive decline seen in SVD over three years is consistent with the pattern of impairments at baseline. Rates of decline were slow and sample sizes would need to be large for clinical trials aimed at halting decline beyond initial diagnosis using cognitive scores as an outcome measure. This emphasizes the importance of more sensitive surrogate markers in this disease.
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- 2015
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3. Relaxin-3 receptor (RXFP3) signalling mediates stress-related alcohol preference in mice.
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Andrew W Walker, Craig M Smith, Berenice E Chua, Elena V Krstew, Cary Zhang, Andrew L Gundlach, and Andrew J Lawrence
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Medicine ,Science - Abstract
Stressful life events are causally linked with alcohol use disorders (AUDs), providing support for a hypothesis that alcohol consumption is aimed at stress reduction. We have previously shown that expression of relaxin-3 mRNA in rat brain correlates with alcohol intake and that central antagonism of relaxin-3 receptors (RXFP3) prevents stress-induced reinstatement of alcohol-seeking. Therefore the objectives of these studies were to investigate the impact of Rxfp3 gene deletion in C57BL/6J mice on baseline and stress-related alcohol consumption. Male wild-type (WT) and Rxfp3 knockout (KO) (C57/B6JRXFP3TM1/DGen) littermate mice were tested for baseline saccharin and alcohol consumption and preference over water in a continuous access two-bottle free-choice paradigm. Another cohort of mice was subjected to repeated restraint followed by swim stress to examine stress-related alcohol preference. Hepatic alcohol and aldehyde dehydrogenase activity was assessed in mice following chronic alcohol intake and in naive controls. WT and Rxfp3 KO mice had similar baseline saccharin and alcohol preference, and hepatic alcohol processing. However, Rxfp3 KO mice displayed a stress-induced reduction in alcohol preference that was not observed in WT littermates. Notably, this phenotype, once established, persisted for at least six weeks after cessation of stress exposure. These findings suggest that in mice, relaxin-3/RXFP3 signalling is involved in maintaining high alcohol preference during and after stress, but does not appear to strongly regulate the primary reinforcing effects of alcohol.
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- 2015
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4. An Annotated Description of Shallow Water Holothurians (Echinodermata: Holothuroidea) from Cayos Cochinos, Honduras
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Carlos Roberto Hasbún and Andrew J Lawrence
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Honduras ,holothurians ,taxonomy ,Echinodermata ,Aspirochidotida ,pearlfish ,Biology (General) ,QH301-705.5 - Abstract
Taxonomic and biological aspects are presented on five species of shallow water holothurians from the Cayos Cochinos Biological Reserve-CCBR located on the northern Honduran shelf, western Caribbean at 16º N, 86º W. This article provides a taxonomic key of the recorded holothurians and morphometric/morphologic descriptions of their corresponding spicules. These five species belong to a single order (Aspidochirotida) and two families: Stichopodidae (Isostichopus badionotus) and Holothuriidae (Holothuria mexicana, H. thomasi, H. arenicola and Actinopyga agassizi). In addition, the commensal pearlfish, Carapus bermudensis is recorded from H. mexicana and A. agassizi
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- 2002
5. The dual orexin receptor antagonist suvorexant in alcohol use disorder and comorbid insomnia: A case report
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Erin J. Campbell, Yvonne Bonomo, Lisa Collins, Amanda Norman, Helen O'Neill, Amanda Streitberg, Kate Galloway, Andrew Kyoong, Andrew Perkins, Adam Pastor, and Andrew J. Lawrence
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alcohol use disorder ,insomnia ,orexin ,relapse ,sleep ,suvorexant ,Medicine ,Medicine (General) ,R5-920 - Abstract
Key Clinical Message This case suggests using dual orexin receptor antagonists to treat alcohol use disorder and comorbid sleep disorders may be effective, commencing treatment in withdrawal and continuing it to prevent relapse. Abstract Effective medications for the treatment of alcohol use disorder are limited. This is partially due to the heterogenous nature of the symptomatology associated with alcohol use disorder and the abundance of presenting comorbidities. One common, and often overlooked, symptom that occurs during withdrawal of alcohol use is sleep disruption. Here, we report a case study of a participant with comorbid alcohol use disorder and insomnia. This participant was treated with a dual orexin receptor antagonist, suvorexant (Belsomra®), currently approved to treat insomnia. We demonstrate improvements in alcohol cravings, physical and psychological health, and sleep outcomes with treatment. These data support abundant preclinical and emerging clinical data in this space. The findings from this case report highlight the potential for suvorexant to treat comorbid alcohol use disorder and insomnia with fully powered, randomized controlled trials moving forward.
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- 2024
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6. Positive environmental modification of depressive phenotype and abnormal hypothalamic-pituitary-adrenal axis activity in female C57BL/6J mice during abstinence from chronic ethanol consumption
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Terence Y Pang, Xin eDu, William Andrew Catchlove, Thibault eRenoir, Andrew J Lawrence, and Anthony J Hannan
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Depression ,Dexamethasone ,alcohol ,HPA axis ,Abstinence ,environmental enrichment ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Depression is a commonly reported co-morbidity during rehabilitation from alcohol use disorders and its presence is associated with an increased likelihood of relapse. Interventions which impede the development of depression could be of potential benefit if incorporated into treatment programs. We previously demonstrated an ameliorative effect of physical exercise on depressive behaviours in a mouse model of alcohol abstinence. Here, we show that environmental enrichment (cognitive and social stimulation) has a similar beneficial effect. The hypothalamic-pituitary-adrenal (HPA) axis is a key physiological system regulating stress responses and its dysregulation has been separably implicated in the pathophysiology of depression and addiction disorders. We performed a series of dexamethasone challenges and found that mice undergoing 2 weeks of alcohol abstinence had significantly greater corticosterone and ACTH levels following a DEX-CRH challenge compared to water controls. Environmental enrichment during alcohol abstinence corrected the abnormal DEX-CRH corticosterone response despite a further elevation of ACTH levels. Examination of gene expression revealed abstinence-associated alterations in glucocorticoid receptor (Gr), corticotrophin releasing hormone (Crh) and pro-opiomelanocortin (Pomc1) mRNA levels which were differentially modulated by environmental enrichment. Overall, our study demonstrates a benefit of environmental enrichment on alcohol abstinence-associated depressive behaviours and HPA axis dysregulation.
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- 2013
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7. The metabotropic glutamate 5 receptor modulates extinction and reinstatement of methamphetamine-seeking in mice.
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Rose Chesworth, Robyn M Brown, Jee Hyun Kim, and Andrew J Lawrence
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Medicine ,Science - Abstract
Methamphetamine (METH) is a highly addictive psychostimulant with no therapeutics registered to assist addicts in discontinuing use. Glutamatergic dysfunction has been implicated in the development and maintenance of addiction. We sought to assess the involvement of the metabotropic glutamate 5 receptor (mGlu5) in behaviours relevant to METH addiction because this receptor has been implicated in the actions of other drugs of abuse, including alcohol, cocaine and opiates. mGlu5 knockout (KO) mice were tested in intravenous self-administration, conditioned place preference and locomotor sensitization. Self-administration of sucrose was used to assess the response of KO mice to a natural reward. Acquisition and maintenance of self-administration, as well as the motivation to self-administer METH was intact in mGlu5 KO mice. Importantly, mGlu5 KO mice required more extinction sessions to extinguish the operant response for METH, and exhibited an enhanced propensity to reinstate operant responding following exposure to drug-associated cues. This phenotype was not present when KO mice were tested in an equivalent paradigm assessing operant responding for sucrose. Development of conditioned place preference and locomotor sensitization were intact in KO mice; however, conditioned hyperactivity to the context previously paired with drug was elevated in KO mice. These data demonstrate a role for mGlu5 in the extinction and reinstatement of METH-seeking, and suggests a role for mGlu5 in regulating contextual salience.
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- 2013
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8. Mechanisms of cognitive impairment in cerebral small vessel disease: multimodal MRI results from the St George's cognition and neuroimaging in stroke (SCANS) study.
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Andrew J Lawrence, Bhavini Patel, Robin G Morris, Andrew D MacKinnon, Philip M Rich, Thomas R Barrick, and Hugh S Markus
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Medicine ,Science - Abstract
Cerebral small vessel disease (SVD) is a common cause of vascular cognitive impairment. A number of disease features can be assessed on MRI including lacunar infarcts, T2 lesion volume, brain atrophy, and cerebral microbleeds. In addition, diffusion tensor imaging (DTI) is sensitive to disruption of white matter ultrastructure, and recently it has been suggested that additional information on the pattern of damage may be obtained from axial diffusivity, a proposed marker of axonal damage, and radial diffusivity, an indicator of demyelination. We determined the contribution of these whole brain MRI markers to cognitive impairment in SVD. Consecutive patients with lacunar stroke and confluent leukoaraiosis were recruited into the ongoing SCANS study of cognitive impairment in SVD (n = 115), and underwent neuropsychological assessment and multimodal MRI. SVD subjects displayed poor performance on tests of executive function and processing speed. In the SVD group brain volume was lower, white matter hyperintensity volume higher and all diffusion characteristics differed significantly from control subjects (n = 50). On multi-predictor analysis independent predictors of executive function in SVD were lacunar infarct count and diffusivity of normal appearing white matter on DTI. Independent predictors of processing speed were lacunar infarct count and brain atrophy. Radial diffusivity was a stronger DTI predictor than axial diffusivity, suggesting ischaemic demyelination, seen neuropathologically in SVD, may be an important predictor of cognitive impairment in SVD. Our study provides information on the mechanism of cognitive impairment in SVD.
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- 2013
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9. Extreme deviations from the normative model reveal cortical heterogeneity and associations with negative symptom severity in first-episode psychosis from the OPTiMiSE and GAP studies
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Amanda Worker, Pierre Berthert, Andrew J. Lawrence, Seyed Mostafa Kia, Celso Arango, Richard Dinga, Silvana Galderisi, Birte Glenthøj, René S. Kahn, Anoushka Leslie, Robin M. Murray, Carmine M. Pariante, Christos Pantelis, Mark Weiser, Inge Winter-van Rossum, Philip McGuire, Paola Dazzan, and Andre F. Marquand
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract There is currently no quantifiable method to predict long-term clinical outcomes in patients presenting with a first episode of psychosis. A major barrier to developing useful markers for this is biological heterogeneity, where many different pathological mechanisms may underly the same set of symptoms in different individuals. Normative modelling has been used to quantify this heterogeneity in established psychotic disorders by identifying regions of the cortex which are thinner than expected based on a normative healthy population range. These brain atypicalities are measured at the individual level and therefore potentially useful in a clinical setting. However, it is still unclear whether alterations in individual brain structure can be detected at the time of the first psychotic episode, and whether they are associated with subsequent clinical outcomes. We applied normative modelling of cortical thickness to a sample of first-episode psychosis patients, with the aim of quantifying heterogeneity and to use any pattern of cortical atypicality to predict symptoms and response to antipsychotic medication at timepoints from baseline up to 95 weeks (median follow-ups = 4). T1-weighted brain magnetic resonance images from the GAP and OPTiMiSE samples were processed with Freesurfer V6.0.0 yielding 148 cortical thickness features. An existing normative model of cortical thickness (n = 37,126) was adapted to integrate data from each clinical site and account for effects of gender and site. Our test sample consisted of control participants (n = 149, mean age = 26, SD = 6.7) and patient data (n = 295, mean age = 26, SD = 6.7), this sample was used for estimating deviations from the normative model and subsequent statistical analysis. For each individual, the 148 cortical thickness features were mapped to centiles of the normative distribution and converted to z-scores reflecting the distance from the population mean. Individual cortical thickness metrics of +/– 2.6 standard deviations from the mean were considered extreme deviations from the norm. We found that no more than 6.4% of psychosis patients had extreme deviations in a single brain region (regional overlap) demonstrating a high degree of heterogeneity. Mann-Whitney U tests were run on z-scores for each region and significantly lower z-scores were observed in FEP patients in the frontal, temporal, parietal and occipital lobes. Finally, linear mixed-effects modelling showed that negative deviations in cortical thickness in parietal and temporal regions at baseline are related to more severe negative symptoms over the medium-term. This study shows that even at the early stage of symptom onset normative modelling provides a framework to identify individualised cortical markers which can be used for early personalised intervention and stratification.
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- 2023
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10. Maternally administered sustained-release naltrexone in rats affects offspring neurochemistry and behaviour in adulthood.
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Waleed O Farid, Andrew J Lawrence, Elena V Krstew, Robert J Tait, Gary K Hulse, and Sarah A Dunlop
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Medicine ,Science - Abstract
Naltrexone is not recommended during pregnancy. However, sustained-release naltrexone implant use in humans has resulted in cases of inadvertent foetal exposure. Here, we used clinically relevant dosing to examine the effects of maternally administered sustained-release naltrexone on the rat brain by examining offspring at birth and in adulthood. Maternal treatment (naltrexone or placebo implant) started before conception and ceased during gestation, birth or weaning. Morphometry was assessed in offspring at birth and adulthood. Adult offspring were evaluated for differences in locomotor behaviour (basal and morphine-induced, 10 mg/kg, s.c.) and opioid neurochemistry, propensity to self-administer morphine and cue-induced drug-seeking after abstinence. Blood analysis confirmed offspring exposure to naltrexone during gestation, birth and weaning. Naltrexone exposure increased litter size and reduced offspring birth-weight but did not alter brain morphometry. Compared to placebo, basal motor activity of naltrexone-exposed adult offspring was lower, yet they showed enhanced development of psychomotor sensitization to morphine. Developmental naltrexone exposure was associated with resistance to morphine-induced down-regulation of striatal preproenkephalin mRNA expression in adulthood. Adult offspring also exhibited greater operant responding for morphine and, in addition, cue-induced drug-seeking was enhanced. Collectively, these data show pronounced effects of developmental naltrexone exposure, some of which persist into adulthood, highlighting the need for follow up of humans that were exposed to naltrexone in utero.
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- 2012
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11. Identity state‐dependent self‐relevance and emotional intensity ratings of words in dissociative identity disorder: A controlled longitudinal study
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Aikaterini I. Strouza, Andrew J. Lawrence, Eline M. Vissia, Andreana Kakouris, Ayse Akan, Ellert R. S. Nijenhuis, Nel Draijer, Sima Chalavi, and Antje A. T. S. Reinders
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dissociation ,posttraumatic stress disorder ,trauma ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Introduction Dissociative identity disorder (DID) is characterized by, among others, amnesic episodes and the recurrence of different dissociative identity states. While consistently observed in clinical settings, to our knowledge, no controlled research study has shown the degree to which different identity states report autobiographical knowledge over time. Hence, the current study investigates self‐relevance and emotional intensity ratings of words longitudinally. Methods Data of 46 participants were included: 13 individuals with DID, 11 DID‐simulating actors, and a control group of 22 paired individuals. Individuals with DID and DID simulators participated once in the neutral identity state (NIS) and once in the trauma‐related dissociative identity state (TIS). The control group paired 11 healthy controls with 11 participants with posttraumatic stress disorder (PTSD) as a NIS–TIS pair. Self‐relevance ratings of different word types were collected in a baseline and a follow‐up session, on average 6 weeks apart. A mixed ANOVA design was used to assess the effects of group, session, word type, and dissociative identity state. Results All participants in TIS and individuals with DID in NIS rated self‐relevant trauma‐related words more negatively. In the NIS, the control group rated self‐relevant trauma‐related words as less negative, whereas the ratings of simulating actors were intermediate. There was no group‐dependent longitudinal effect for intensity ratings. Conclusions This study was the first to confirm clinical observations that self‐relevant and emotional processing are different between individuals with DID and controls, but consistent over time. Actors were unable to perfectly simulate DID. The finding that ratings of self‐relevant trauma‐related words differ between subgroups as included in the study is in line with clinical observations.
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- 2023
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12. Cocaine regulates sensory filtering in cortical pyramidal neurons
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Sean C. Murphy, Luca Godenzini, Robertas Guzulaitis, Andrew J. Lawrence, and Lucy M. Palmer
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CP: Neuroscience ,Biology (General) ,QH301-705.5 - Abstract
Summary: Exposure to cocaine leads to robust changes in the structure and function of neurons within the mesocorticolimbic pathway. However, little is known about how cocaine influences the processing of information within the sensory cortex. We address this by using patch-clamp and juxtacellular voltage recordings and two-photon Ca2+ imaging in vivo to investigate the influence of acute cocaine exposure on layer 2/3 (L2/3) pyramidal neurons within the primary somatosensory cortex (S1). Here, cocaine dampens membrane potential state transitions and decreases spontaneous somatic action potentials and Ca2+ transients. In contrast to the uniform decrease in background spontaneous activity, cocaine has a heterogeneous influence on sensory encoding, increasing tactile-evoked responses in dendrites that do not typically encode sensory information and decreasing responses in those dendrites that are more reliable sensory encoders. Combined, these findings suggest that cocaine acts as a filter that suppresses background noise to selectively modulate incoming sensory information.
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- 2023
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13. Dissociative identity state-dependent working memory in dissociative identity disorder: a controlled functional magnetic resonance imaging study
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Eline M. Vissia, Andrew J. Lawrence, Sima Chalavi, Mechteld E. Giesen, Nel Draijer, Ellert R. S. Nijenhuis, André Aleman, Dick J. Veltman, and Antje A. T. S. Reinders
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dissociative disorders ,simulation ,post-traumatic stress disorder ,trauma ,cognitive neuroscience ,Psychiatry ,RC435-571 - Abstract
Background Memory function is at the core of the psychopathology of dissociative identity disorder (DID), but little is known about its psychobiological correlates. Aims This study aims to investigate whether memory function in DID differs between dissociative identity states Method Behavioural data and neural activation patterns were assessed in 92 sessions during an n-back working memory task. Participants were people with genuine diagnosed DID (n = 14), DID-simulating controls (n = 16) and a paired control group (post-traumatic stress disorder (n = 16), healthy controls (n = 16)). Both DID groups participated as authentic or simulated neutral and trauma-related identity states. Reaction times and errors of omission were analysed with repeated measures ANOVA. Working memory neural activation (main working memory and linear load) was investigated for effects of identity state, participant group and their interaction. Results Identity state-dependent behavioural performance and neural activation was found. DID simulators made fewer errors of omission than those with genuine DID. Regarding the prefrontal parietal network, main working memory in the left frontal pole and ventrolateral prefrontal cortex (Brodmann area 44) was activated in all three simulated neutral states, and in trauma-related identity states of DID simulators, but not those with genuine DID or post-traumatic stress disorder; for linear load, trauma-related identity states of those with genuine DID did not engage the parietal regions. Conclusions Behavioural performance and neural activation patterns related to working memory in DID are dependent on the dissociative identities involved. The narrowed consciousness of trauma-related identity states, with a proneness to re-experiencing traumatising events, may relate to poorer working memory functioning.
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- 2022
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14. Dissociative identity state-dependent working memory in dissociative identity disorder:A controlled functional magnetic resonance imaging study
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Eline M. Vissia, Andrew J. Lawrence, Sima Chalavi, Mechteld E. Giesen, Nel Draijer, Ellert R. S. Nijenhuis, André Aleman, Dick J. Veltman, Antje A. T. S. Reinders, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Clinical Neuropsychology, VU University medical center, Anatomy and neurosciences, Psychiatry, Amsterdam Neuroscience - Brain Imaging, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
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Psychiatry ,Science & Technology ,AMNESIA ,EYE-MOVEMENT DESENSITIZATION ,PERFORMANCE ,simulation ,post-Traumatic stress disorder ,Psychiatry and Mental health ,cognitive neuroscience ,dissociative disorders ,POSTTRAUMATIC-STRESS-DISORDER ,PSYCHOMETRIC CHARACTERISTICS ,trauma ,COGNITIVE INHIBITION ,post-traumatic stress disorder ,MORPHOLOGY ,BRAIN ,Life Sciences & Biomedicine ,METAANALYSIS - Abstract
Background Memory function is at the core of the psychopathology of dissociative identity disorder (DID), but little is known about its psychobiological correlates. Aims This study aims to investigate whether memory function in DID differs between dissociative identity states Method Behavioural data and neural activation patterns were assessed in 92 sessions during an n-back working memory task. Participants were people with genuine diagnosed DID (n = 14), DID-simulating controls (n = 16) and a paired control group (post-traumatic stress disorder (n = 16), healthy controls (n = 16)). Both DID groups participated as authentic or simulated neutral and trauma-related identity states. Reaction times and errors of omission were analysed with repeated measures ANOVA. Working memory neural activation (main working memory and linear load) was investigated for effects of identity state, participant group and their interaction. Results Identity state-dependent behavioural performance and neural activation was found. DID simulators made fewer errors of omission than those with genuine DID. Regarding the prefrontal parietal network, main working memory in the left frontal pole and ventrolateral prefrontal cortex (Brodmann area 44) was activated in all three simulated neutral states, and in trauma-related identity states of DID simulators, but not those with genuine DID or post-traumatic stress disorder; for linear load, trauma-related identity states of those with genuine DID did not engage the parietal regions. Conclusions Behavioural performance and neural activation patterns related to working memory in DID are dependent on the dissociative identities involved. The narrowed consciousness of trauma-related identity states, with a proneness to re-experiencing traumatising events, may relate to poorer working memory functioning.
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- 2022
15. Symptom Remission and Brain Cortical Networks at First Clinical Presentation of Psychosis
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Kate Merritt, Andrew J. Lawrence, Arsime Demjaha, Kie W Nam, Roberto Rodriguez-Jimenez, Gareth J. Barker, Marina Díaz-Marsá, Brian V. Broberg, Richard Drake, Antje A. T. S. Reinders, Iris E. C. Sommer, Silvana Galderisi, Covadonga M. Díaz-Caneja, Birte Glenthøj, Kyra-Verena Sendt, Alice Egerton, Egill Rostrup, Armida Mucci, Inge Winter van Rossum, Neeltje E.M. van Haren, W. Wolfgang Fleischhacker, Lone Baandrup, Paola Dazzan, Shôn Lewis, René S. Kahn, Celso Arango, Bjørn H Ebdrup, Rocío Pérez-Iglesias, Mark Weiser, Philip McGuire, Christos Pantelis, Joost Janssen, Dazzan, P., Lawrence, A. J., Reinders, A. A. T. S., Egerton, A., Van Haren, N. E. M., Merritt, K., Barker, G. J., Perez-Iglesias, R., Sendt, K. -V., Demjaha, A., Nam, K. W., Sommer, I. E., Pantelis, C., Wolfgang Fleischhacker, W., Van Rossum, I. W., Galderisi, S., Mucci, A., Drake, R., Lewis, S., Weiser, M., Martinez Diaz-Caneja, C. M., Janssen, J., Diaz-Marsa, M., Rodriguez-Jimenez, R., Arango, C., Baandrup, L., Broberg, B., Rostrup, E., Ebdrup, B. H., Glenthoj, B., Kahn, R. S., Mcguire, P., Child and Adolescent Psychiatry / Psychology, Clinical Cognitive Neuropsychiatry Research Program (CCNP), and Movement Disorder (MD)
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Adult ,Male ,medicine.medical_specialty ,Psychosis ,Time Factors ,Adolescent ,medicine.medical_treatment ,Schizoaffective disorder ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Internal medicine ,Outcome Assessment, Health Care ,Humans ,Medicine ,Schizophreniform disorder ,Antipsychotic ,cortical thickne ,Gyrification ,first episode ,Cerebral Cortex ,First episode ,medicine.diagnostic_test ,business.industry ,Remission Induction ,Magnetic resonance imaging ,gyrification ,trial ,cortical thickness ,medicine.disease ,Magnetic Resonance Imaging ,OPTiMiSE ,030227 psychiatry ,schizophrenia ,Psychiatry and Mental health ,Psychotic Disorders ,Schizophrenia ,Female ,Nerve Net ,business ,030217 neurology & neurosurgery ,Regular Articles ,Antipsychotic Agents ,Follow-Up Studies ,MRI - Abstract
Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined.
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- 2021
16. M1 muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior
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Leigh C. Walker, Erin J. Campbell, Kate L. Huckstep, Nicola A. Chen, Christopher J. Langmead, and Andrew J. Lawrence
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consummatory behavior ,muscarinic receptor ,allosteric modulation ,Neurology ,addiction ,Therapeutics. Pharmacology ,RM1-950 ,General Pharmacology, Toxicology and Pharmaceutics ,alcohol use disorder - Abstract
Muscarinic acetylcholine receptors (mAChRs) have been shown to mediate alcohol consumption and seeking. Both M4 and M5 mAChRs have been highlighted as potential novel treatment targets for alcohol use disorders (AUD). Similarly, M1 mAChRs are expressed throughout reward circuitry, and their signaling has been implicated in cocaine consumption. However, whether the same effects are seen for alcohol consumption, or whether natural reward intake is inadvertently impacted is still unknown. To determine the role of M1 mAChRs in alcohol consumption, we tested operant self‐administration of alcohol under both fixed ratio (FR3) and progressive ratio (PR3‐4) schedules. Enhancing M1 mAChR signaling (via the M1 PAM‐Agonist PF‐06767832, 1 mg/kg, i.p.) reduced operant alcohol consumption on a fixed schedule but had no effect on motivation to acquire alcohol. To determine whether these actions were specific to alcohol, we examined the effects of M1 enhancement on natural reward (sucrose) self‐administration. Systemic administration of PF‐06767832 (1 mg/kg, i.p.) also reduced operant sucrose self‐administration, suggesting the actions of the M1 receptor may be non‐selective across drug and natural rewards. Finally, to understand whether this reduction extended to natural consummatory behaviors, we assessed home cage standard chow and water consumption. M1 enhancement via systemic PF‐06767832 administration reduced food and water consumption. Together our results suggest the M1 PAM‐agonist, PF‐06767832, non‐specifically reduces consummatory behaviors that are not associated with motivational strength for the reward. These data highlight the need to further characterize M1 agonists, PAMs, and PAM‐agonists, which may have varying degrees of utility in the treatment of neuropsychiatric disorders including AUD.
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- 2022
17. Effects of Pollution on Fish: Molecular Effects and Population Responses
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Andrew J. Lawrence, Krystal L. Hemingway, Andrew J. Lawrence, Krystal L. Hemingway and Andrew J. Lawrence, Krystal L. Hemingway, Andrew J. Lawrence, Krystal L. Hemingway
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- 2008
18. Chronic voluntary alcohol consumption causes persistent cognitive deficits and cortical cell loss in a rodent model
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Christina J. Perry, Annai J Charlton, Emma L. Burrows, Andrew J Lawrence, Sophia J Luikinga, Jee Hyun Kim, and Carlos May
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0301 basic medicine ,Serial reaction time ,Operant learning ,Alcohol Drinking ,media_common.quotation_subject ,Prefrontal Cortex ,lcsh:Medicine ,Attentional bias ,Article ,Discrimination Learning ,03 medical and health sciences ,0302 clinical medicine ,Cognition ,Reaction Time ,Medicine ,Animals ,Humans ,Cognitive Dysfunction ,Discrimination learning ,Cognitive decline ,Prefrontal cortex ,lcsh:Science ,media_common ,Multidisciplinary ,Ethanol ,business.industry ,Cognitive ageing ,Addiction ,lcsh:R ,Rats ,Alcoholism ,Disease Models, Animal ,030104 developmental biology ,Orbitofrontal cortex ,lcsh:Q ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Chronic alcohol use is associated with cognitive decline that impedes behavioral change during rehabilitation. Despite this, addiction therapy does not address cognitive deficits, and there is poor understanding regarding the mechanisms that underlie this decline. We established a rodent model of chronic voluntary alcohol use to measure ensuing cognitive effects and underlying pathology. Rats had intermittent access to alcohol or an isocaloric solution in their home cage under voluntary 2-bottle choice conditions. In Experiments 1 and 2 cognition was assessed using operant touchscreen chambers. We examined performance in a visual discrimination and reversal task (Experiment 1), and a 5-choice serial reaction time task (Experiment 2). For Experiment 3, rats were perfused immediately after cessation of alcohol access period, and volume, cell density and microglial populations were assessed in the prefrontal cortex and striatum. Volume was assessed using the Cavalieri probe, while cell and microglial counts were estimated using unbiased stereology with an optical fractionator. Alcohol-exposed and control rats showed comparable acquisition of pairwise discrimination; however, performance was impaired when contingencies were reversed indicating reduced behavioral flexibility. When tested in a 5-choice serial reaction time task alcohol-exposed rats showed increased compulsivity and increased attentional bias towards a reward associated cue. Consistent with these changes, we observed decreased cell density in the prefrontal cortex. These findings confirm a detrimental effect of chronic alcohol and establish a model of alcohol-induced cognitive decline following long-term voluntary intake that may be used for future intervention studies.
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- 2019
19. Altered dynamics of the prefrontal networks are associated with the risk for postpartum psychosis: a functional magnetic resonance imaging study
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Andrew J. Lawrence, Mitul A. Mehta, Susan Conroy, Paola Dazzan, Fabio Sambataro, Carmine M. Pariante, Montserrat Fusté, Giulia Cattarinussi, Alessandra Biaggi, Susan Pawlby, Gertrude Seneviratne, Katie Hazelgrove, Michael C. Craig, and Maddalena Miele
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Bipolar disorder ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Asymptomatic ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Salience (neuroscience) ,Neural Pathways ,medicine ,Humans ,Biological Psychiatry ,Brain Mapping ,Pregnancy ,medicine.diagnostic_test ,business.industry ,Functional connectivity ,Postpartum Period ,Brain ,Diagnostic markers ,medicine.disease ,Magnetic Resonance Imaging ,030227 psychiatry ,Psychiatry and Mental health ,Psychotic Disorders ,Female ,Postpartum psychosis ,medicine.symptom ,Functional magnetic resonance imaging ,business ,030217 neurology & neurosurgery ,RC321-571 ,Clinical psychology - Abstract
Postpartum psychosis (PP) is a severe mental disorder that affects women in the first few weeks after delivery. To date there are no biomarkers that distinguish which women at risk (AR) develop a significant psychiatric relapse postpartum. While altered brain connectivity may contribute to the risk for psychoses unrelated to the puerperium, this remains unexplored in PP. We followed up 32 AR and 27 healthy (HC) women from pregnancy to 8-week postpartum. At this point, we classified women as AR-unwell (n = 15) if they had developed a psychiatric relapse meeting DSM-IV diagnostic criteria, or impacting on daily functioning and requiring treatment, or AR-well (n = 17) if they remained asymptomatic. Women also underwent an fMRI scan at rest and during an emotional-processing task, to study within- and between-networks functional connectivity. Women AR, and specifically those in the AR-well group, showed increased resting connectivity within an executive network compared to HC. During the execution of the emotional task, women AR also showed decreased connectivity in the executive network, and altered emotional load-dependent connectivity between executive, salience, and default-mode networks. AR-unwell women particularly showed increased salience network-dependent modulation of the default-mode and executive network relative to AR-well, who showed greater executive network-dependent modulation of the salience network. Our finding that the executive network and its interplay with other brain networks implicated in goal-directed behavior are intrinsically altered suggest that they could be considered neural phenotypes for postpartum psychosis and help advance our understanding of the pathophysiology of this disorder.
- Published
- 2021
20. The 5‐HT2C receptor as a therapeutic target for alcohol and methamphetamine use disorders: A pilot study in treatment‐seeking individuals
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Lisa Collins, Janice Johnstone, Yvonne Bonomo, Peter Galettis, Erin J. Campbell, Andrew J Lawrence, Adam Pastor, and Amanda Norman
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medicine.medical_specialty ,Vital signs ,Contingency management ,Alcohol abuse ,Craving ,Alcohol use disorder ,RM1-950 ,030226 pharmacology & pharmacy ,Lorcaserin ,03 medical and health sciences ,0302 clinical medicine ,5‐HT2C agonist ,medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Psychiatry ,methamphetamine ,business.industry ,alcohol ,craving ,Methamphetamine ,medicine.disease ,serotonin ,Substance abuse ,Neurology ,030220 oncology & carcinogenesis ,Therapeutics. Pharmacology ,medicine.symptom ,business ,lorcaserin ,medicine.drug - Abstract
Alcohol use disorder (AUD) and methamphetamine use disorder (MUD) are prevalent and have high adverse impacts on both the individual and society. Current treatment strategies for these disorders are ineffective at a population level. Lorcaserin, a 5‐HT2C receptor agonist, has shown potential at reducing the symptoms of substance use disorder. This pilot study (initiated prior to market withdrawal) examined feasibility and safety of lorcaserin treatment in people undergoing residential detoxification and treatment for AUD and MUD. This was an open label pilot study of lorcaserin where participants (n = 10 AUD; n = 8 MUD) received 10‐mg lorcaserin daily for 4 days then twice daily for 1 month. Primary outcome measures included recruitment and retention rate, incidence of treatment‐emergent events, incidence of methamphetamine or alcohol withdrawal‐related events, heart rate, and blood pressure. Secondary measures included pharmacokinetic data and self‐reported alcohol or methamphetamine use, craving, and psychological distress. AUD participants were recruited faster and had a greater retention rate compared with MUD participants. Lorcaserin did not alter vital signs, was well tolerated, and had a similar pharmacokinetic profile to individuals with obesity. Lorcaserin reduced self‐reported alcohol and amphetamine‐type substance use and craving in AUD and MUD participants, respectively. Self‐reported psychological health also improved over the treatment period for all participants. Despite the pilot nature of this study, our data support the notion of 5‐HT2C receptors as a therapeutic target for drug and alcohol abuse.
- Published
- 2021
21. Anterior Insular Cortex is Critical for the Propensity to Relapse Following Punishment-Imposed Abstinence of Alcohol Seeking
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Erin J. Campbell, Andrew J Lawrence, Mitchell K.R.I. Hill, Leigh C Walker, Jeremy P. M. Flanagan, Nathan J. Marchant, Anatomy and neurosciences, and Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention
- Subjects
Male ,medicine.medical_specialty ,Alcohol Drinking ,Punishment (psychology) ,media_common.quotation_subject ,Drug-Seeking Behavior ,Context (language use) ,Alcohol use disorder ,Insular cortex ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Punishment ,Recurrence ,Animals ,Medicine ,Psychiatry ,GABA Agonists ,Research Articles ,media_common ,Cerebral Cortex ,Motivation ,Ethanol ,Alcohol Abstinence ,business.industry ,General Neuroscience ,Central Nervous System Depressants ,Genes, fos ,Extinction (psychology) ,Abstinence ,Receptors, GABA-A ,medicine.disease ,Rats ,030227 psychiatry ,Baclofen ,chemistry ,GABA-B Receptor Agonists ,business ,030217 neurology & neurosurgery - Abstract
Humans with alcohol use disorder typically abstain because of the negative consequences associated with excessive drinking, and exposure to contexts previously associated with alcohol use can trigger relapse. We used a rat model that captures a characteristic of this human condition: namely voluntary abstinence from alcohol use because of contingent punishment. There is substantial variability in the propensity to relapse following extended periods of abstinence, and this is a critical feature preventing the successful treatment of alcohol use disorder. Here we examined relapse following acute or prolonged abstinence. In male alcohol preferring P rats, we found an increased propensity to relapse in Context B, the punishment context after prolonged abstinence. Next, we found that neither alcohol intake history nor the motivational strength of alcohol predicted the propensity to relapse. We next examined the putative circuitry of context-induced relapse to alcohol seeking following prolonged abstinence using Fos as a marker of neuronal activation. The anterior insular cortex (AI) was the only brain region examined where Fos expression correlated with alcohol seeking behavior in Context B after prolonged abstinence. Finally, we used local infusion of GABAAand GABABreceptor agonists (muscimol + baclofen) to show a causal role of the AI in context-induced relapse in Context B, the punishment context after prolonged abstinence. Our results show that there is substantial individual variability in the propensity to relapse in the punishment-associated context after prolonged abstinence, and this is mediated by activity in the AI.SIGNIFICANCE STATEMENTA key feature of alcohol use disorder is that sufferers show an enduring propensity to relapse throughout their lifetime. Relapse typically occurs despite the knowledge of adverse consequences including health complications or relationship breakdowns. Here we use a recently developed rodent model that recapitulates this behavior. After an extended period of abstinence, relapse propensity is markedly increased in the “adverse consequence” environment, akin to humans with alcohol use disorder relapsing in the face of adversity. From a circuitry perspective, we demonstrate a causal role of the anterior insular cortex in relapse to alcohol seeking after extended abstinence following punishment imposed voluntary cessation of alcohol use.
- Published
- 2019
22. Silent myelin-weighted magnetic resonance imaging [version 2; peer review: 2 approved, 2 approved with reservations]
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Tobias C. Wood, Nikou L. Damestani, Andrew J. Lawrence, Emil Ljungberg, Gareth J. Barker, Ana Beatriz Solana, Florian Wiesinger, and Steven C.R. Williams
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lcsh:R ,lcsh:Medicine ,lcsh:Q ,lcsh:Science - Abstract
Background: Inhomogeneous Magnetization Transfer (ihMT) is an emerging, uniquely myelin-specific magnetic resonance imaging (MRI) contrast. Current ihMT acquisitions utilise fast Gradient Echo sequences which are among the most acoustically noisy MRI sequences, reducing patient comfort during acquisition. We sought to address this by modifying a near silent MRI sequence to include ihMT contrast. Methods: A Magnetization Transfer preparation module was incorporated into a radial Zero Echo-Time sequence. Repeatability of the ihMT ratio and inverse ihMT ratio were assessed in a cohort of healthy subjects. We also investigated how head orientation affects ihMT across subjects, as a previous study in a single subject suggests this as a potential confound. Results: We demonstrated that ihMT ratios comparable to existing, acoustically loud, implementations could be obtained with the silent sequence. We observed a small but significant effect of head orientation on inverse ihMTR. Conclusions: Silent ihMT imaging is a comparable alternative to conventional, noisy, alternatives. For all future ihMT studies we recommend careful positioning of the subject within the scanner.
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- 2020
23. New author guidelines and launch of Short Reports
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Andrew J Lawrence and Michael F. Jarvis
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Editorial ,Neurology ,Computer science ,Therapeutics. Pharmacology ,RM1-950 ,General Pharmacology, Toxicology and Pharmaceutics - Published
- 2020
24. A sleeping giant: Suvorexant for the treatment of alcohol use disorder?
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Andrew J Lawrence, Nathan J. Marchant, Erin J. Campbell, Anatomy and neurosciences, and Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention
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0301 basic medicine ,Sleep Wake Disorders ,medicine.medical_specialty ,media_common.quotation_subject ,Alcohol use disorder ,Relapse prevention ,Naltrexone ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,medicine ,Animals ,Humans ,Psychiatry ,Molecular Biology ,media_common ,business.industry ,General Neuroscience ,Suvorexant ,Azepines ,Abstinence ,Triazoles ,medicine.disease ,Substance Withdrawal Syndrome ,Sleep deprivation ,Alcoholism ,030104 developmental biology ,Acamprosate ,Disulfiram ,Orexin Receptor Antagonists ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Developmental Biology ,medicine.drug - Abstract
There are currently 3 FDA approved treatments for alcohol use disorder (AUD) in the USA, opioid receptor antagonists such as naltrexone, disulfiram and acamprosate. To date, these have been largely inadequate at preventing relapse at a population level and this may be because they only target certain aspects of AUD. Recently, suvorexant, a dual orexin receptor antagonist, has been FDA approved for the treatment of insomnia. Importantly, sleep disruptions occur during both acute and prolonged alcohol exposure and sleep deprivation is a potent factor promoting relapse to alcohol use. In this mini review article, we explore the therapeutic potential of suvorexant for the treatment of AUD. In particular, we highlight that in addition to altering the motivational properties of alcohol, suvorexant may also address key physiological components associated with alcohol withdrawal and abstinence, such as sleep disruptions, which should in turn help reduce or prevent relapse.
- Published
- 2020
25. A comparison of functional and tractography based networks in cerebral small vessel disease
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Hugh S. Markus, D Tozer, Emmanuel Stamatakis, Andrew J. Lawrence, Tozer, Daniel [0000-0002-0404-3214], Stamatakis, Emmanuel [0000-0001-6955-9601], Markus, Hugh [0000-0002-9794-5996], and Apollo - University of Cambridge Repository
- Subjects
Male ,Lacunar stroke ,Cognitive Neuroscience ,Neuropsychological Tests ,lcsh:Computer applications to medicine. Medical informatics ,lcsh:RC346-429 ,03 medical and health sciences ,Functional connectivity ,0302 clinical medicine ,Singular value decomposition ,Neural Pathways ,Image Processing, Computer-Assisted ,Medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,030212 general & internal medicine ,Diffusion Tractography ,Correlation of Data ,lcsh:Neurology. Diseases of the nervous system ,Aged ,Reproducibility ,Resting state fMRI ,business.industry ,Reproducibility of Results ,Regular Article ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,White Matter ,Reproducibility diffusion imaging ,Small vessel disease ,Diffusion Tensor Imaging ,Neurology ,Sample size determination ,Cerebral Small Vessel Diseases ,lcsh:R858-859.7 ,Network analysis ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Tractography ,Biomedical engineering ,MRI - Abstract
Objective MRI measures of network integrity may be useful disease markers in cerebral small vessel disease (SVD). We compared the sensitivity and reproducibility of MRI derived structural and functional network measures in healthy controls and SVD subjects. Methods Diffusion tractography and resting state fMRI were used to create connectivity matrices from 26 subjects with symptomatic MRI confirmed lacunar stroke and 19 controls. Matrices were constructed at multiple scales based on a multi-resolution cortical atlas and at multiple thresholds for the matrix density. Network parameters were calculated over the multiple resolutions and thresholds. In addition the reproducibility of structural and functional network parameters was determined in a subset of the subjects (15 SVD, 10 controls) who were scanned twice. Results Structural networks showed a highly significant loss of network integrity in SVD cases compared to controls, for all network measures. In contrast functional networks showed no difference between SVD and controls. Structural network measures were highly reproducible in both cases and controls, with ICC values consistently over 0.8. In contrast functional network measures showed much poorer reproducibility with ICC values in the range 0.4–0.6 overall, and even lower in SVD cases. Conclusions Structural networks identify impaired network integrity, and are highly reproducible, in SVD, supporting their use as markers of SVD disease severity. In contrast, functional networks showed low reproducibility, particularly in SVD cases, and were unable to detect differences between SVD cases and controls with this sample size., Highlights • Diffusion based networks are reproducible in both small vessel disease and controls. • Functional connectivity in controls is less reproducible. • Functional connectivity in small vessel disease is not reproducible. • This limits the ability of whole brain functional networks to distinguish groups.
- Published
- 2018
26. A neuroethics framework for the Australian Brain Initiative
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Glenda M. Halliday, Anne Castles, Ian B. Hickie, Olivia Carter, Matthew C. Kiernan, Tina Soulis, Timothy J. Silk, Jason B. Mattingley, Jonathan Tapson, Andrew P. Bradley, Geoff Mackellar, Judith Gullifer, Greg de Zubicaray, Alan M. Brichta, John Parker, David Shum, Zoltán Sarnyai, Chris Hatherly, Patricia T. Michie, Wayne Hall, Pankaj Sah, Alice Mason, Neil Levy, John M. Bekkers, Jonathan M. Payne, André van Schaik, Laura A. Poole-Warren, Sarah Cohen-Woods, Mark Slee, Bryce Vissel, Sharath Sriram, Stefan Harrer, Deborah Apthorp, Linda J. Richards, Kim Cornish, Bernadette M. Fitzgibbon, Trevor J. Kilpatrick, Adrian Carter, Cynthia Forlini, Jeanette Kennett, Khaled Chakli, Peter G. Enticott, Anthony J. Hannan, Michael Berk, Michael Breakspear, James A. Bourne, Alan R. Harvey, Peter R. Schofield, Nigel H. Lovell, Ashleigh E. Smith, Julio Licinio, David R. Badcock, Sarah E. Medland, Isabell Kiral-Kornek, Mayuresh S. Korgaonkar, Allison Waters, Richard J. Leventer, Mostafa Rahimi Azghadi, Andrew J. Lawrence, Bernard W. Balleine, Simon J. Conn, Lyn R. Griffiths, Jess Nithianantharajah, Gary F. Egan, Alex Fornito, Jennifer L. Cornish, Greg J. Stuart, Lynne Malcolm, Matthew B. Thompson, Nicole A. Vincent, Olga Shimoni, Carter, Adrian, Richards, Linda J, Apthorp, Deborah, Smith, Ashleigh E, Waters, Allison, Australian Brain Alliance, and Alliance, Australian Brain
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0301 basic medicine ,General Neuroscience ,Australia ,Neurosciences ,Stakeholder engagement ,Bioethics ,neurotechnology translation ,Mental health ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Mental Health ,Neurotechnology ,Political science ,Thriving ,Practice Guidelines as Topic ,Humans ,Engineering ethics ,neurotechnology ,Neuroethics ,030217 neurology & neurosurgery - Abstract
Neuroethics is central to the Australian Brain Initiative’s aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative. Refereed/Peer-reviewed
- Published
- 2019
27. Glucose Availability Predicts the Feeding Response to Ghrelin in Male Mice, an Effect Dependent on AMPK in AgRP Neurons
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Zane B. Andrews, Mathieu Méquinion, Romana Stark, David Spanswick, Sarah S Ch'ng, Dong Kong, Sarah Kathleen Haas Lockie, and Andrew J Lawrence
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0301 basic medicine ,Male ,medicine.medical_specialty ,Antimetabolites ,medicine.medical_treatment ,Hypothalamus ,Neuropeptide ,Gene Expression ,Biology ,AMP-Activated Protein Kinases ,Deoxyglucose ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Endocrinology ,AMP-activated protein kinase ,Internal medicine ,medicine ,Animals ,Agouti-Related Protein ,Neuropeptide Y ,RNA, Messenger ,Neurons ,Leptin ,Insulin ,digestive, oral, and skin physiology ,Arcuate Nucleus of Hypothalamus ,AMPK ,Feeding Behavior ,Neuropeptide Y receptor ,Ghrelin ,030104 developmental biology ,Glucose ,Gene Knockdown Techniques ,biology.protein ,030217 neurology & neurosurgery ,hormones, hormone substitutes, and hormone antagonists ,Research Article - Abstract
Metabolic feedback from the periphery to the brain results from a dynamic physiologic fluctuation of nutrients and hormones, including glucose and fatty acids, ghrelin, leptin, and insulin. The specific interactions between humoral factors and how they influence feeding is largely unknown. We hypothesized that acute glucose availability may alter how the brain responds to ghrelin, a hormonal signal of energy availability. Acute glucose administration suppressed a range of ghrelin-induced behaviors as well as gene expression changes in hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons after ghrelin administration. Knockdown of the energy-sensing molecule AMP-activated protein kinase (AMPK) in AgRP neurons resulted in loss of the glucose effect, and mice responded as though pretreated with saline. Conversely, 2-deoxyglucose (2-DG), which decreases glucose availability, potentiated ghrelin-induced feeding and increased hypothalamic NPY mRNA levels. AMPK knockdown did not alter the additive effect of 2-DG and ghrelin on feeding. Our findings support the idea that computation of energy status is dynamic, is informed by multiple signals, and responds to acute fluctuations in metabolic state. These observations are broadly relevant to the investigation of neuroendocrine control of feeding and highlight the underappreciated complexity of control within these systems.
- Published
- 2018
28. B Part of It protocol: a cluster randomised controlled trial to assess the impact of 4CMenB vaccine on pharyngeal carriage of Neisseria meningitidis in adolescents
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Jane Whelan, Ray Borrow, Helen Marshall, Jenny M. MacLennan, Kumaran Vadivelu, Shamez N Ladhani, Thomas Sullivan, Adam Finn, Caroline Trotter, Mary Ramsay, Andrew J Lawrence, Peter Richmond, Charlene M. Kahler, Martin C. J. Maiden, Mark McMillan, Ann P. Koehler, Trotter, Caroline [0000-0003-4000-2708], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Adolescent ,education ,030106 microbiology ,Meningococcal Vaccines ,Meningococcal vaccine ,Neisseria meningitidis ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Risk Factors ,law ,Informed consent ,South Australia ,Epidemiology ,Protocol ,Prevalence ,medicine ,Humans ,030212 general & internal medicine ,Cluster randomised controlled trial ,carriage ,Randomized Controlled Trials as Topic ,meningococcal disease ,Schools ,business.industry ,Public health ,public health ,General Medicine ,3. Good health ,Vaccination ,Infectious Diseases ,Carriage ,Research Design ,Family medicine ,Carrier State ,Pharynx ,epidemiology ,business ,randomised controlled trial - Abstract
IntroductionSouth Australia (SA) has the highest notification rate of invasive meningococcal disease in Australia with the majority of cases due to serogroup B.Neisseria meningitidisis carried in the pharynx, with adolescents having the highest rates of carriage. A vaccine designed to offer protection against serogroup B (4CMenB) is licensed in Australia. The SA MenB vaccine carriage study aims to assess the impact of 4CMenB on carriage ofN. meningitidisin adolescents.Methods and analysisThis is a parallel cluster randomised controlled trial enrolling year 10, 11 and 12 school students (approximately 16–18 years of age) throughout SA, in metropolitan and rural/remote areas. Schools are randomised to intervention (4CMenB vaccination at baseline) or control (4CMenB vaccination at study completion) with randomisation stratified by school size and socioeconomic status, as measured by the Index of Community Socio-Educational Advantage (Australian Curriculum). Oropharyngeal swabs will be taken from all students at visit 1, and 12 months later from year 11 and 12 students. Students unvaccinated in 2017 will receive vaccine at the 12-month follow-up. Carriage prevalence ofN. meningitidiswill be determined by PCR at baseline and 12 months following 4CMenB vaccination and compared with carriage prevalence at 12 months in unvaccinated students. A questionnaire will be completed at baseline and 12 months to assess risk factors associated with carriage. The primary outcome of carriage prevalence of disease causingN. meningitidisat 12 months will be compared between groups using logistic regression, with generalised estimating equations used to account for clustering at the school level. The difference in carriage prevalence between groups will be expressed as an OR with 95% CI.Ethics and disseminationThe study was approved by the Women’s and Children’s Health Network Human Research Ethics Committee (WCHN HREC). The protocol, informed consent forms, recruitment materials, social media and all participant materials have been reviewed and approved by the WCHN HREC and updated on ClinicalTrials.gov. Results will be published in international peer-reviewed journals and presented at national and international conferences. The study findings will be provided in public forums and to study participants and participating schools.Trial registration numberACTRN12617000079347.NCT03089086; Pre-results.
- Published
- 2018
29. Reduced alcohol-seeking in male offspring of sires exposed to alcohol self-administration followed by punishment-imposed abstinence
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Erin J. Campbell, Nathan J. Marchant, Andrew J Lawrence, Jeremy P. M. Flanagan, Anatomy and neurosciences, and Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention
- Subjects
Male ,iP rats ,Punishment (psychology) ,Alcohol Drinking ,Offspring ,media_common.quotation_subject ,Alcohol ,Context (language use) ,Self Administration ,Alcohol use disorder ,alcohol use disorder ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Punishment ,paternal alcohol exposure ,medicine ,inheritance ,Animals ,General Pharmacology, Toxicology and Pharmaceutics ,Paternal Behavior ,media_common ,Ethanol ,business.industry ,Addiction ,Original Articles ,Abstinence ,medicine.disease ,030227 psychiatry ,Rats ,Behavior, Addictive ,Neurology ,chemistry ,intergenerational ,behavior and behavior mechanisms ,Original Article ,Female ,Self-administration ,business ,Reinforcement, Psychology ,030217 neurology & neurosurgery ,Clinical psychology - Abstract
Emerging evidence has demonstrated that paternal alcohol use can modify the behavior of offspring, particularly male offspring. However, preclinical studies to date have not used voluntary self‐administration of alcohol to examine alcohol‐related behaviors in offspring. Here, we tested the hypothesis that paternal alcohol self‐administration followed by punishment‐imposed abstinence alters alcohol consumption and seeking in male offspring. Male inbred alcohol preferring iP rats were trained to self‐administer alcohol in one context followed by punishment‐imposed suppression of alcohol‐seeking in a different context using contingent footshock. Following this, all rats were bred with alcohol naïve female iP rats. F1 offspring were then trained to self‐administer alcohol in an identical operant paradigm as sires. Alcohol intake and self‐administration behaviors of alcohol‐sired offspring were compared to control‐sired offspring whose fathers had not been exposed to the alcohol operant conditioning experience. We found that paternal alcohol self‐administration reduced context‐induced relapse to alcohol‐seeking in male offspring. These findings indicate that voluntary paternal alcohol experience, operant conditioning, and punishment can result in intergenerational changes in offspring behavior, and that this effect may protect against the vulnerability to relapse after alcohol use. We also noted reduced alcohol responding in the punishment‐associated context in alcohol‐sired offspring, suggesting altered perception of punishment sensitivity or the anxiogenic response to footshock. Collectively, these findings provide evidence that paternal alcohol abuse can impact alcohol‐related behaviors in male offspring.
- Published
- 2018
30. Behavioral Neuroscience of Orexin/Hypocretin
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Andrew J Lawrence, Luis de Lecea, Andrew J Lawrence, and Luis de Lecea
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- Neurosciences, Orexins, Neuropsychology
- Abstract
This issue of Current Topics in Behavioral Neuroscience focuses on the neuropeptide orexin (hypocretin) and brings together scientists from around the world who will provide a timely discussion of how this peptide regulates behavior. This is a fast-moving field, and with the incorporation of novel technologies, new breakthroughs are likely to continue. For example, the use of optogenetic approaches has enabled the identification of the role of orexin-containing neurons in arousal states, critical for higher order functioning. From a clinical perspective, genetic polymorphisms in hypocretin/orexin and orexin receptors are implicated in a number of psychiatric disorders. In addition, advanced clinical trials are currently underway for orexin receptor antagonists in the treatment of insomnia and sleep disorders. We aim to capture a broad audience of basic scientists and clinicians.
- Published
- 2017
31. Aripiprazole Facilitates Extinction of Conditioned Fear in Adolescent Rats
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Danny L. D. Nguyen, Andrew J Lawrence, Isabel Zbukvic, Despina E. Ganella, Russell Coulthard, Heather B Madsen, Liubov Lee-Kardashyan, Sophia J Luikinga, and Jee Hyun Kim
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cognitive Neuroscience ,medicine.medical_treatment ,Exposure therapy ,Partial agonist ,Amygdala ,lcsh:RC321-571 ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,aripiprazole ,Dopamine receptor D2 ,Internal medicine ,medicine ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Original Research ,prefrontal cortex ,extinction ,Dopaminergic ,Extinction (psychology) ,social sciences ,humanities ,030104 developmental biology ,Neuropsychology and Physiological Psychology ,Endocrinology ,medicine.anatomical_structure ,Anesthesia ,fear ,Aripiprazole ,adolescence ,dopamine ,Psychology ,030217 neurology & neurosurgery ,medicine.drug ,Basolateral amygdala ,Neuroscience - Abstract
Anxiety disorders are the most common type of mental disorder during adolescence, which is at least partly due to the resistance to extinction exhibited at this age. The dopaminergic system is known to be dysregulated during adolescence; therefore, we aimed to facilitate extinction in adolescent rats using the dopamine receptor 2 partial agonist aripiprazole (Abilify™), and examine the behavioral and neural outcomes. Adolescent rats were conditioned to fear a tone. The next day, rats received extinction 30 min after a systemic injection of either 5 mg/kg aripiprazole or vehicle, and then were tested the following day. For the immunohistochemistry experiment, naïve and “no extinction” conditions were added and rats were perfused either on the extinction day or test day. To assess the activation of neurons receiving dopaminergic input, c-Fos, and dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) labeled neurons were quantified in the amygdala and the medial prefrontal cortex (mPFC). Systemic treatment with aripiprazole at the time of extinction significantly reduced freezing at test the next day. This effect was not observed in rats that were fear conditioned but did not receive any extinction. Aripiprazole's facilitation of extinction was accompanied by increased activation of neurons in the mPFC. Taken together, aripiprazole represents a novel pharmacological adjunct to exposure therapy worthy of further examination. The effect of aripiprazole is related to enhanced activation of mPFC neurons receiving dopaminergic innervation.
- Published
- 2017
32. Prefrontal Dopaminergic Mechanisms of Extinction in Adolescence Compared to Adulthood in Rats
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Chun Hui J. Park, Andrew J Lawrence, Isabel Zbukvic, Despina E. Ganella, and Jee Hyun Kim
- Subjects
0301 basic medicine ,Cognitive Neuroscience ,Infralimbic cortex ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Quinpirole ,conditioning ,Dopamine ,Dopamine receptor D2 ,medicine ,natural sciences ,Fear conditioning ,Prefrontal cortex ,Original Research ,prefrontal cortex ,extinction ,social sciences ,medicine.disease ,musculoskeletal system ,humanities ,030104 developmental biology ,medicine.anatomical_structure ,Neuropsychology and Physiological Psychology ,Dopamine receptor ,Extinction (neurology) ,fear ,adolescence ,dopamine ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,geographic locations ,medicine.drug - Abstract
Adolescents with anxiety disorders attain poorer outcomes following extinction-based treatment compared to adults. Extinction deficit during adolescence has been identified to involve immaturity in the medial prefrontal cortex (mPFC). Findings from adult rodents suggest extinction involves dopamine signaling in the mPFC. This system changes dramatically during adolescence, but its role in adolescent extinction is unknown. Therefore, we investigated the role of prefrontal dopamine in extinction using Pavlovian fear conditioning in adolescent and adult rats. Using quantitative PCR (qPCR) analyses, we measured changes in dopamine receptor gene expression in the mPFC before and after extinction. We then enhanced dopamine 1 receptor (D1R) or dopamine 2 receptor (D2R) signaling in the infralimbic cortex (IL) of the mPFC using agonists at the time of extinction. Adolescent rats displayed a deficit in extinction retention compared to adults. Extinction induced a reduction in D1R compared to D2R gene expression in adolescent rats, whereas an increase of D1R compared to D2R gene expression was observed in adult rats. Acutely enhancing IL D1R signaling using SKF-81297 had no effect on extinction at either age. In contrast, acutely enhancing IL D2R signaling with quinpirole significantly enhanced long-term extinction in adolescents, and impaired within-session extinction in adults. Our results suggest a dissociated role for prefrontal dopamine in fear extinction during adolescence compared to adulthood. Findings highlight the dopamine system as a potential pharmacological target to improve extinction-based treatments for adolescents.
- Published
- 2017
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33. Conventional Concepts and New Perspectives for Understanding the Addictive Properties of Inhalants
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Jhodie R. Duncan and Andrew J Lawrence
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Adolescent ,Inhalant Abuse ,media_common.quotation_subject ,Nucleus accumbens ,Receptors, Ionotropic Glutamate ,Receptors, Metabotropic Glutamate ,Receptors, N-Methyl-D-Aspartate ,Glutamatergic ,Glutamates ,Dopamine ,Dopaminergic Cell ,medicine ,Animals ,Humans ,GABAergic Neurons ,gamma-Aminobutyric Acid ,media_common ,Pharmacology ,Neurotransmitter Agents ,business.industry ,Dopaminergic Neurons ,Addiction ,Dopaminergic ,lcsh:RM1-950 ,Brain ,Receptors, GABA-A ,lcsh:Therapeutics. Pharmacology ,Solvents ,Molecular Medicine ,GABAergic ,business ,Neuroscience ,Toluene ,medicine.drug - Abstract
The abuse of inhaled chemical vapors is a growing problem especially among adolescent populations. This is partly driven by the fact that inhaled products are cheap, accessible, and provide a rapid ‘high’. In the brain inhalants have multiple effects. They are neurotoxic, targeting primarily white matter pathways, which is believed to underlie the long-term neurological consequences associated with repeated use. Inhalants are also addictive, resulting in adaptive responses in pathways mediating reward and reinforcement. This includes an ability to alter dopaminergic cell firing and result in long-term mesocorticolimbic dopaminergic dysfunction. However, growing evidence suggests that the reinforcing properties of inhalants may also be driven by their ability to affect neurotransmitter systems other than the dopaminergic system. Both glutamatergic and γ-aminobutyric acid (GABA)ergic systems are emerging as key targets of inhalants with differential responses observed following either acute or chronic exposures. These responses appear particularly important in circuits which appear vulnerable to inhalants and which can also modulate dopaminergic function such as the corticostriatal pathway. Thus in combination with the effects of inhalants on dopaminergic systems, our increased understanding of the role(s) of glutamatergic and GABAergic systems provide new and exciting targets to consider for intervention strategies to limit inhalant use. Keywords:: adolescence, toluene, dopamine, glutamate, GABA
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- 2013
34. The Nuclear Transcription Factor CREB: Involvement in Addiction, Deletion Models and Looking Forward
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Andrew J Lawrence and Cameron S McPherson
- Subjects
media_common.quotation_subject ,behavior ,CREB ,Article ,cAMP response element binding protein ,Conditional gene knockout ,mental disorders ,Medicine ,Pharmacology (medical) ,conditional knockout ,Gene ,Transcription factor ,media_common ,Pharmacology ,biology ,business.industry ,Addiction ,General Medicine ,Element binding protein ,Phenotype ,Psychiatry and Mental health ,Neurology ,biology.protein ,Neurology (clinical) ,addiction ,business ,Neuroscience ,Cocaine seeking - Abstract
Addiction involves complex physiological processes, and is characterised not only by broad phenotypic and behavioural traits, but also by ongoing molecular and cellular adaptations. In recent years, increasingly effective and novel techniques have been developed to unravel the molecular implications of addiction. Increasing evidence has supported a contribution of the nuclear transcription factor CREB in the development of addiction, both in contribution to phenotype and expression in brain regions critical to various aspects of drug-seeking behaviour and drug reward. Abstracting from this, models have exploited these data by removing the CREB gene from the developing or developed mouse, to crucially determine its impact upon addiction-related processes. More recent models, however, hold greater promise in unveiling the contribution of CREB to disorders such as addiction.
- Published
- 2007
35. Relaxin-3 Receptor (RXFP3) Signalling Mediates Stress-Related Alcohol Preference in Mice
- Author
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Cary Zhang, Andrew L. Gundlach, Andrew J Lawrence, Berenice E. Chua, Andrew W. Walker, Elena Krstew, and Craig M. Smith
- Subjects
Male ,medicine.medical_specialty ,Alcohol Drinking ,Aldehyde dehydrogenase ,lcsh:Medicine ,Alcohol ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Saccharin ,Stress, Physiological ,Internal medicine ,medicine ,Animals ,Receptor ,lcsh:Science ,030304 developmental biology ,Alcohol dehydrogenase ,Mice, Knockout ,0303 health sciences ,Multidisciplinary ,Ethanol ,biology ,business.industry ,lcsh:R ,Acetaldehyde ,Alcohol Dehydrogenase ,Feeding Behavior ,Aldehyde Dehydrogenase ,Rats ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Liver ,biology.protein ,lcsh:Q ,business ,Relaxin-3 ,030217 neurology & neurosurgery ,Research Article ,Signal Transduction - Abstract
Stressful life events are causally linked with alcohol use disorders (AUDs), providing support for a hypothesis that alcohol consumption is aimed at stress reduction. We have previously shown that expression of relaxin-3 mRNA in rat brain correlates with alcohol intake and that central antagonism of relaxin-3 receptors (RXFP3) prevents stress-induced reinstatement of alcohol-seeking. Therefore the objectives of these studies were to investigate the impact of Rxfp3 gene deletion in C57BL/6J mice on baseline and stress-related alcohol consumption. Male wild-type (WT) and Rxfp3 knockout (KO) (C57/B6JRXFP3TM1/DGen) littermate mice were tested for baseline saccharin and alcohol consumption and preference over water in a continuous access two-bottle free-choice paradigm. Another cohort of mice was subjected to repeated restraint followed by swim stress to examine stress-related alcohol preference. Hepatic alcohol and aldehyde dehydrogenase activity was assessed in mice following chronic alcohol intake and in naive controls. WT and Rxfp3 KO mice had similar baseline saccharin and alcohol preference, and hepatic alcohol processing. However, Rxfp3 KO mice displayed a stress-induced reduction in alcohol preference that was not observed in WT littermates. Notably, this phenotype, once established, persisted for at least six weeks after cessation of stress exposure. These findings suggest that in mice, relaxin-3/RXFP3 signalling is involved in maintaining high alcohol preference during and after stress, but does not appear to strongly regulate the primary reinforcing effects of alcohol.
- Published
- 2015
36. Pattern and Rate of Cognitive Decline in Cerebral Small Vessel Disease: A Prospective Study
- Author
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Thomas R. Barrick, Robin G. Morris, Andrew J. Lawrence, Rebecca L. Brookes, Eva Zeestraten, Hugh S. Markus, Markus, Hugh [0000-0002-9794-5996], and Apollo - University of Cambridge Repository
- Subjects
Male ,medicine.medical_specialty ,Lacunar stroke ,Science ,Neuropsychological Tests ,Physical medicine and rehabilitation ,Cognition ,medicine ,Humans ,Neuropsychological assessment ,Longitudinal Studies ,Prospective Studies ,Cognitive decline ,Stroke ,Aged ,Multidisciplinary ,medicine.diagnostic_test ,Working memory ,business.industry ,Leukoaraiosis ,Middle Aged ,medicine.disease ,3. Good health ,Memory, Short-Term ,Sample size determination ,Cerebral Small Vessel Diseases ,Medicine ,Female ,business ,Cognition Disorders ,Research Article - Abstract
OBJECTIVES: Cognitive impairment, predominantly affecting processing speed and executive function, is an important consequence of cerebral small vessel disease (SVD). To date, few longitudinal studies of cognition in SVD have been conducted. We determined the pattern and rate of cognitive decline in SVD and used the results to determine sample size calculations for clinical trials of interventions reducing cognitive decline.METHODS: 121 patients with MRI confirmed lacunar stroke and leukoaraiosis were enrolled into the prospective St George's Cognition And Neuroimaging in Stroke (SCANS) study. Patients attended one baseline and three annual cognitive assessments providing 36 month follow-up data. Neuropsychological assessment comprised a battery of tests assessing working memory, long-term (episodic) memory, processing speed and executive function. We calculated annualized change in cognition for the 98 patients who completed at least two time-points.RESULTS: Task performance was heterogeneous, but significant cognitive decline was found for the executive function index (pCONCLUSIONS: The pattern of cognitive decline seen in SVD over three years is consistent with the pattern of impairments at baseline. Rates of decline were slow and sample sizes would need to be large for clinical trials aimed at halting decline beyond initial diagnosis using cognitive scores as an outcome measure. This emphasizes the importance of more sensitive surrogate markers in this disease.
- Published
- 2015
37. Penicillinase-Producing Plasmid Types in Neisseria gonorrhoeae Clinical Isolates from Australia
- Author
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Andrew J Lawrence, Monica M Lahra, Julie C. Pearson, Athena Limnios, Helen V. Smith, David M. Whiley, Cameron Buckley, Ella Trembizki, Kevin Freeman, and Kerrie Stevens
- Subjects
medicine.drug_class ,Penicillin Resistance ,Cephalosporin ,Gonorrhea ,Microbial Sensitivity Tests ,Penicillins ,Biology ,medicine.disease_cause ,urologic and male genital diseases ,Microbiology ,Plasmid ,Mechanisms of Resistance ,medicine ,Humans ,Pharmacology (medical) ,Gene ,Cephalosporin Resistance ,Pharmacology ,Australia ,Penicillinase ,medicine.disease ,bacterial infections and mycoses ,Virology ,female genital diseases and pregnancy complications ,Neisseria gonorrhoeae ,Anti-Bacterial Agents ,Bacterial Typing Techniques ,Cephalosporins ,Infectious Diseases ,Penicillin resistance ,Stepping stone ,Plasmids - Abstract
Penicillinase-producing Neisseria gonorrhoeae (PPNG) carrying the bla TEM-135 gene is of particular concern, as it is considered a stepping stone toward resistance to extended-spectrum cephalosporins. Here, we sought to characterize plasmid types and the occurrence of the bla TEM-135 gene for N. gonorrhoeae clinical isolates from Australia. We found that bla TEM-135 was prevalent in Australian PPNG and was detected on all three major plasmid types.
- Published
- 2014
38. Structural network efficiency is associated with cognitive impairment in small-vessel disease
- Author
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Andrew J, Lawrence, Ai Wern, Chung, Robin G, Morris, Hugh S, Markus, and Thomas R, Barrick
- Subjects
Male ,Time Factors ,DIFFUSION TENSOR ,DT-MRI ,Neuropsychological Tests ,Nerve Fibers, Myelinated ,Severity of Illness Index ,Article ,HUMAN CONNECTOME ,Executive Function ,Cognition ,AGE ,Neural Pathways ,PARCELLATION ,Humans ,BRAIN ,Aged ,Leukoaraiosis ,Brain ,TRACTOGRAPHY ,MULTIPLE-SCLEROSIS ,Magnetic Resonance Imaging ,Cross-Sectional Studies ,Diffusion Tensor Imaging ,Cerebral Small Vessel Diseases ,REGISTRATION ,Anisotropy ,Regression Analysis ,Female ,Cognition Disorders ,MATTER - Abstract
Objective: To characterize brain network connectivity impairment in cerebral small-vessel disease (SVD) and its relationship with MRI disease markers and cognitive impairment. Methods: A cross-sectional design applied graph-based efficiency analysis to deterministic diffusion tensor tractography data from 115 patients with lacunar infarction and leukoaraiosis and 50 healthy individuals. Structural connectivity was estimated between 90 cortical and subcortical brain regions and efficiency measures of resulting graphs were analyzed. Networks were compared between SVD and control groups, and associations between efficiency measures, conventional MRI disease markers, and cognitive function were tested. Results: Brain diffusion tensor tractography network connectivity was significantly reduced in SVD: networks were less dense, connection weights were lower, and measures of network efficiency were significantly disrupted. The degree of brain network disruption was associated with MRI measures of disease severity and cognitive function. In multiple regression models controlling for confounding variables, associations with cognition were stronger for network measures than other MRI measures including conventional diffusion tensor imaging measures. A total mediation effect was observed for the association between fractional anisotropy and mean diffusivity measures and executive function and processing speed. Conclusions: Brain network connectivity in SVD is disturbed, this disturbance is related to disease severity, and within a mediation framework fully or partly explains previously observed associations between MRI measures and SVD-related cognitive dysfunction. These cross-sectional results highlight the importance of network disruption in SVD and provide support for network measures as a disease marker in treatment studies.
- Published
- 2014
39. Brucine suppresses ethanol intake and preference in alcohol-preferring Fawn-Hooded rats
- Author
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Hui Liang, Yu-Ling Li, Li Jing, Jun-Xu Li, Zheng Yong, Yan-Ting Wang, Qing Liu, Qi Gong, Jian-Hui Liang, Shoupeng Wei, Min Zhang, and Andrew J Lawrence
- Subjects
Gerontology ,Male ,medicine.medical_specialty ,Alcohol Drinking ,Motor Activity ,Open field ,chemistry.chemical_compound ,Receptors, Glycine ,Internal medicine ,medicine ,Animals ,Pharmacology (medical) ,Ethanol metabolism ,Pharmacology ,Ethanol ,business.industry ,Strychnos nux-vomica ,Rats, Inbred Strains ,General Medicine ,Strychnine ,Glycine receptor antagonist ,Conditioned place preference ,Rats ,Alcoholism ,Acamprosate ,Endocrinology ,chemistry ,Morphine ,Original Article ,business ,medicine.drug - Abstract
Brucine (BRU) extracted from the seeds of Strychnos nux-vomica L is glycine receptor antagonist. We hypothesize that BRU may modify alcohol consumption by acting at glycine receptors, and evaluated the pharmacodynamic profiles and adverse effects of BRU in rat models of alcohol abuse. Alcohol-preferring Fawn-Hooded (FH/Wjd) rats were administered BRU (10, 20 or 30 mg/kg, sc). The effects of BRU on alcohol consumption were examined in ethanol 2-bottle-choice drinking paradigm, ethanol/sucrose operant self-administration paradigm and 5-d ethanol deprivation test. In addition, open field test was used to assess the general locomotor activity of FH/Wjd rats, and conditioned place preference (CPP) was conducted to assess conditioned reinforcing effect. In ethanol 2-bottle-choice drinking paradigm, treatment with BRU for 10 consecutive days dose-dependently decreased the ethanol intake associated with a compensatory increase of water intake, but unchanged the daily total fluid intake and body weight. In ethanol/sucrose operant self-administration paradigms, BRU (30 mg/kg) administered before each testing session significantly decreased the number of lever presses for ethanol and the ethanol intake, without affecting the number of sucrose (10%) responses, total sucrose intake, and the number of lever presses for water. Acute treatment with BRU (30 mg/kg) completely suppressed the deprivation-induced elevation of ethanol consumption. Treatment with BRU (10, 20, and 30 mg/kg) did not alter locomotion of FH/Wjd rats, nor did it produce place preference or aversion. BRU selectively decreases ethanol consumption with minimal adverse effects. Therefore, BRU may represent a new pharmacotherapy for alcoholism.
- Published
- 2014
40. Escherichia coli Nissle 1917-derived factors reduce cell death and late apoptosis and increase transepithelial electrical resistance in a model of 5-fluorouracil-induced intestinal epithelial cell damage
- Author
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Hanru Wang, Susan E.P. Bastian, Ker Y. Cheah, Gordon S. Howarth, and Andrew J Lawrence
- Subjects
Cancer Research ,Programmed cell death ,Antimetabolites, Antineoplastic ,Necrosis ,Cell Survival ,Cell ,Apoptosis ,Biology ,Permeability ,Flow cytometry ,Microbiology ,Cell Line ,chemistry.chemical_compound ,Ileum ,medicine ,Electric Impedance ,Escherichia coli ,Animals ,Viability assay ,Pharmacology ,Biological Products ,medicine.diagnostic_test ,Cell Death ,Epithelial Cells ,Molecular biology ,Rats ,medicine.anatomical_structure ,Oncology ,chemistry ,Cell culture ,Tryptone ,Culture Media, Conditioned ,Molecular Medicine ,Fluorouracil ,medicine.symptom ,Research Paper - Abstract
We evaluated the capacity for supernatants (SNs) derived from Escherichia coli Nissle 1917 (EcN), cultured under different growth conditions, to prevent 5-fluorouracil (5-FU)-induced intestinal epithelial cell damage. EcN was cultured in: Luria Bertani (LB) broth, tryptone soya broth (TSB), de Man Rogosa Sharpe (MRS) broth, and M17 broth supplemented with 10% (v/v) lactose solution (M17). Intestinal epithelial cells (IEC-6) were treated with the following EcN SNs: LB(+), TSB(+), MRS(+), and M17(+) in the presence and absence of 5-FU (1.5 or 5 μM). Cell viability, apoptotic activity and cell monolayer permeability were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and transepithelial electrical resistance (TER) assays, respectively. 5-FU significantly reduced cell viability (P
- Published
- 2014
41. Strategic lacunes and their relationship to cognitive impairment in cerebral small vessel disease
- Author
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Philip Benjamin, Andrew J. Lawrence, Christian Lambert, Bhavini Patel, Ai Wern Chung, Andrew D. MacKinnon, Robin G. Morris, Thomas R. Barrick, and Hugh S. Markus
- Subjects
Cognitive Impairment ,Lacunes ,lcsh:R858-859.7 ,lcsh:Computer applications to medicine. Medical informatics ,lcsh:Neurology. Diseases of the nervous system ,lcsh:RC346-429 ,Small vessel disease - Abstract
Objectives: Lacunes are an important disease feature of cerebral small vessel disease (SVD) but their relationship to cognitive impairment is not fully understood. To investigate this we determined (1) the relationship between lacune count and total lacune volume with cognition, (2) the spatial distribution of lacunes and the cognitive impact of lacune location, and (3) the whole brain anatomical covariance associated with these strategically located regions of lacune damage.\ud \ud Methods: One hundred and twenty one patients with symptomatic lacunar stroke and radiological leukoaraiosis were recruited and multimodal MRI and neuropsychological data acquired. Lacunes were mapped semi-automatically and their volume calculated. Lacune location was automatically determined by projection onto atlases, including an atlas which segments the thalamus based on its connectivity to the cortex. Lacune locations were correlated with neuropsychological results. Voxel based morphometry was used to create anatomical covariance maps for these ‘strategic’ regions.\ud \ud Results: Lacune number and lacune volume were positively associated with worse executive function (number p < 0.001; volume p < 0.001) and processing speed (number p < 0.001; volume p < 0.001). Thalamic lacunes, particularly those in regions with connectivity to the prefrontal cortex, were associated with impaired processing speed (Bonferroni corrected p = 0.016). Regions of associated anatomical covariance included the medial prefrontal, orbitofrontal, anterior insular cortex and the striatum.\ud \ud Conclusion: Lacunes are important predictors of cognitive impairment in SVD. We highlight the importance of spatial distribution, particularly of anteromedial thalamic lacunes which are associated with impaired information processing speed and may mediate cognitive impairment via disruption of connectivity to the prefrontal cortex.
- Published
- 2014
42. Positive environmental modification of depressive phenotype and abnormal hypothalamic-pituitary-adrenal axis activity in female C57BL/6J mice during abstinence from chronic ethanol consumption
- Author
-
William Andrew Catchlove, Terence Y. Pang, Thibault Renoir, Andrew J Lawrence, Anthony J. Hannan, and Xin Du
- Subjects
medicine.medical_specialty ,endocrine system ,media_common.quotation_subject ,Physical exercise ,Dexamethasone ,chemistry.chemical_compound ,Glucocorticoid receptor ,Corticosterone ,Internal medicine ,Medicine ,Pharmacology (medical) ,Original Research Article ,media_common ,pomc1 ,Pharmacology ,Environmental enrichment ,Abstinence ,business.industry ,Depression ,alcohol ,Addiction ,HPA axis ,lcsh:RM1-950 ,GR ,Endocrinology ,medicine.anatomical_structure ,lcsh:Therapeutics. Pharmacology ,chemistry ,environmental enrichment ,business ,Hypothalamic–pituitary–adrenal axis ,hormones, hormone substitutes, and hormone antagonists ,Alcohol Abstinence - Abstract
Depression is a commonly reported co-morbidity during rehabilitation from alcohol use disorders and its presence is associated with an increased likelihood of relapse. Interventions which impede the development of depression could be of potential benefit if incorporated into treatment programs. We previously demonstrated an ameliorative effect of physical exercise on depressive behaviours in a mouse model of alcohol abstinence. Here, we show that environmental enrichment (cognitive and social stimulation) has a similar beneficial effect. The hypothalamic-pituitary-adrenal (HPA) axis is a key physiological system regulating stress responses and its dysregulation has been separably implicated in the pathophysiology of depression and addiction disorders. We performed a series of dexamethasone challenges and found that mice undergoing 2 weeks of alcohol abstinence had significantly greater corticosterone and ACTH levels following a DEX-CRH challenge compared to water controls. Environmental enrichment during alcohol abstinence corrected the abnormal DEX-CRH corticosterone response despite a further elevation of ACTH levels. Examination of gene expression revealed abstinence-associated alterations in glucocorticoid receptor (Gr), corticotrophin releasing hormone (Crh) and pro-opiomelanocortin (Pomc1) mRNA levels which were differentially modulated by environmental enrichment. Overall, our study demonstrates a benefit of environmental enrichment on alcohol abstinence-associated depressive behaviours and HPA axis dysregulation.
- Published
- 2013
43. The metabotropic glutamate 5 receptor modulates extinction and reinstatement of methamphetamine-seeking in mice
- Author
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Robyn M Brown, Andrew J Lawrence, Rose Chesworth, and Jee Hyun Kim
- Subjects
Male ,Anatomy and Physiology ,Gene Expression ,lcsh:Medicine ,Self Administration ,Pharmacology ,Biochemistry ,Extinction, Psychological ,Methamphetamine ,Mice ,chemistry.chemical_compound ,lcsh:Science ,media_common ,Psychiatry ,Mice, Knockout ,Multidisciplinary ,Neurochemistry ,Long-term potentiation ,Mental Health ,Medicine ,NMDA receptor ,Neurochemicals ,Glutamate ,Cues ,Self-administration ,Research Article ,medicine.drug ,Reinforcement Schedule ,Receptor, Metabotropic Glutamate 5 ,media_common.quotation_subject ,Amphetamine-Related Disorders ,Biology ,Neurological System ,Reward ,medicine ,Animals ,Humans ,Motivation ,Addiction ,lcsh:R ,Feeding Behavior ,Meth ,Conditioned place preference ,Behavior, Addictive ,Metabotropic receptor ,chemistry ,Conditioning, Operant ,Central Nervous System Stimulants ,lcsh:Q ,Neuroscience - Abstract
Methamphetamine (METH) is a highly addictive psychostimulant with no therapeutics registered to assist addicts in discontinuing use. Glutamatergic dysfunction has been implicated in the development and maintenance of addiction. We sought to assess the involvement of the metabotropic glutamate 5 receptor (mGlu5) in behaviours relevant to METH addiction because this receptor has been implicated in the actions of other drugs of abuse, including alcohol, cocaine and opiates. mGlu5 knockout (KO) mice were tested in intravenous self-administration, conditioned place preference and locomotor sensitization. Self-administration of sucrose was used to assess the response of KO mice to a natural reward. Acquisition and maintenance of self-administration, as well as the motivation to self-administer METH was intact in mGlu5 KO mice. Importantly, mGlu5 KO mice required more extinction sessions to extinguish the operant response for METH, and exhibited an enhanced propensity to reinstate operant responding following exposure to drug-associated cues. This phenotype was not present when KO mice were tested in an equivalent paradigm assessing operant responding for sucrose. Development of conditioned place preference and locomotor sensitization were intact in KO mice; however, conditioned hyperactivity to the context previously paired with drug was elevated in KO mice. These data demonstrate a role for mGlu5 in the extinction and reinstatement of METH-seeking, and suggests a role for mGlu5 in regulating contextual salience.
- Published
- 2013
44. Effects of streptococcus thermophilus TH-4 in a rat model of doxorubicin-induced mucositis
- Author
-
Gordon S. Howarth, Andrew J Lawrence, Hanru Wang, Caitlin L Brook, Alexandra L. Whittaker, Roger Yazbeck, Wang, Hanru, Brook, Caitlin L, Whittaker, Alexandra L, Lawrence, Andrew, Yazbeck, Roger, and Howarth, Gordon S
- Subjects
Mucositis ,Side effect ,Anthracycline ,medicine.medical_treatment ,Intraperitoneal injection ,gastroenterology ,Pharmacology ,chemotherapy ,doxorubicin ,Random Allocation ,Ileum ,Weight Loss ,Animals ,Streptococcus thermophilus ,Medicine ,cancer ,Doxorubicin ,Peroxidase ,Chemotherapy ,Antibiotics, Antineoplastic ,streptococcus thermophilus ,business.industry ,Probiotics ,Gastroenterology ,medicine.disease ,Rats ,Jejunum ,Treatment Outcome ,mucositis ,probiotics ,hepatology ,Female ,Methotrexate ,business ,Biomarkers ,Injections, Intraperitoneal ,Antimetabolite Chemotherapy ,medicine.drug - Abstract
Aims. The authors investigated the effects of TH-4 in a rat model of mucositis induced by the anthracycline chemotherapy drug, doxorubicin. Background. Mucositis is a debilitating intestinal side effect of chemotherapeutic regimens. Probiotics have been considered a possible preventative treatment for mucositis. Streptococcus thermophilus TH-4 (TH-4), a newly identified probiotic, has been shown to partially alleviate mucositis induced by administration of the antimetabolite chemotherapy drug, methotrexate in rats; likely mediated through a mechanism of folate production. However, its effects against other classes of chemotherapy drug have yet to be determined. Conclusions. The minimal amelioration of doxorubicin-induced mucositis by TH-4 further supports folate production as a likely mechanism of TH-4 action against methotrexate-induced mucositis. Further studies into TH-4 are required to confirm its applicability to other conventional chemotherapy regimens. Methods. Gastrointestinal damage was induced in female Dark Agouti rats (148.3 ± 1.5 g) by intraperitoneal injection of doxorubicin (20 mg/kg). Animals recieved a daily oral gavage of TH-4 at 109 cfu/ml or skim milk (vehicle) from days 0 to 8. At day 6, rats were injected with either saline or doxorubicin. At kill, small intestinal tissues were collected for determination of sucrase and myeloperoxidase (MPO) activities and histological assessment. Results. Body weight was significantly decreased by doxorubicin compared with normal controls (p < 0.05). Histological parameters, such as crypt depth and villus height, were also significantly decreased by doxorubicin. TH-4 partially prevented the loss of body weight induced by doxorubicin (2.3% compared with 4%), but provided no further therapeutic benefit. Refereed/Peer-reviewed
- Published
- 2013
45. The role of orexins/hypocretins in alcohol use and abuse: an appetitive-reward relationship
- Author
-
Andrezza Kyunmi Kim, Andrew J Lawrence, and Robyn M Brown
- Subjects
drug-seeking ,Lateral hypothalamus ,Cognitive Neuroscience ,Neurotransmitter systems ,Neuropeptide ,Review Article ,lcsh:RC321-571 ,Behavioral Neuroscience ,mental disorders ,Medicine ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,relapse ,business.industry ,alcohol ,digestive, oral, and skin physiology ,medicine.disease ,Orexin ,Ventral tegmental area ,Substance abuse ,Neuropsychology and Physiological Psychology ,medicine.anatomical_structure ,nervous system ,orexin ,Hypothalamus ,reward-seeking behavior ,Locus coeruleus ,ethanol ,hypocretin ,business ,Neuroscience ,psychological phenomena and processes - Abstract
Orexins (hypocretins) are neuropeptides synthesized in neurons located in the lateral (LH), perifornical, and dorsomedial (DMH) hypothalamus. These neurons innervate many regions in the brain and modulate multiple other neurotransmitter systems. As a result of these extensive projections and interactions orexins are involved in numerous functions, such as feeding behavior, neuroendocrine regulation, the sleep-wake cycle, and reward-seeking. This review will summarize the literature to date which has evaluated a role of orexins in the behavioral effects of alcohol, with a focus on understanding the importance of this peptide and its potential as a clinical therapeutic target for alcohol use disorders.
- Published
- 2012
46. Neuroplasticity in addiction: cellular and transcriptional perspectives
- Author
-
Andrew J Lawrence, Heather B Madsen, and Robyn M Brown
- Subjects
media_common.quotation_subject ,Addiction ,Review ,CREB ,lcsh:RC321-571 ,Synapse ,Cellular and Molecular Neuroscience ,FosB ,Neuroplasticity ,medicine ,histone modification ,Epigenetics ,skin and connective tissue diseases ,Molecular Biology ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,media_common ,DNA methylation ,biology ,epigenetics ,Long-term potentiation ,microRNAs ,Ventral tegmental area ,medicine.anatomical_structure ,plasticity ,deltaFosB ,biology.protein ,sense organs ,Psychology ,Neuroscience ,FOSB - Abstract
Drug addiction is a chronic, relapsing brain disorder which consists of compulsive patterns of drug-seeking and taking that occurs at the expense of other activities. The transition from casual to compulsive drug use and the enduring propensity to relapse is thought to be underpinned by long lasting neuroadaptations in specific brain circuitry, analogous to those that underlie long-term memory formation. Research spanning the last two decades has made great progress in identifying cellular and molecular mechanisms that contribute to drug-induced changes in plasticity and behaviour. Alterations in synaptic transmission within the mesocorticolimbic and corticostriatal pathways, and changes in the transcriptional potential of cells by epigenetic mechanisms are two important means by which drugs of abuse can induce lasting changes in behaviour. In this review we provide a summary of more recent research that has furthered our understanding of drug-induced neuroplastic changes both at the level of the synapse, and on a transcriptional level, and how these changes may relate to the human disease of addiction.
- Published
- 2012
47. The Role of Mitogen-Activated Protein Kinase in Treatment Strategies for Fear and Drug Addiction
- Author
-
Robyn M Brown, Andrew J Lawrence, and Jee Hyun Kim
- Subjects
medicine.medical_specialty ,Generalized anxiety disorder ,business.industry ,Addiction ,media_common.quotation_subject ,Public health ,Alcohol abuse ,medicine.disease ,Substance abuse ,National Comorbidity Survey ,medicine ,Anxiety ,medicine.symptom ,Psychiatry ,business ,Disease burden ,media_common ,Clinical psychology - Abstract
Fear-avoidance and reward-seeking are necessary motivations to guide survival; however, both can lead to maladaptive behavior when expressed inappropriately, manifesting as anxiety disorders and drug addiction. Both disorders are a major worldwide public health concern with a high co-morbidity (M. S. O'Brien et al., 2005; Wasserman et al., 1997). Specifically, the World Health Organization (WHO) pin-pointed generalized anxiety disorder and substance abuse as the most common mental disorders across the world, ranking them highly as a cause of disease burden (WHO, 2001). Furthermore, in the recent United States National Comorbidity Survey Replication study, it was reported that 18.1% and 8.9% of adults met the 12-month Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 2000) criteria for an anxiety or substance abuse disorder, respectively (Kessler et al., 2005). These staggering statistics also highlight the economic costs of anxiety disorders and substance abuse. For example, one estimate puts the yearly economic cost of alcohol abuse to be $148 billion, and the economic cost of harmful drug use and dependence has been estimated to be $98 billion in the United States alone (Harwood et al., 1998). Another study reported the economic cost of anxiety disorders to be $42 billion in the United States (Greenberg et al., 1999).
- Published
- 2012
48. Adolescent toluene inhalation in rats affects white matter maturation with the potential for recovery following abstinence
- Author
-
Alec L.W. Dick, David W. Wright, Andrew J Lawrence, Maria Gavrilescu, Gary F. Egan, Scott C Kolbe, Dan I. Lubman, and Jhodie R. Duncan
- Subjects
Male ,Pathology ,Time Factors ,Physiology ,Corpus callosum ,Behavioral Neuroscience ,0302 clinical medicine ,Neurobiology of Disease and Regeneration ,Young adult ,media_common ,Psychiatry ,0303 health sciences ,Multidisciplinary ,medicine.diagnostic_test ,Substance Abuse ,Brain ,Animal Models ,Neurotransmitters ,Diffusion Tensor Imaging ,Mental Health ,medicine.anatomical_structure ,Inhalation ,Medicine ,medicine.symptom ,Research Article ,medicine.medical_specialty ,Neural Networks ,Substance-Related Disorders ,media_common.quotation_subject ,Science ,Neuroimaging ,Anterior commissure ,Motor Activity ,Biology ,White matter ,03 medical and health sciences ,Model Organisms ,Developmental Neuroscience ,medicine ,Animals ,Rats, Wistar ,030304 developmental biology ,Magnetic resonance imaging ,Recovery of Function ,Abstinence ,Animal Cognition ,Rats ,Rotarod Performance Test ,Rat ,Neural Circuit Formation ,Weight gain ,030217 neurology & neurosurgery ,Toluene ,Developmental Biology ,Neuroscience ,Synaptic Plasticity ,Diffusion MRI - Abstract
Inhalant misuse is common during adolescence, with ongoing chronic misuse associated with neurobiological and cognitive abnormalities. While human imaging studies consistently report white matter abnormalities among long-term inhalant users, longitudinal studies have been lacking with limited data available regarding the progressive nature of such abnormalities, including the potential for recovery following periods of sustained abstinence. We exposed adolescent male Wistar rats (postnatal day 27) to chronic intermittent inhaled toluene (3,000 ppm) for 1 hour/day, 3 times/week for 8 weeks to model abuse patterns observed in adolescent and young adult human users. This dosing regimen resulted in a significant retardation in weight gain during the exposure period (p
- Published
- 2012
49. Identification of Brain Nuclei Implicated in Cocaine-Primed Reinstatement of Conditioned Place Preference: A Behaviour Dissociable from Sensitization
- Author
-
Jennifer L. Short, Andrew J Lawrence, and Robyn M Brown
- Subjects
Male ,Mouse ,lcsh:Medicine ,Biochemistry ,Behavioral Neuroscience ,Mice ,Learning and Memory ,Cocaine ,Conditioning, Psychological ,Premovement neuronal activity ,lcsh:Science ,Sensitization ,media_common ,Drug Dependence ,Neurons ,Multidisciplinary ,Behavior, Animal ,Brain ,Neurochemistry ,Animal Models ,Immunohistochemistry ,medicine.anatomical_structure ,Hypothalamus ,Behavioral Pharmacology ,Medicine ,Analysis of variance ,medicine.symptom ,Immunohistochemical Analysis ,Proto-Oncogene Proteins c-fos ,Reinforcement, Psychology ,Research Article ,Behavioral addiction ,Drugs and Devices ,media_common.quotation_subject ,Immunology ,Biology ,Model Organisms ,medicine ,Animals ,Cell Nucleus ,Addiction ,lcsh:R ,Conditioned place preference ,Behavior, Addictive ,Stria terminalis ,Immunologic Techniques ,Conditioning, Operant ,lcsh:Q ,Neuroscience - Abstract
Relapse prevention represents the primary therapeutic challenge in the treatment of drug addiction. As with humans, drug-seeking behaviour can be precipitated in laboratory animals by exposure to a small dose of the drug (prime). The aim of this study was to identify brain nuclei implicated in the cocaine-primed reinstatement of a conditioned place preference (CPP). Thus, a group of mice were conditioned to cocaine, had this place preference extinguished and were then tested for primed reinstatement of the original place preference. There was no correlation between the extent of drug-seeking upon reinstatement and the extent of behavioural sensitization, the extent of original CPP or the extinction profile of mice, suggesting a dissociation of these components of addictive behaviour with a drug-primed reinstatement. Expression of the protein product of the neuronal activity marker c-fos was assessed in a number of brain regions of mice that exhibited reinstatement (R mice) versus those which did not (NR mice). Reinstatement generally conferred greater Fos expression in cortical and limbic structures previously implicated in drug-seeking behaviour, though a number of regions not typically associated with drug-seeking were also activated. In addition, positive correlations were found between neural activation of a number of brain regions and reinstatement behaviour. The most significant result was the activation of the lateral habenula and its positive correlation with reinstatement behaviour. The findings of this study question the relationship between primed reinstatement of a previously extinguished place preference for cocaine and behavioural sensitization. They also implicate activation patterns of discrete brain nuclei as differentiators between reinstating and non-reinstating mice.
- Published
- 2010
50. Impulsivity and response inhibition in alcohol dependence and problem gambling
- Author
-
Nadine A. Bogdan, Barbara J. Sahakian, Luke Clark, Jason Luty, and Andrew J. Lawrence
- Subjects
Drug ,Adult ,Male ,medicine.medical_specialty ,Impulse control disorder ,media_common.quotation_subject ,Neuropsychological Tests ,Impulsivity ,Choice Behavior ,Severity of Illness Index ,03 medical and health sciences ,Executive Function ,0302 clinical medicine ,Predictive Value of Tests ,mental disorders ,Inhibitory control ,medicine ,Reaction Time ,Humans ,Psychiatry ,Response inhibition ,media_common ,Original Investigation ,Pharmacology ,Pathological gambling ,Analysis of Variance ,Addiction ,Alcohol dependence ,Compulsivity ,Middle Aged ,medicine.disease ,030227 psychiatry ,Alcoholism ,Inhibition, Psychological ,Gambling ,Impulsive Behavior ,Post-error adjustment ,Regression Analysis ,medicine.symptom ,Psychology ,030217 neurology & neurosurgery ,Addiction vulnerability - Abstract
Introduction Impulsivity is a central feature of drug addiction and may arise as a result of impaired inhibitory control. The extent to which inhibitory deficits arise as a consequence of drug exposure or relate to pre-existing addiction vulnerability is unknown. Materials and methods This study compared measures of impulsivity in outpatients with alcohol dependence (n = 23) and problem gambling (n = 21), a putative behavioural addiction where direct effects of drug exposure may be minimal. Healthy controls (n = 27) were also tested, in a cross-sectional design. Subjects completed the stop-signal test as a neurocognitive probe of response inhibition, alongside self-report ratings of impulsivity, adult ADHD and OCD. Results On the stop-signal test, Go reaction time and stop-signal reaction time were significantly slower in the alcohol-dependent group, compared with healthy controls. Healthy controls slowed their responding after successful and failed stop trials. Slowing after failed stop trials was significantly attenuated in the alcohol-dependent subjects. Go reaction time and post-error slowing were correlated with chronicity and severity, respectively, in the alcohol-dependent subjects. Problem gamblers did not differ significantly from controls on the stop-signal test, despite trait elevations in impulsivity ratings. Conclusion Inhibitory control is impaired in alcohol dependence but occurs in the context of psychomotor slowing. In addition, alcohol-dependent individuals failed to show behavioral adjustment following failed stops. These deficits may represent direct effects of chronic alcohol administration on fronto-striatal circuitry.
- Published
- 2009
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