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Introduction: Alcohol use disorder (AUD) is one of the most common psychiatric disorders and a leading cause of mortality worldwide. While the pathophysiology underlying AUD is relatively well known, the cognitive mechanisms of an individual's susceptibility to the development of alcohol dependence remain poorly understood. In this study, we investigated the theoretical claim that sensitivity to positive feedback (PF), as a stable and enduring behavioural trait, can predict individual susceptibility to the acquisition and maintenance of alcohol-seeking behaviour in rats. Methods: Trait sensitivity to PF was assessed using a series of probabilistic reversal learning tests. The escalation of alcohol intake in rats was achieved by applying a mix of intermittent free access and instrumental paradigms of alcohol drinking. The next steps included testing the influence of sensitivity to PF on the acquisition of compulsive alcohol-seeking behaviour in the seeking-taking punishment task, measuring motivation to seek alcohol, and comparing the speed of extinction and reinstatement of alcohol-seeking after a period of abstinence between rats expressing trait insensitivity and sensitivity to PF. Finally, trait differences in the level of stress hormones and in the expression of genes and proteins in several brain regions of interest were measured to identify potential physiological and neuromolecular mechanisms of the observed interactions. Results: We showed that trait sensitivity to PF in rats determines the level of motivation to seek alcohol following the experience of its negative consequences. They also revealed significant differences between animals classified as insensitive and sensitive to PF in their propensity to reinstate alcohol-seeking behaviours after a period of forced abstinence. The abovementioned effects were accompanied by differences in blood levels of stress hormones and differences in the cortical and subcortical expression of genes and proteins related to dopaminergic, serotonergic, and GABAergic neurotransmission. Conclusion: Trait sensitivity to PF can determine the trajectory of alcohol addiction in rats. This effect is, at least partially, mediated via distributed physiological and molecular changes within cortical and subcortical regions of the brain. [ABSTRACT FROM AUTHOR]

Rationale and objectives: Fear conditioning is an important aspect in the pathophysiology of anxiety disorders. The fear-potentiated startle test is based on classical fear conditioning and over the years, a broad range of drugs have been tested in this test. Synthesis of the available data may further our understanding of the neurotransmitter systems that are involved in the expression of conditioned fear. Methods: Following a comprehensive search in Medline and Embase, we included 68 research articles that reported on 103 drugs, covering 56 different drug classes. The systematic review was limited to studies using acute, systemic drug administration in naive animals. Results: Qualitative data synthesis showed that most clinically active anxiolytics, but not serotonin-reuptake inhibitors, reduced cued fear. Anxiogenic drugs increased fear potentiation in 35% of the experiments, reduced fear potentiation in 29% of the experiments, and were without effect in 29% of the experiments. Meta-analyses could be performed for five drug classes and showed that benzodiazepines, buspirone, 5-HT1A agonists, 5-HT1A antagonists, and mGluR2,3 agonists reduced cued conditioned fear. The non-cued baseline startle response, which may reflect contextual anxiety, was only significantly reduced by benzodiazepines and 5-HT1A antagonists. No associations were found between drug effects and methodological characteristics, except for strain. Conclusions: The fear-potentiated startle test appears to have moderate to high predictive validity and may serve as a valuable tool for the development of novel anxiolytics. Given the limited available data, the generally low study quality and high heterogeneity additional studies are warranted to corroborate the findings of this review. [ABSTRACT FROM AUTHOR]

In this study, we examined whether trait sensitivity to negative feedback (NF) can interact with the effects of chronic stress and antidepressant treatment on anxiety and stress-induced coping strategies in rats. Results of the conducted experiments indicated that animals displaying trait insensitivity to NF were more prone to develop stress-induced anxiety than their NF-sensitive conspecifics. Moreover, an analysis of the behavioral patterns displayed by the NF-insensitive animals during the forced swim test (FST) revealed complementary (anxiety-driven) effects of trait sensitivity to NF on the strategy of coping with an acute, stressful situation. Finally, an analysis of the interactions between NF sensitivity and the effects of antidepressant drug — mirtazapine — revealed that in animals subjected to chronic stress, the effects of the drug on anxiety and coping strategies differ significantly between animals classified as NF insensitive and NF sensitive. The present results suggest that NF sensitivity screening could be potentially used to determine individual vulnerability to development of affective disorders and effectivity of their treatment. [ABSTRACT FROM AUTHOR]

Rationale: Kratom derives from Mitragyna speciosa (Korth.), a tropical tree in the genus Mitragyna (Rubiaceae) that also includes the coffee tree. Kratom leaf powders, tea-like decoctions, and commercial extracts are taken orally, primarily for health and well-being by millions of people globally. Others take kratom to eliminate opioid use for analgesia and manage opioid withdrawal and use disorder. There is debate over the possible respiratory depressant overdose risk of the primary active alkaloid, mitragynine, a partial μ-opioid receptor agonist, that does not signal through ß-arrestin, the primary opioid respiratory depressant pathway. Objectives: Compare the respiratory effects of oral mitragynine to oral oxycodone in rats with the study design previously published by US Food and Drug Administration (FDA) scientists for evaluating the respiratory effects of opioids (Xu et al., Toxicol Rep 7:188–197, 2020). Methods: Blood gases, observable signs, and mitragynine pharmacokinetics were assessed for 12 h after 20, 40, 80, 240, and 400 mg/kg oral mitragynine isolate and 6.75, 60, and 150 mg/kg oral oxycodone hydrochloride. Findings: Oxycodone administration produced significant dose-related respiratory depressant effects and pronounced sedation with one death each at 60 and 150 mg/kg. Mitragynine did not yield significant dose-related respiratory depressant or life-threatening effects. Sedative-like effects, milder than produced by oxycodone, were evident at the highest mitragynine dose. Maximum oxycodone and mitragynine plasma concentrations were dose related. Conclusions: Consistent with mitragynine's pharmacology that includes partial µ-opioid receptor agonism with little recruitment of the respiratory depressant activating β-arrestin pathway, mitragynine produced no evidence of respiratory depression at doses many times higher than known to be taken by humans. [ABSTRACT FROM AUTHOR]

Rationale: While neural correlates of hallucinations are known, the mechanisms have remained elusive. Mechanistic insight is more practicable in animal models, in which causal relationships can be established. Recent work developing animal models of hallucination susceptibility has focused on the genesis of perceptual expectations and perceptual decision-making. Both processes are encompassed within mediated learning, which involves inducing a strong perceptual expectation via associative learning, retrieving that memory representation, and deciding whether this internally generated percept is predictive of an external outcome. Mediated learning in rodents is sensitive to many psychotomimetic manipulations. However, we do not know if these manipulations selectively alter learning of perceptual expectations versus their retrieval because of their presence throughout all task phases. Objectives: Here, we used mediated learning to study the targeted effect of a psychotomimetic agent on the retrieval of perceptual expectation. Methods: We administered (R,S)-ketamine to rats selectively during the devaluation phase of a mediated learning task, when the representation of the expected cue is retrieved, to test the hypothesis that internally generated perceptual experiences underlie this altered mediated learning. Results: We found that ketamine increased only mediated learning at a moderate dose in rats, but impaired direct learning at the high dose. Conclusions: These results suggest that ketamine can augment retrieval of perceptual expectations and thus this may be how it induces hallucination-like experiences in humans. More broadly, mediated learning may unite the conditioning, perceptual decision-making, and even reality monitoring accounts of psychosis in a manner that translates across species. [ABSTRACT FROM AUTHOR]

Rationale: Rates of depression and suicide increase with altitude. In our animal model, rats housed at moderate altitude vs. at sea level exhibit increased depressive symptoms in the forced swim test (FST) and lack of response to selective serotonin reuptake inhibitors (SSRIs). Depression and SSRI resistance are linked to disrupted serotonergic function, and hypobaric hypoxia may reduce the oxygen-dependent synthesis of serotonin. We therefore tested brain serotonin in rats housed at altitude. Methods: Sprague–Dawley rats were housed at altitude (4,500 ft, 10,000 ft) vs. sea level for 7–36 days. Brain serotonin was measured by ELISA, or behavior evaluated in the FST, sucrose preference (SPT), or open-field tests (OFT). Results: After 2 weeks at 4,500 ft or 10,000ft vs. sea level, serotonin levels decreased significantly at altitude in the female prefrontal cortex, striatum, hippocampus, and brainstem, but increased with altitude in the male hippocampus and brainstem. Female brain serotonin decreased from 7 to 36 days at 4,500 ft, but males did not vary. At 2 weeks and 24 days, females at altitude exhibit lower brain serotonin and increased depressive symptoms in the FST and SPT, with motor behavior unaltered. In males, serotonin, passive coping in the FST and OFT immobility increased with altitude at 2 weeks, but not at 24 days. Male SPT behavior did not change with altitude. Conclusions: Females may be more vulnerable to depressive symptoms at altitude, while males may be resilient. Chronic hypoxic stress at altitudes as low as 4,500 ft may cause a brain serotonin imbalance to worsen vulnerability to depression and SSRI resistance, and potentially worsen suicide risk. [ABSTRACT FROM AUTHOR]

Neuropsychiatric disorders are multifactorial disturbances that encompass several hypotheses, including changes in neurodevelopment. It is known that brain development disturbances during early life can predict psychosis in adulthood. As we have previously demonstrated, rotenone, a mitochondrial complex I inhibitor, could induce psychiatric-like behavior in 60-day-old rats after intraperitoneal injections from the 5th to the 11th postnatal day. Because mitochondrial deregulation is related to psychiatric disorders and the establishment of animal models is a high-value preclinical tool, we investigated the responsiveness of the rotenone (Rot)-treated newborn rats to pharmacological agents used in clinical practice, haloperidol (Hal), and methylphenidate (MPD). Taken together, our data show that Rot-treated animals exhibit hyperlocomotion, decreased social interaction, and diminished contextual fear conditioning response at P60, consistent with positive, negative, and cognitive deficits of schizophrenia (SZ), respectively, that were reverted by Hal, but not MPD. Rot-treated rodents also display a prodromal-related phenotype at P35. Overall, our results seem to present a new SZ animal model as a consequence of mitochondrial inhibition during a critical neurodevelopmental period. Therefore, our study is crucial not only to elucidate the relevance of mitochondrial function in the etiology of SZ but also to fulfill the need for new and trustworthy experimentation models and, likewise, provide possibilities to new therapeutic avenues for this burdensome disorder. [ABSTRACT FROM AUTHOR]

Rationale: Since the precise mechanisms of posttraumatic stress disorder (PTSD) remain unknown, effective treatment interventions have not yet been established. Numerous clinical studies have led to the hypothesis that elevated glucocorticoid levels in response to extreme stress might trigger a pathophysiological cascade which consequently leads to functional and morphological changes in the hippocampus. Objectives: To elucidate the pathophysiology of PTSD, we examined the alteration of hippocampal gene expression through the glucocorticoid receptor (GR) in the single prolonged stress (SPS) paradigm, a rat model of PTSD. Methods: We measured nuclear GRs by western blot, and the binding of GR to the promoter of Bcl-2 and Bax genes by chromatin immunoprecipitation-qPCR as well as the expression of these 2 genes by RT-PCR in the hippocampus of SPS rats. In addition, we examined the preventive effects of a GR antagonist on SPS-induced molecular, morphological, and behavioral alterations (hippocampal gene expression of Bcl-2 and Bax, hippocampal apoptosis using TUNEL staining, impaired fear memory extinction (FME) using the contextual fear conditioning paradigm). Results: Exposure to SPS increased nuclear GR expression and GR binding to Bcl-2 gene, and decreased Bcl-2 mRNA expression. Administration of GR antagonist immediately after SPS prevented activation of the glucocorticoid cascade, hippocampal apoptosis, and impairment FME in SPS rats. Conclusion: The activation of GRs in response to severe stress may trigger the pathophysiological cascade leading to impaired FME and hippocampal apoptosis. In contrast, administration of GR antagonist could be useful for preventing the development of PTSD. [ABSTRACT FROM AUTHOR]

Introduction: Placebo effects in human clinical trials for depression treatment are robust and often comparable to drug effects. Placebo effects are traditionally difficult to study in rodents due to the slow-onset action of classical antidepressant drugs. We hypothesized that the rapid antidepressant actions of ketamine would allow modeling antidepressant placebo effects in rodents. Methods: Male and female CD-1 mice received either ketamine or saline injections with concomitant exposure to specific environmental conditioning stimuli, for a total of three drug/conditioning sessions each 2 weeks apart. Two weeks later, during an evocation phase, mice were exposed to the drug-paired conditioning stimuli or no conditioned stimuli followed by testing for motor stimulatory actions and antidepressant-like effects using the forced swim test. Negative (no ketamine administration at any time) and positive (acute ketamine administration prior to evocation testing) control groups were included as comparators. Results: Both male and female mice exhibited increased locomotor activity following ketamine administration during the conditioning phase, which was not observed following exposure to the conditioning stimuli. Exposure to the conditioning stimuli previously paired with ketamine, similar to an acute ketamine administration, reduced immobility time in the forced swim test both 1 and 24 h after administration in male, but not female, mice. Conclusions: These results represent the first evidence of antidepressant-like placebo-conditioned effects in an animal model. The developed approach can be used as a model to explore the neurobiological mechanisms of placebo effects, their possible sexually dimorphic effects, and relevance to mechanisms underlying antidepressant action. [ABSTRACT FROM AUTHOR]

Rationale: According to psychological theories, cognitive distortions play a pivotal role in the aetiology and recurrence of mood disorders. Although clinical evidence for the coexistence of depression and altered sensitivity to performance feedback is relatively coherent, we still do not know whether increased or decreased sensitivity to positive or negative feedback is associated with 'pro-depressive' profile in healthy subjects. Objective: Our research has been designed to answer this question, and here, we present the first steps in that direction. Methods: Using a rat version of the probabilistic reversal-learning (PRL) paradigm, we evaluated how sensitivity to negative and positive feedback influences other cognitive processes associated with mood disorders, such as motivation in the progressive ratio schedule of reinforcement (PRSR) paradigm, hedonic status in the sucrose preference (SP) test, locomotor and exploratory activity in the open field (OF) test, and anxiety in the light/dark box (LDB) test. Results: The results of our study demonstrated for the first time that in rodents, sensitivity to negative and positive feedback could be considered a stable and enduring behavioural trait. Importantly, we also showed that these traits are independent of each other and that trait sensitivity to positive feedback is associated with cognitive flexibility in the PRL test. The computational modelling results also revealed that in animals classified as sensitive to positive feedback, the α learning rates for both positive and negative reward prediction errors were higher than those in animals classified as insensitive. We observed no statistically significant interactions between sensitivity to negative or positive feedback and the parameters measured in the PRSR, SP, OF or LDB tests. Conclusions: Further studies using animal models of depression based on chronic stress should reveal whether sensitivity to feedback is a latent trait that when interacts with stressful life events, could produce correlates of depressive symptoms in rats. [ABSTRACT FROM AUTHOR]

Rationale: The 5-choice serial reaction time task (5-CSRTT) is a widely used operant task for measuring attention and motor impulsivity in rodents. Training animals in this task requires an extensive period of daily operant sessions. Recently, a self-paced, automated version of this task has been developed for mice, which substantially reduces training time. Whether a similar approach is effective for rats is currently unknown. Objective: Here, we tested whether attention and impulsivity can be assessed in rats with a self-paced version of the 5-CSRTT. Methods: Operant boxes were connected to home-cages with tunnels. Two groups of rats self-paced their training by means of an automated script. The first group of animals was allowed unlimited access (UA) to start trials in the task; for the second group, trial availability was restricted to the first 2.5 h of the dark cycle (TR). Task parameter manipulations, such as variable inter-trial intervals and stimulus durations as well as pharmacological challenges with scopolamine, were tested to validate the task. Results: Self-paced training took less than 1 week. Animals in the UA group showed higher levels of omissions compared with the TR group. In both protocols, variable inter-trial intervals increased impulsivity, and variable stimulus durations decreased attentional performance. Scopolamine affected cognitive performance in the TR group only. Conclusions: Home-cage-based training of the 5-CSRTT in rats, especially the TR protocol, presents a valid and fast alternative for measuring attention and impulsivity. [ABSTRACT FROM AUTHOR]

Rationale: The ability to memorize threat-associated cues and subsequently react to them, exhibiting escape or avoidance responses, is an essential, often life-saving behavioral mechanism that can be experimentally studied using the fear (threat) conditioning training paradigm. Presently, there is substantial evidence supporting the Synaptic Plasticity-Memory (SPM) hypothesis in relation to the mechanisms underlying the acquisition, retention, and extinction of conditioned fear memory.Objectives: The purpose of this review article is to summarize findings supporting the SPM hypothesis in the context of conditioned fear control, applying the set of criteria and tests which were proposed as necessary to causally link lasting changes in synaptic transmission in corresponding neural circuits to fear memory acquisition and extinction with an emphasis on their pharmacological diversity.Results: The mechanisms of synaptic plasticity in fear circuits exhibit complex pharmacological profiles and satisfy all four SPM criteria—detectability, anterograde alteration, retrograde alteration, and mimicry.Conclusion: The reviewed findings, accumulated over the last two decades, provide support for both necessity and sufficiency of synaptic plasticity in fear circuits for fear memory acquisition and retention, and, in part, for fear extinction, with the latter requiring additional experimental work. [ABSTRACT FROM AUTHOR]

Rationale: Metabotropic glutamate receptors and muscarinic M4 receptors have been proposed as novel targets for various brain disorders, including schizophrenia. Both receptors are coupled to Go/i proteins and are expressed in brain circuits that are important in schizophrenia. Therefore, their mutual activation may be an effective treatment and allow minimizing the doses of ligands required for optimal activity.Objectives: In the present studies, subactive doses of mGlu4 and M4 activators (LSP4-2022 and VU152100, respectively) were administered to investigate the mutual interaction between mGlu4 and M4 receptors in animal models of schizophrenia.Methods: The behavioral tests used were MK-801-induced hyperactivity, (±)-2.5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced head twitches, the modified forced swim test, and MK-801-induced disruptions of social interactions and novel object recognition. DOI-induced spontaneous excitatory postsynaptic currents (sEPSCs) in brain slices and positron emission tomography (PET) in were used to establish the ability of these compounds to modulate the glutamatergic and dopaminergic systems. Rotarod was used to assess putative adverse effects.Results: The mutual administration of subactive doses of LSP4-2022 and VU152100 exerted similar antipsychotic-like efficacy in animals as observed for active doses of both compounds, indicating their additive actions. VU152100 inhibited the DOI-induced frequency (but not amplitude) of sEPSCs in the frontal cortex, confirming presynaptic regulation of glutamate release. Both compounds reversed amphetamine-induced decrease in D2 receptor levels in the striatum, as measured with [18F]fallypride. The compounds did not induce any motor impartments when measured in rotarod test.Conclusions: Based on our results, the simultaneous activation of M4 and mGlu4 receptors is beneficial in reversing MK-801- and amphetamine-induced schizophrenia-related changes in animals. [ABSTRACT FROM AUTHOR]

Rationale: Impairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies. Objectives: We assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs. Methods: MAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated. Results: Two cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity ( d′) and increased false alarm rates (FARs). Sulpiride (0-30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d′ in sham controls. ABT-594 (5.9-19.4 μg/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3-1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1-1 mg/kg) showed near-significant enhancements in d′, and EVP-6124 (0.3-3 mg/kg) exerted no effects in the rCPT paradigm. Conclusion: The MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction. [ABSTRACT FROM AUTHOR]

Rationale: Depression is characterized by an excessive attribution of value to negative feedback. This imbalance in feedback sensitivity can be measured using the probabilistic reversal-learning (PRL) task. This task was initially designed for clinical research, but introduction of its rodent version provides a new and much needed translational paradigm to evaluate potential novel antidepressants. Objectives: In the present study, we aimed at evaluating the effects of a compound showing clear antidepressant properties-ketamine (KET)-on the sensitivity of rats to positive and negative feedback in the PRL paradigm. Methods: We trained healthy rats in an operant version of the PRL task. For successful completion of the task, subjects had to learn to ignore infrequent and misleading feedback, arising from the probabilistic (80:20) nature of the discrimination. Subsequently, we evaluated the effect of KET (5, 10, and 20 mg/kg) on feedback sensitivity 1, 24, and 48 h after administration. Results: We report that acute administration of the highest dose of KET (20 mg/kg) rapidly and persistently decreases the proportion of lose-shift responses made by rats after receiving negative feedback. Conclusion: Present results suggest that KET decreases negative feedback sensitivity and that changes in this basic neurocognitive function might be one of the factors responsible for its antidepressant action. [ABSTRACT FROM AUTHOR]

Rational: Prepulse inhibition (PPI) is suppression of the startle reflex by a weaker sensory stimulus (prepulse) preceding the startling stimulus. In people with schizophrenia, impairment of attentional modulation of PPI, but not impairment of baseline PPI, is correlated with symptom severity. In rats, both fear conditioning of prepulse and perceptually spatial separation between the conditioned prepulse and a noise masker enhance PPI (the paradigms of attentional modulation of PPI). Objectives: As a neurodevelopmental model of schizophrenia, isolation rearing impairs both baseline PPI and attentional modulations of PPI in rats. This study examined in Sprague-Dawley male rats whether neonatally blocking N-methyl- d-aspartate (NMDA) receptors specifically affects attentional modulations of PPI during adulthood. Results: Both socially reared rats with neonatal exposure to the NMDA receptor antagonist MK-801 and isolation-reared rats exhibited augmented startle responses, but only isolation rearing impaired baseline PPI. Fear conditioning of the prepulse enhanced PPI in socially reared rats, but MK-801-treated rats lost the prepulse feature specificity. Perceptually spatial separation between the conditioned prepulse and a noise masker further enhanced PPI only in normally reared rats. Clozapine administration during adulthood generally weakened startle, enhanced baseline PPI in neonatally interrupted rats, and restored the fear conditioning-induced PPI enhancement in isolation-reared rats with a loss of the prepulse feature specificity. Clozapine administration also abolished both the perceptual separation-induced PPI enhancement in normally reared rats and the fear conditioning-induced PPI enhancement in MK-801-treated rats. Conclusions: Isolation rearing impairs both baseline PPI and attentional modulations of PPI, but neonatally disrupting NMDA receptor-mediated transmissions specifically impair attentional modulations of PPI. Clozapine has limited alleviating effects. [ABSTRACT FROM AUTHOR]

Rationale: Anxiety disorders are the most common mental disorders in the USA. Characterized by feelings of uncontrollable apprehension, they are accompanied by physical, affective, and behavioral symptoms. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1 (PACR) are highly expressed in the central nucleus of the amygdala (CeA), and they have gained growing attention for their proposed role in mediating the body's response to stress. Objectives: The aim of this study was to evaluate the anxiogenic effects of PACAP in the CeA and its effects on the hypothalamic-pituitary-adrenal (HPA) axis. Furthermore, the mechanism of action of PACAP in the CeA was investigated. Methods: PACAP was microinfused into the CeA of rats, and its effects in the elevated plus maze (EPM), the defensive withdrawal tests, and plasma corticosterone levels were evaluated. The ability of the melanocortin receptor antagonist SHU9119 to block PACAP effect in the EPM was assessed. Results: Intra-CeA PACAP exerted a dose-dependent anxiogenic effect and activated the HPA axis. In contrast, PACAP microinfused into the basolateral nucleus of the amygdala (BlA) had no effect. Finally, the anxiogenic effect of intra-CeA PACAP was prevented by SHU9119. Conclusions: These data prove an anxiogenic role for the PACAP system of the CeA and reveal that the melanocortin receptor 4 (MCR) system of CeA mediates these effects. Our data provide insights into this neuropeptide system as a mechanism for modulating the behavioral and endocrine response to stress and suggest that dysregulations of this system may contribute to the pathophysiology of anxiety-related disorders. [ABSTRACT FROM AUTHOR]

Rationale: A microdeletion at locus 15q13.3 is associated with high incidence rates of psychopathology, including schizophrenia. A mouse model of the 15q13.3 microdeletion syndrome has been generated (Df[h15q13]/+) with translational utility for modelling schizophrenia-like pathology. Among other deficits, schizophrenia is characterised by dysfunctions in prefrontal cortical (PFC) inhibitory circuitry and attention. Objectives: The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays. Method: Experiments 1-2 investigated baseline firing and auditory-evoked responses of PFC interneurons and pyramidal neurons. Experiment 3 measured pyramidal firing in response to intra-PFC GABA receptor antagonism. Experiments 4-6 assessed PFC-dependent attentional functioning through the touchscreen 5-choice serial reaction time task (5-CSRTT). Experiments 7-12 assessed reversal learning, paired-associate learning, extinction learning, progressive ratio, trial-unique non-match to sample, and object recognition. Results: In experiments 1-3, the Df(h15q13)/+ mouse showed reduced baseline firing rate of fast-spiking interneurons and in the ability of the GABA receptor antagonist gabazine to increase the firing rate of pyramidal neurons. In assays of auditory-evoked responses, PFC interneurons in the Df(h15q13)/+ mouse had reduced detection amplitudes and increased detection latencies, while pyramidal neurons showed increased detection latencies. In experiments 4-6, the Df(h15q13)/+ mouse showed a stimulus duration-dependent decrease in percent accuracy in the 5-CSRTT. The impairment was insensitive to treatment with the partial αnAChR agonist EVP-6124. The Df(h15q13)/+ mouse showed no cognitive impairments in experiments 7-12. Conclusion: The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function. [ABSTRACT FROM AUTHOR]

Rationale: Brain-derived neurotrophic factor (BDNF) and signaling at its receptor, tropomyosin-related kinase B (TrkB), are implicated in the rapid and long-lasting antidepressant effects of ketamine. Moreover, a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), and/or TrkB antagonist, ANA-12, shows antidepressant effects in animal models of depression. Objective: The objective of this study is to compare the influence of ketamine, 7,8-DHF, and ANA-12 on antidepressant activity in the social defeat stress model. Results: In the tail suspension and forced swimming tests, ketamine, 7,8-DHF, or ANA-12 markedly attenuated the increased immobility time in depressed mice compared with the vehicle-treated group. In the sucrose preference test, all drugs significantly improved the reduced preference in depressed mice at both 1 and 3 days after a single dose. Antidepressant effect of ketamine, but not 7,8-DHF or ANA-12, was still detectable 7 days after a single dose. Western blot analyses showed that ketamine, but not 7,8-DHF or ANA-12, markedly attenuated reduced levels of BDNF and postsynaptic density protein 95 (PSD-95) in the prefrontal cortex (PFC), dentate gyrus (DG), and CA3 of the hippocampus in depressed mice 8 days after a single dose. Furthermore, ketamine markedly increased reduced levels of GluA1 in the PFC and DG of depressed mice. In contrast, ketamine showed no effect against increased levels of BDNF, PSD-95, and GluA1 observed in the nucleus accumbens of depressed mice. Conclusions: Compared with 7,8-DHF and ANA-12, ketamine is a longer-lasting antidepressant in the social defeat stress model, and synaptogenesis may be required for the mechanisms that promote sustained antidepressant effects of ketamine. [ABSTRACT FROM AUTHOR]

Rationale: Gestational day 17 methylazoxymethanol (MAM) treatment has been shown to reproduce, in rodents, some of the alterations in cortical and mesolimbic circuitries thought to contribute to schizophrenia. Objective: We characterized the behavior of MAM animals in tasks dependent on these circuitries to see what behavioral aspects of schizophrenia the model captures. We then characterized the integrity of mesolimbic dopamine neurotransmission in a subset of animals used in the behavioral experiments. Methods: MAM animals' capacity for working memory, attention, and resilience to distraction was tested with two different paradigms. Cue-reward learning and motivation were assayed with Pavlovian conditioned approach. Measurements of electrically stimulated phasic and tonic DA release in the nucleus accumbens with fast-scan cyclic voltammetry were obtained from the same animals used in the Pavlovian task. Results: MAM animals' basic attentional capacities were intact. MAM animals took longer to acquire the working memory task, but once learned, performed at the same level as shams. MAM animals were also slower to develop a Pavlovian conditioned response, but otherwise no different from controls. These same animals showed alterations in terminal DA release that were unmasked by an amphetamine challenge. Conclusions: The predominant behavioral-cognitive feature of the MAM model is a learning impairment that is evident in acquisition of executive function tasks as well as basic Pavlovian associations. MAM animals also have dysregulated terminal DA release, and this may contribute to observed behavioral differences. The MAM model captures some functional impairments of schizophrenia, particularly those related to acquisition of goal-directed behavior. [ABSTRACT FROM AUTHOR]

Rationale: It is becoming increasingly clear that the development of treatments for cognitive symptoms of schizophrenia requires urgent attention, and that valid animal models of relevant impairments are required. With subchronic psychotomimetic agent phencyclidine (scPCP), a putative model of such impairment, the extent to which changes following scPCP do or do not resemble those following dysfunction of the prefrontal cortex is of importance. Objectives: The present study carried out a comparison of the most common scPCP dosing regimen with excitotoxin-induced medial prefrontal cortex (mPFC) dysfunction in rats, across several cognitive tests relevant to schizophrenia. Methods: ScPCP subjects were dosed intraperitoneal with 5 mg/kg PCP or vehicle twice daily for 1 week followed by 1 week washout prior to behavioural testing. mPFC dysfunction was induced via fibre-sparing excitotoxin infused into the pre-limbic and infralimbic cortex. Subjects were tested on spontaneous novel object recognition, touchscreen object-location paired-associates learning and touchscreen reversal learning. Results: A double-dissociation was observed between object-location paired-associates learning and object recognition: mPFC dysfunction impaired acquisition of the object-location task but not spontaneous novel object recognition, while scPCP impaired spontaneous novel object recognition but not object-location associative learning. Both scPCP and mPFC dysfunction resulted in a similar facilitation of reversal learning. Conclusions: The pattern of impairment following scPCP raises questions around its efficacy as a model of cognitive impairment in schizophrenia, particularly if importance is placed on faithfully replicating the effects of mPFC dysfunction. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is a chronic, life-threatening psychiatric condition characterized by depressed mood, psychomotor alterations, and a markedly diminished interest or pleasure in most activities known as anhedonia. Available pharmacotherapies have limited success and the need for new strategies is clear. Recent studies attribute a major role to the pituitary adenylate cyclase-activating polypeptide (PACAP) system in mediating the response to stress. PACAP knockout mice display profound alterations in depressive-like behaviors, and genetic association studies have demonstrated that genetic variants of the PACAP gene are associated with MDD. However, the effects of PACAP administration on depressive-like behaviors in rodents have not yet been systematically examined. Objectives: The present study investigated the effects of central administration of PACAP in rats on depressive-like behaviors, using well-established animal models that represent some of the endophenotypes of depression. Methods: We used intracranial self-stimulation (ICSS) to assess the brain reward function, saccharin preference test to assess anhedonia, social interaction to assess social withdrawal, and forced swim test (FST) to assess behavioral despair. Results: PACAP raised the current threshold for ICSS, elevation blocked by the PACAP antagonist PACAP(6-38). PACAP reduced the preference for a sweet saccharin solution and reduced the time the rats spent interacting with a novel animal. Interestingly, PACAP administration did not affect immobility in the FST. Conclusions: Our results demonstrate a role for the central PACAP/PACR system in the regulation of depressive-like behaviors and suggest that hyperactivity of the PACAP/PAC1R system may contribute to the pathophysiology of depression, particularly the associated anhedonic symptomatology and social dysfunction. [ABSTRACT FROM AUTHOR]

Rationale: Addiction is characterized by persistence to seek drug reinforcement despite negative consequences. Drug-induced aberrations in approach and avoidance processing likely facilitate the sustenance of addiction pathology. Currently, the effects of repeated drug exposure on the resolution of conflicting approach and avoidance motivational signals have yet to be thoroughly investigated. Objective: The present study sought to investigate the effects of cocaine pre-exposure on conflict resolution using novel approach-avoidance paradigms. Methods: We used a novel mixed-valence conditioning paradigm to condition cocaine-pre-exposed rats to associate visuo-tactile cues with either the delivery of sucrose reward or shock punishment in the arms in which the cues were presented. Following training, exploration of an arm containing a superimposition of the cues was assessed as a measure of conflict resolution behavior. We also used a mixed-valence runway paradigm wherein cocaine-pre-exposed rats traversed an alleyway toward a goal compartment to receive a pairing of sucrose reward and shock punishment. Latency to enter the goal compartment across trials was taken as a measure of motivational conflict. Results: Our results reveal that cocaine pre-exposure attenuated learning for the aversive cue association in our conditioning paradigm and enhanced preference for mixed-valence stimuli in both paradigms. Conclusions: Repeated cocaine pre-exposure allows appetitive approach motivations to gain greater influence over behavioral output in the context of motivational conflict, due to aberrant positive and negative incentive motivational processing. [ABSTRACT FROM AUTHOR]

Rationale: Major depression has been associated with higher levels of air pollution that in turn leads to neurodegeneration via increased oxidative stress. There is a need for suitable translational animal models to study the role of oxidative stress in depression and antidepressant action. Objective: Considering the gene X environment hypothesis of depression, the present study investigated the effect of chronic ozone inhalation on depression and anxiety-related behavior, cognition, and brain markers of oxidative stress in the Flinders Sensitive Line (FSL) rat. In addition, response to the antioxidant melatonin, and the antidepressants desipramine or escitalopram, was assessed. Methods: Rats were exposed to ozone (0.0 or 0.3 parts per million (ppm)) per inhalation for 4 h daily for a period of 15 days, while simultaneously receiving saline or the above-mentioned drugs. Results: The data indicate that chronic ozone inhalation induced memory impairment, anxiety and depression-like effects, reduced cortical and hippocampal superoxide dismutase and catalase activity, and compromised central monoamine levels similar to that noted in depression. Moreover, the behavioral and neurochemical effects of melatonin, desipramine, and escitalopram were mostly attenuated in the presence of ozone. Conclusion: Thus, genetically susceptible individuals exposed to high levels of oxidative stress are at higher risk of developing mood and/or an anxiety disorders, showing greater redox imbalance and altered behavior. These animals are also more resistant to contemporary antidepressant treatment. The presented model provides robust face, construct, and predictive validity, suitable for studying neuronal oxidative stress in depression, antidepressant action and mechanisms to prevent neuronal oxidative stress. [ABSTRACT FROM AUTHOR]

Rationale: Phosphodiesterase-4 (PDE4) and neuroimmune signaling have been posited to regulate alcohol drinking. Objectives: This study evaluated the involvement of PDE4 and Il22ra2 on ethanol (EtOH) intake by alcohol-preferring (P) and high-alcohol-drinking (HAD1) rats. Methods: Exp 1 determined the dose-response effects of PDE4 inhibitors, rolipram, and Ro 20-1724, on 2 h/day free-choice EtOH intake by adult P and HAD1 rats. Exps 2-3 examined the effects of repeated administration with the PDE4 inhibitors on EtOH or sucrose intake and locomotor behavior. Exp 4 determined Pde4-associated gene expression differences in subregions of the extended amygdala, between high- and low-alcohol-consuming rat lines. Exp 5 evaluated the effects of infusing short hairpin RNA to knock down Il22ra2 in the nucleus accumbens (NAc) shell on a 24-h free-choice EtOH drinking by P rats. Results: Administration of rolipram or Ro 20-1724 reduced EtOH intake by P rats; Ro 20-1724 reduced EtOH intake by HAD1 rats. Repeated rolipram or Ro 20-1724 exposure reduced EtOH intake by P and HAD1 rats. PDE4 inhibition induced motor impairment during the first hour of EtOH intake by P rats. Higher gene expression levels for PDE4A were found in the NAc shell of P vs NP rats. ShRNAs targeting Il22ra2 in the NAc shell significantly reduced chronic EtOH intake. Conclusions: PDE4 and neuroinflammatory/immune signaling pathways could represent molecular targets for the treatment of alcohol use disorders in genetically predisposed subjects. This study underscores the importance of testing compounds over multiple days and rat lines when determining efficacy to disrupt excessive alcohol intake. [ABSTRACT FROM AUTHOR]

Rationale and objectives: Both valproic acid (VPA) and lithium (LI) are well-established treatments for therapy of intense and sustained mood shifts, which are characteristics of affective disorders, such as bipolar disorder (BP). As mood and cognitive judgment bias have been found to be strongly interrelated, the present study investigated, in an animal model, whether acute treatment with VPA or LI could affect cognitive judgment bias. Methods: To accomplish this goal, two groups of rats received single injections of either VPA or LI after initial behavioral training and were subsequently tested with the ambiguous-cue interpretation (ACI) test. Both drugs were administered in three doses using the fully randomized Latin square design. Results: VPA (100, 200, and 400 mg/kg) had no significant effect on the interpretation of the ambiguous cue. LI at the lowest dose (10 mg/kg) had no effect; at an intermediate dose (50 mg/kg), it significantly biased animals towards positive interpretation of the ambiguous cue, and at the highest dose (100 mg/kg), it impaired the ability of animals to complete the test. Conclusion: To our knowledge, this is the first study demonstrating lithium's effects on increased optimistic judgment bias. Future studies may focus on the ability of putative pharmacotherapies to modify the cognitive judgment bias dimension of patients at risk for bipolar disorder or depression. [ABSTRACT FROM AUTHOR]

Rational: Nicotine use in schizophrenia has traditionally been explained as 'self-medication' of cognitive and/or nicotinic acetylcholinergic receptor (nAChR) abnormalities. Objectives: We test this hypothesis in a neurodevelopmental rat model of schizophrenia that shows increased addiction behaviors including enhanced nicotine reinforcement and drug-seeking. Methods: Nicotine transdermal patch (5 mg/kg/day vs. placebo × 10 days in adolescence or adulthood) effects on subsequent radial-arm maze learning (15 sessions) and frontal-cortical-striatal nAChR densities (αβ; [3H]-epibatidine binding) were examined in neonatal ventral hippocampal lesion (NVHL) and SHAM-operated rats. Results: NVHL cognitive deficits were not differentially affected by nicotine history compared to SHAMs. Nicotine history produced minimal cognitive effects while increasing food-reward consumption on the maze, compounding with NVHL-induced overconsumption. Acute nicotine (0.5 mg/kg) delivered before the final maze sessions produced modest improvements in maze performance in rats with nicotine patch histories only, but not differentially so in NVHLs. Consistent with in vivo neuroimaging of β nAChR binding in schizophrenia smokers vs. non-smokers and healthy controls, adult NVHLs showed 12% reductions in nAChR binding in MPFC ( p < 0.05) but not ventral striatum (<5% changes, p > .40), whereas nicotine history elevated nAChRs across both regions (>30%, p < 0.001) without interacting with NVHLs. Adolescent vs. adult nicotine exposure did not alter nAChRs differentially. Conclusions: Although replicating nicotine-induced upregulation of nAChRs in human smokers and demonstrating NVHL validity in terms of schizophrenia-associated nAChR density patterns, these findings do not support hypotheses explaining increased nicotine use in schizophrenia as reflecting illness-specific effects of nicotine to therapeutically alter cognition or nAChR densities. [ABSTRACT FROM AUTHOR]

Rationale: Alterations in brainstem circuits have been proposed as a possible mechanism underlying the etiology of mood disorders. Projections from the median raphe nucleus (MnR) modulate dopaminergic activity in the forebrain and are also part of a behavioral disinhibition/inhibition system that produces phenotypes resembling behavioral variations manifested during manic and depressive phases of bipolar disorder. Objective: The aim of this study is to assess the effect of chronic lithium treatment on behavioral disinhibition induced by MnR lesions. Methods: MnR electrolytic lesions were performed in C57BL/6J mice, with sham-operated and intact animals as control groups. Following recovery, mice were chronically treated with lithium (LiCl, added in chow) followed by behavioral testing. Results: MnR lesion induced manic-like behavioral alterations including hyperactivity in the open field (OF), stereotyped circling, anxiolytic/risk taking in the elevated plus maze (EPM) and light/dark box (LDB) tests, and increased basal body temperature. Lithium was specifically effective in reducing OF hyperactivity and stereotypy but did not reverse (EPM) or had a nonspecific effect (LDB) on anxiety/risk-taking measures. Additionally, lithium decreased saccharin preference and prevented weight loss during single housing. Conclusions: Our data support electrolytic lesions of the MnR as an experimental model of a hyper-excitable/disinhibited phenotype consistent with some aspects of mania that are attenuated by the mood stabilizer lithium. Given lithium's relatively specific efficacy in treating mania, these data support the hypothesis that manic symptoms derive not only from the stimulation of excitatory systems but also from inactivation or decreased activity of inhibitory mechanisms. [ABSTRACT FROM AUTHOR]

Rationale: Imperatorin, a naturally occurring furanocoumarin, inactivates gamma-aminobutyric acid transaminase and inhibits acetylcholinesterase activity. Objectives: The purpose of our experiment was to examine the influence of imperatorin on cognitive impairment and oxidative stress in the brain induced by scopolamine in male Swiss mice. Methods: In the present studies, we used scopolamine-invoke memory deficit measured in passive avoidance (PA) paradigm as an animal model of Alzheimer disease (AD). Results: Our finding revealed that imperatorin administered acutely at the doses of 5 and 10 mg/kg prior to the injection of scopolamine (1 mg/kg) improved memory acquisition and consolidation impaired by scopolamine. Furthermore, repeatable (7 days, twice daily) administration of the highest dose of imperatorin (10 mg/kg) significantly attenuated the effects of scopolamine on memory acquisition, whereas the doses of 5 and 10 mg/kg of this furanocoumarin were effective when memory consolidation was measured. Imperatorin, administered with scopolamine, increased antioxidant enzymes activity and decreased concentration of malondiamide, an indicator of lipid peroxidation level. Conclusions: These results demonstrate that imperatorin may offer protection against scopolamine-induced memory impairments and possesses antioxidant properties, thus after further preclinical and clinical studies this compound may provide an interesting approach in pharmacotherapy, as well as prophylactics of AD. [ABSTRACT FROM AUTHOR]

Rationale: Schedule-induced polydipsia (SIP) is an established model for studying compulsive behaviour in rats. Serotoninergic drugs effectively reduce compulsive drinking on SIP, and high compulsive drinker rats selected by SIP have shown differences in serotoninergic brain activity. However, the specific serotoninergic receptors that modulate compulsive SIP remain unclear. Objective: We investigated the functional role of serotonin 5-hydroxytryptamine 2A or C (5-HT) receptors in compulsive SIP behaviour. Methods: Rats were selected for low (LD) versus high drinking (HD) behaviour on SIP. The effects of the systemic administration of the selective serotonin reuptake inhibitor citalopram, selective norepinephrine reuptake inhibitor atomoxetine, serotonin 5-HT receptor agonist DOI hydrochloride ((±)-2,5-dimethoxy-4-iodoamphetamine), serotonin 5-HT receptor antagonist SB242084, serotonin 5-HT receptor antagonist ketanserin and M100907 were assessed on SIP. Subsequently, the effects of DOI were tested after the pre-administration of SB242084, ketanserin and M100907 on SIP. Results: Citalopram and DOI reduced compulsive drinking in HD compared with LD rats on SIP. In contrast, SB242084 increased compulsive drinking in HD compared with LD rats on SIP. Atomoxetine, ketanserin and M100907 had no effect on SIP. The reduction in water intake produced by DOI was blocked by ketanserin and M100907, but not by SB242084 administration, in HD rats. Conclusions: These findings highlight the contribution of serotoninergic 5-HT receptors compared with noradrenergic mechanisms on SIP and reveal the 'therapeutic' activation of serotonin 5-HT in the inhibition of the compulsive drinking behaviour in HD rats. Thus, it may represent a potentially new marker of vulnerability and provides additional insight for potential treatments on compulsive behaviours in neuropsychiatric populations. [ABSTRACT FROM AUTHOR]

Rationale: Animal models of mania lack genuine cognitive parameters. The present gold standard of mania models, amphetamine-induced hyperlocomotion, is rather unspecific and does not necessarily target its cardinal symptoms. Therefore, alternative behavioral markers that are sensitive to stimulants are required. Objectives: In the present study, by combining the psychostimulant-induced model of mania in rodents with the recently developed ambiguous-cue interpretation (ACI) tests, we investigated the effects of chronic administration of d-amphetamine and cocaine on the cognitive judgment bias of rats. Methods: To accomplish this goal, in two separate experiments, previously trained animals received chronic, daily injections of either d-amphetamine (2 mg/kg) or cocaine (10 mg/kg) for 2 weeks and were subsequently tested with the ACI procedure. Results: Chronic treatment with both psychostimulants did not make rats more 'optimistic.' Conclusions: The results are discussed in terms of behavioral and pharmacological actions of the tested compounds and their implications for modeling mania in animals. [ABSTRACT FROM AUTHOR]

Rationale: Pharmacological magnetic resonance imaging (phMRI) provides an approach to study effects of drug challenges on brain processes. Elucidating mechanisms of drug action helps us to better understand the workings of neurotransmitter systems, map brain function or facilitate drug development. phMRI is increasingly used in preclinical research employing rodent models; however, data interpretation and integration are complicated by the use of different experimental approaches between laboratories. In particular, the effects of different anaesthetic regimes upon neuronal and haemodynamic processes and baseline physiology could be problematic. Objectives: This paper investigates how differences in phMRI research methodologies are manifested and considers associated implications, placing particular emphasis on choice of anaesthetic regimes. Methods: A systematic review of rodent phMRI studies was conducted. Factors such as those describing anaesthetic regimes (e.g. agent, dosage) and parameters relating to physiological maintenance (e.g. ventilatory gases) and MRI method were recorded. Results: We identified 126 eligible studies and found that the volatile agents isoflurane (43.7 %) and halothane (33.3 %) were most commonly used for anaesthesia, but dosage and mixture of ventilatory gases varied substantially between laboratories. Relevant physiological parameters were usually recorded, although 32 % of studies did not provide cardiovascular measures. Conclusions: Anaesthesia and animal preparation can influence phMRI data profoundly. The variation of anaesthetic type, dosage regime and ventilatory gases makes consolidation of research findings (e.g. within a specific neurotransmitter system) difficult. Standardisation of a small(er) number of preclinical phMRI research methodologies and/or increased consideration of approaches that do not require anaesthesia is necessary to address these challenges. [ABSTRACT FROM AUTHOR]

Rationale: We previously demonstrated in mice that the activation of prelimbic medial prefrontal cortex (PL) with the sodium channel activator veratrine induces anxiety-like behaviors via NMDA receptor-mediated glutamatergic neurotransmission. Riluzole directly affects the glutamatergic system and has recently been suggested to have an anxiolytic-like effect in both experimental animals and patients with anxiety disorders. Objectives: We investigated the effects of co-perfusion of riluzole on veratrine-induced anxiety-like behaviors in mice. Methods: Extracellular glutamate levels were measured in 7-week-old male C57BL6 mice by using an in vivo microdialysis-HPLC/ECD system, and behaviors were assessed simultaneously in an open field (OF) test. Basal levels of glutamate were measured by collecting samples every 10 min for 60 min. The medium containing drugs was perfused for 30 min, and the OF test was performed during the last 10 min of drug perfusion. After the drug treatments, the drug-containing medium was switched to perfusion of control medium lacking drugs, and then samples were collected for another 90 min. Results: Riluzole co-perfusion attenuated veratrine-induced increase in extracellular glutamate levels in the PL and completely diminished veratrine-induced anxiety-like behaviors. Interestingly, riluzole perfusion alone in the PL did not affect the basal levels of glutamate and anxiety-like behaviors. Conclusions: Our results suggest that compounds like riluzole that inhibit glutamatergic function in the PL are possible candidates for novel anxiolytics. [ABSTRACT FROM AUTHOR]

Here, we present the pharmacological characterisation of Lu AF64280, a novel, selective, brain penetrant phosphodiesterase (PDE) 2A inhibitor, in in vitro/in vivo assays indicative of PDE2A inhibition, and in vivo models/assays relevant to cognitive processing or antipsychotic-like activity. The in vitro selectivity of Lu AF64280 was determined against a panel of PDE enzymes and 3′,5′-cyclic guanosine monophosphate (cGMP) levels in the hippocampus were determined using in vivo microdialysis. Lu AF64280 potently inhibited hPDE2A (Ki = 20 nM), 50-fold above moderate inhibition of both hPDE9A (Ki = 1,000 nM) and hPDE10A (Ki = 1,800 nM), and displayed a >250-fold selectivity over all other full-length human recombinant PDE family members (Ki above 5,000 nM). Lu AF64280 (20 mg/kg) significantly increased cGMP levels in the hippocampus ( p < 0.01 versus vehicle-treated mice), attenuated sub-chronic phencyclidine-induced deficits in novel object exploration in rats (10 mg/kg, p < 0.001 versus vehicle-treated), blocked early postnatal phencyclidine-induced deficits in the intradimensional/extradimensional shift task in rats (1 and 10 mg/kg, p < 0.001 versus vehicle-treated) and attenuated spontaneous P20-N40 auditory gating deficits in DBA/2 mice (20 mg/kg, p < 0.05 versus vehicle-treated). In contrast, Lu AF64280 failed to attenuate phencyclidine-induced hyperactivity in mice, and was devoid of antipsychotic-like activity in the conditioned avoidance response paradigm in rats, at any dose tested. Lu AF64280 represents a novel tool compound for selective PDE2A inhibition that substantiates a critical role of this enzyme in cognitive processes under normal and pathological conditions. [ABSTRACT FROM AUTHOR]

Background and rationale: An enormous amount of resources has been devoted to the development of pharmacotherapies for drug addiction, with relatively little or no long-term success reported. The current review argues that a successful drug addiction treatment program will likely be one that focuses on both the neural mechanisms and the environmental contingencies that mediate drug use. Further, because the neural mechanisms and environmental factors that support abstinence in humans are similar in laboratory animals, several animal models of abstinence and relapse have been developed. Thus, this review also compares the similarities in the mechanisms that lead to abstinence between animals and humans. Objective: We evaluate the construct and face validities of the behavioral strategies that help support human drug abstinence. Further, we crucially evaluate animal models by assessing their validity and utility in addressing human behavior that leads to long-term abstinence. Conclusions: We found that the behavioral strategies with the greatest likelihood of supporting long-term abstinence are those that are carried out in drug addicts' natural setting(s) and while drug is readily available. Further, the behavioral strategies that may be most successful in supporting abstinence in humans are those that employ both positive consequences for abstinent related behavior and negative consequences for continued drug seeking or taking. Moreover, the animal models of abstinence and relapse that more closely represent the factors that support long-term abstinence in humans are those that limit their use of extinction or forced abstinence and present negative consequences for drug seeking and taking. [ABSTRACT FROM AUTHOR]

Rationale: Self-injurious behaviour is not one of the three core symptoms that define autism. However, children on the autism spectrum appear to be particularly vulnerable. Afflicted children typically slap their faces, punch or bang their heads, and bite or pinch themselves. These behaviours can be extremely destructive, and they interfere with normal social and educational activities. However, the neurobiological mechanisms that confer vulnerability in children with autism have not been adequately described. Objectives: This review explores behavioural and neurobiological characteristics of children with autism that may be relevant for an increased understanding of their vulnerability for self-injurious behaviour. Methods: Behavioural characteristics that are co-morbid for self-injurious behaviour in children with autism are examined. In addition, the contributions of social and environmental deprivation in self-injurious institutionalized orphans, isolated rhesus macaques, and additional animal models are reviewed. Results: There is extensive evidence that social and environmental deprivation promotes self-injurious behaviour in both humans (including children with autism) and animal models. Moreover, there are multiple lines of convergent neuroanatomical, neurophysiological, and neurochemical data that draw parallels between self-injurious children with autism and environmentally deprived humans and animals. Conclusions: A hypothesis is presented that describes how the core symptoms of autism make these children particularly vulnerable for self-injurious behaviour. Relevant neurodevelopmental pathology is described in cortical, limbic, and basal ganglia brain regions, and additional research is suggested. [ABSTRACT FROM AUTHOR]

The establishment of robust and replicable behavioural testing paradigms with translational value for psychiatric diseases is a major step forward in developing and testing etiology-directed treatment for these complex disorders. Based on the existing literature, we have generated an inventory of applied rodent behavioural testing paradigms relevant to autism spectrum disorders (ASD). This inventory focused on previously used paradigms that assess behavioural domains that are affected in ASD, such as social interaction, social communication, repetitive behaviours and behavioural inflexibility, cognition as well as anxiety behaviour. A wide range of behavioural testing paradigms for rodents were identified. However, the level of face and construct validity is highly variable. The predictive validity of these paradigms is unknown, as etiology-directed treatments for ASD are currently not on the market. To optimise these studies, future efforts should address aspects of reproducibility and take into account data about the neurodevelopmental underpinnings and trajectory of ASD. In addition, with the increasing knowledge of processes underlying ASD, such as sensory information processes and synaptic plasticity, phenotyping efforts should include multi-level automated analysis of, for example, representative task-related behavioural and electrophysiological read-outs. [ABSTRACT FROM AUTHOR]

Introduction: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by core differences and impairments in social behavioral functioning. There are no approved medications for improving social cognition and behavior in ASD, and the underlying mechanisms needed to discover safer, more effective medications are unclear. Discussion: In this review, we diagram the basic neurocircuitry governing social behaviors in order to provide a neurobiological framework for the origins of the core social behavioral symptoms of ASD. In addition, we discuss recent technological innovations in research tools that provide unprecedented observation of cellular morphology and activity deep within the intact brain and permit the precise control of discrete brain regions and specific cell types at distinct developmental stages. Conclusions: The use of new technologies to reveal the neural circuits underlying social behavioral impairments associated with ASD is advancing our understanding of the brain changes underlying ASD and enabling the discovery of novel and effective therapeutic interventions. [ABSTRACT FROM AUTHOR]

Rationale: In psychiatric drug discovery, a critical step is predicting the psychopharmacological effect and therapeutic potential of novel (or repurposed) compounds early in the development process. This process is hampered by the need to utilize multiple disorder-specific and labor-intensive behavioral assays. Objectives: This study aims to investigate the feasibility of a single high-throughput behavioral assay to classify psychiatric drugs into multiple psychopharmacological classes. Methods: Using Pattern Array, a procedure for data mining exploratory behavior in mice, we mined ~100,000 complex movement patterns for those that best predict psychopharmacological class and dose. The best patterns were integrated into a classification model that assigns psychopharmacological compounds to one of six clinically relevant classes-antipsychotic, antidepressant, opioids, psychotomimetic, psychomotor stimulant, and α-adrenergic. Results: Surprisingly, only a small number of well-chosen behaviors were required for successful class prediction. One of them, a behavior termed 'universal drug detector', was dose-dependently decreased by drugs from all classes, thus providing a sensitive index of psychopharmacological activity. In independent validation in a blind fashion, simulating the process of in vivo pre-clinical drug screening, the classification model correctly classified nine out of 11 'unknown' compounds. Interestingly, even 'misclassifications' match known alternate therapeutic indications, illustrating drug 'repurposing' potential. Conclusions: Unlike standard animal models, the discovered classification model can be systematically updated to improve its predictive power and add therapeutic classes and subclasses with each additional diversification of the database. Our study demonstrates the power of data mining approaches for behavior analysis, using multiple measures in parallel for drug screening and behavioral phenotyping. [ABSTRACT FROM AUTHOR]

Rationale: Acetylcholinesterase inhibitors (AChEIs) are approved to treat the symptoms of mild to moderate Alzheimer's disease by restoring acetylcholine levels at synapses where the neurotransmitter has been depleted due to neurodegeneration. This assumption is challenged by more recent clinical studies suggesting the potential for disease-modifying effects of AChEIs as well as in vitro studies showing neuroprotective effects. However, few preclinical studies have assessed whether the improvement of cognitive symptoms may be mediated by reductions in Abeta or Tau pathology. Objectives: The objective of the present study was to determine whether short-duration treatment with donepezil could improve spatial learning and memory in transgenic mice overexpressing mutant human amyloid precursor protein (hAPP) and presenilin 1 (PS1) (Dewachter et al., J Neurosci 20(17):6452-6458, ) after amyloid pathology has fully developed, consistent with early stages of Alzheimer'sdisease in humans. In parallel, the effect of donepezil treatment on brain amyloid, Tau, and glial endpoints was measured. Results: This study showed a significant improvement in reference memory in hAPP/PS1 mice along with dose-dependent reductions in brain amyloid-β (Aβ). Conclusion: These results suggest that the observed cognitive improvement produced by donepezil in Alzheimer's disease may be due, at least in part, to reduction of brain Aβ. [ABSTRACT FROM AUTHOR]

Rationale: Glutamatergic and γ-aminobutyric acid (GABA)ergic abnormalities have recently been proposed to contribute to depression. The learned helplessness (LH) paradigm produces a reliable animal model of depression that expresses a deficit in escape behavior (LH model); an alternative phenotype that does not exhibit LH is a model of resilience to depression (non-LH model). Objectives: We measured the contents of amino acids in the brain to investigate the mechanisms involved in the pathology of depression. Methods: LH and non-LH models were subjected to inescapable electric footshocks at random intervals following a conditioned avoidance test to determine acquirement of predicted escape deficits. Tissue amino acid contents in eight brain regions were measured via high-performance liquid chromatography. Results: The non-LH model showed increased GABA levels in the dentate gyrus and nucleus accumbens and increased glutamine levels in the dentate gyrus and the orbitofrontal cortex. The LH model had reduced glutamine levels in the medial prefrontal cortex. Changes in the ratios of GABA, glutamine, and glutamate were detected in the non-LH model, but not in the LH model. Reductions in threonine levels occurred in the medial prefrontal cortex in both models, whereas elevated alanine levels were detected in the medial prefrontal cortex in non-LH animals. Conclusions: The present study demonstrates region-specific compensatory elevations in GABA levels in the dentate gyrus and nucleus accumbens of non-LH animals, supporting the implication of the GABAergic system in the recovery of depression. [ABSTRACT FROM AUTHOR]

Rationale: Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new way to achieve antipsychotic-like activity. LSP1-2111, the group III mGlu receptor orthosteric agonist, with a high affinity towards mGlu receptors, was previously shown to exhibit antipsychotic-like action in animal models displaying positive symptoms of schizophrenia. Objectives: Here, we decided to investigate the possible role of LSP1-2111 in models of negative (social interaction) and cognitive (NOR) symptoms of psychosis. We also investigated the involvement of 5-HT receptors in the LSP1-2111-induced antipsychotic effects. Apart from the above-mentioned models of negative and cognitive symptoms, MK-801 and amphetamine-induced hyperactivity tests, plus the DOI-induced head twitches in mice as models for positive symptoms of psychosis, were used in this part of the investigations. Results: LSP1-2111 (0.5, 2, and 5 mg/ kg) dose-dependently inhibited MK-801-induced deficits in social interaction and NOR tests. The effects of the drug were antagonized by 5-HT antagonist, WAY100635 (0.1 mg/kg). A similar inhibition of LSP1-2111-induced effects was observed in models of positive symptoms of schizophrenia. Moreover, the concomitant administration of subeffective doses of LSP1-2111 (0.3-0.5 mg/kg) with a subeffective dose of 5-HT agonist, (R)-(+)-8-Hydroxy-DPAT (0.01 mg/kg), induced a clear antipsychotic-like effect in all of the procedures used. Conclusions: Altogether, we propose that the activation of group III mGlu receptors may be a promising target for the development of novel antipsychotic drugs, towards not only positive but also negative and cognitive symptoms. The action of the compound is 5-HT-dependent. [ABSTRACT FROM AUTHOR]