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Cannabis remains by far the most consumed illicit drug in Europe. The availability of more potent cannabis has raised concerns regarding the enhanced health risks associated with its use, particularly among pregnant women. Growing evidence shows that cannabis use during pregnancy increases the risks of child psychopathology. We have previously shown that only male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), display a hyperdopaminergic phenotype associated with a differential susceptibility to acute THC- and stress-mediated effects on sensorimotor gating functions. Here, we explore the contribution of the hypothalamic-pituitary-adrenal (HPA) axis, key regulator of body adaptive stress responses, to the detrimental effects of acute stress on ventral tegmental area (VTA) dopamine neurons and sensorimotor gating function of PCE rats. We report a sex-dependent compromised balance in mRNA levels of genes encoding mineralocorticoid and glucocorticoid receptors in the VTA, alongside with stress-induced pre-pulse inhibition (PPI) impairment. Notably, VTA dopamine neuronal activity is causally linked to the manifestation of stress-dependent deterioration of PPI. Finally, pharmacological manipulations targeting glycogen-synthase-kinase-3-β signaling during postnatal development correct these stress-induced, sex-specific and dopamine-dependent disruption of PPI. Collectively, these results highlight the critical sex-dependent interplay between HPA axis and dopamine system in the regulation of sensorimotor gating functions in rats.

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is an at least 6-mo noninfectious bladder inflammation of unknown origin characterized by chronic suprapubic, abdominal, and/or pelvic pain. Although the term cystitis suggests an inflammatory or infectious origin, no definite cause has been identified. It occurs in both sexes, but women are twice as much affected., Aim: To systematically review evidence of psychiatric/psychological changes in persons with IC/BPS., Methods: Hypothesizing that particular psychological characteristics could underpin IC/BPS, we investigated in three databases the presence of psychiatric symptoms and/or disorders and/or psychological characteristics in patients with IC/BPS using the following strategy: ("interstitial cystitis" OR "bladder pain syndrome") AND ("mood disorder" OR depressive OR antidepressant OR depression OR depressed OR hyperthymic OR mania OR manic OR rapid cycl asterisk OR dysthymi asterisk OR dysphori asterisk )., Results: On September 27, 2023, the PubMed search produced 223 articles, CINAHL 62, and the combined PsycLIT/ PsycARTICLES/PsycINFO/Psychology and Behavioral Sciences Collection search 36. Search on ClinicalTrials.gov produced 14 studies, of which none had available data. Eligible were peer-reviewed articles reporting psychiatric/psychological symptoms in patients with IC/BPS, i.e. 63 articles spanning from 2000 to October 2023. These studies identified depression and anxiety problems in the IC/BPS population, along with sleep problems and the tendency to catastrophizing., Conclusion: Psychotherapies targeting catastrophizing and life stress emotional awareness and expression reduced perceived pain in women with IC/BPS. Such concepts should be considered when implementing treatments aimed at reducing IC/BPS-related pain., Competing Interests: Conflict-of-interest statement: All authors declare having no conflicts of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Stimulant use disorder is a continuously growing medical and social burden without approved medications available for its treatment. Psychosocial interventions could be a valid approach to help people reduce or cease stimulant consumption. This is an update of a Cochrane review first published in 2016., Objectives: To assess the efficacy and safety of psychosocial interventions for stimulant use disorder in adults., Search Methods: We searched the Cochrane Drugs and Alcohol Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, three other databases, and two trials registers in September 2023. All searches included non-English language literature. We handsearched the references of topic-related systematic reviews and the included studies., Selection Criteria: We included randomised controlled trials (RCTs) comparing any psychosocial intervention with no intervention, treatment as usual (TAU), or a different intervention in adults with stimulant use disorder., Data Collection and Analysis: We used the standard methodological procedures expected by Cochrane., Main Results: We included a total of 64 RCTs (8241 participants). Seventy-three percent of studies included participants with cocaine or crack cocaine use disorder; 3.1% included participants with amphetamine use disorder; 10.9% included participants with methamphetamine use disorder; and 12.5% included participants with any stimulant use disorder. In 18 studies, all participants were in methadone maintenance treatment. In our primary comparison of any psychosocial treatment to no intervention, we included studies which compared a psychosocial intervention plus TAU to TAU alone. In this comparison, 12 studies evaluated cognitive behavioural therapy (CBT), 27 contingency management, three motivational interviewing, one study looked at psychodynamic therapy, and one study evaluated CBT plus contingency management. We also compared any psychosocial intervention to TAU. In this comparison, seven studies evaluated CBT, two contingency management, two motivational interviewing, and one evaluated a combination of CBT plus motivational interviewing. Seven studies compared contingency management reinforcement related to abstinence versus contingency management not related to abstinence. Finally, seven studies compared two different psychosocial approaches. We judged 65.6% of the studies to be at low risk of bias for random sequence generation and 19% at low risk for allocation concealment. Blinding of personnel and participants was not possible for the type of intervention, so we judged all the studies to be at high risk of performance bias for subjective outcomes but at low risk for objective outcomes. We judged 22% of the studies to be at low risk of detection bias for subjective outcomes. We judged most of the studies (69%) to be at low risk of attrition bias. When compared to no intervention, we found that psychosocial treatments: reduce the dropout rate (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.74 to 0.91; 30 studies, 4078 participants; high-certainty evidence); make little to no difference to point abstinence at the end of treatment (RR 1.15, 95% CI 0.94 to 1.41; 12 studies, 1293 participants; high-certainty evidence); make little to no difference to point abstinence at the longest follow-up (RR 1.22, 95% CI 0.91 to 1.62; 9 studies, 1187 participants; high-certainty evidence); probably increase continuous abstinence at the end of treatment (RR 1.89, 95% CI 1.20 to 2.97; 12 studies, 1770 participants; moderate-certainty evidence); may make little to no difference in continuous abstinence at the longest follow-up (RR 1.14, 95% CI 0.89 to 1.46; 4 studies, 295 participants; low-certainty evidence); reduce the frequency of drug intake at the end of treatment (standardised mean difference (SMD) -0.35, 95% CI -0.50 to -0.19; 10 studies, 1215 participants; high-certainty evidence); and increase the longest period of abstinence (SMD 0.54, 95% CI 0.41 to 0.68; 17 studies, 2118 participants; high-certainty evidence). When compared to TAU, we found that psychosocial treatments reduce the dropout rate (RR 0.79, 95% CI 0.65 to 0.97; 9 studies, 735 participants; high-certainty evidence) and may make little to no difference in point abstinence at the end of treatment (RR 1.67, 95% CI 0.64 to 4.31; 1 study, 128 participants; low-certainty evidence). We are uncertain whether they make any difference in point abstinence at the longest follow-up (RR 1.31, 95% CI 0.86 to 1.99; 2 studies, 124 participants; very low-certainty evidence). Compared to TAU, psychosocial treatments may make little to no difference in continuous abstinence at the end of treatment (RR 1.18, 95% CI 0.92 to 1.53; 1 study, 128 participants; low-certainty evidence); probably make little to no difference in the frequency of drug intake at the end of treatment (SMD -1.17, 95% CI -2.81 to 0.47, 4 studies, 479 participants, moderate-certainty evidence); and may make little to no difference in the longest period of abstinence (SMD -0.16, 95% CI -0.54 to 0.21; 1 study, 110 participants; low-certainty evidence). None of the studies for this comparison assessed continuous abstinence at the longest follow-up. Only five studies reported harms related to psychosocial interventions; four of them stated that no adverse events occurred., Authors' Conclusions: This review's findings indicate that psychosocial treatments can help people with stimulant use disorder by reducing dropout rates. This conclusion is based on high-certainty evidence from comparisons of psychosocial interventions with both no treatment and TAU. This is an important finding because many people with stimulant use disorders leave treatment prematurely. Stimulant use disorders are chronic, lifelong, relapsing mental disorders, which require substantial therapeutic efforts to achieve abstinence. For those who are not yet able to achieve complete abstinence, retention in treatment may help to reduce the risks associated with stimulant use. In addition, psychosocial interventions reduce stimulant use compared to no treatment, but they may make little to no difference to stimulant use when compared to TAU. The most studied and promising psychosocial approach is contingency management. Relatively few studies explored the other approaches, so we cannot rule out the possibility that the results were imprecise due to small sample sizes., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Cocaine is a psychostimulant used by approximately 0.4% of the general population worldwide. Cocaine dependence is a chronic mental disorder characterised by the inability to control cocaine use and a host of severe medical and psychosocial complications. There is current no approved pharmacological treatment for cocaine dependence. Some researchers have proposed disulfiram, a medication approved to treat alcohol use disorder. This is an update of a Cochrane review first published in 2010., Objectives: To evaluate the efficacy and safety of disulfiram for the treatment of cocaine dependence., Search Methods: We updated our searches of the following databases to August 2022: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and PsycINFO. We also searched for ongoing and unpublished studies via two trials registries. We handsearched the references of topic-related systematic reviews and included studies. The searches had no language restrictions., Selection Criteria: We included randomised controlled trials that evaluated disulfiram alone or associated with psychosocial interventions versus placebo, no intervention, other pharmacological interventions, or any psychosocial intervention for the treatment of cocaine dependence., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane., Main Results: Thirteen studies (1191 participants) met our inclusion criteria. Disulfiram versus placebo or no treatment Disulfiram compared to placebo may increase the number of people who are abstinent at the end of treatment (point abstinence; risk ratio (RR) 1.58, 95% confidence interval (CI) 1.05 to 2.36; 3 datasets, 142 participants; low-certainty evidence). However, compared to placebo or no pharmacological treatment, disulfiram may have little or no effect on frequency of cocaine use (standardised mean difference (SMD) -0.11 standard deviations (SDs), 95% CI -0.39 to 0.17; 13 datasets, 818 participants), amount of cocaine use (SMD -0.00 SDs, 95% CI -0.30 to 0.30; 7 datasets, 376 participants), continuous abstinence (RR 1.23, 95% CI 0.80 to 1.91; 6 datasets, 386 participants), and dropout for any reason (RR 1.20, 95% CI 0.92 to 1.55; 14 datasets, 841 participants). The certainty of the evidence was low for all these outcomes. We are unsure about the effects of disulfiram versus placebo on dropout due to adverse events (RR 12.97, 95% CI 0.77 to 218.37; 1 study, 67 participants) and on the occurrence of adverse events (RR 3.00, 95% CI 0.35 to 25.98), because the certainty of the evidence was very low for these outcomes. Disulfiram versus naltrexone Disulfiram compared with naltrexone may reduce the frequency of cocaine use (mean difference (MD) -1.90 days, 95% CI -3.37 to -0.43; 2 datasets, 123 participants; low-certainty evidence) and may have little or no effect on amount of cocaine use (SMD 0.12 SDs, 95% CI -0.27 to 0.51, 2 datasets, 123 participants; low-certainty evidence). We are unsure about the effect of disulfiram versus naltrexone on dropout for any reason (RR 0.86, 95% CI 0.56 to 1.32, 3 datasets, 131 participants) and dropout due to adverse events (RR 0.50, 95% CI 0.07 to 3.55; 1 dataset, 8 participants), because the certainty of the evidence was very low for these outcomes., Authors' Conclusions: Our results show that disulfiram compared to placebo may increase point abstinence. However, disulfiram compared to placebo or no pharmacological treatment may have little or no effect on frequency of cocaine use, amount of cocaine use, continued abstinence, and dropout for any reason. We are unsure if disulfiram has any adverse effects in this population. Caution is required when transferring our results to clinical practice., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Rationale: The prepulse inhibition (PPI) of the startle reflex is the best-established index of sensorimotor gating. We documented that the neurosteroid allopregnanolone (AP) is necessary to reduce PPI in response to D 1 dopamine receptor agonists. Since Sprague-Dawley (SD) rats are poorly sensitive to the PPI-disrupting effects of these drugs, we hypothesized that AP might increase this susceptibility., Objectives: We tested whether AP is sufficient to increase the vulnerability of SD rats to PPI deficits in response to the D 1 receptor full agonist SKF82958., Methods: SD rats were tested for PPI after treatment with SKF82958 (0.05-0.3 mg/kg, SC) in combination with either intraperitoneal (1-10 mg/kg) or intracerebral (0.5 μg/μl/side) AP administration into the medial prefrontal cortex (mPFC) or nucleus accumbens shell. To rule out potential confounds, we measured whether SKF82958 affected the endogenous mPFC levels of AP., Results: SD rats exhibited marked PPI deficits in response to the combination of systemic and intra-mPFC AP with SKF82958 but not with the D 2 receptor agonist quinpirole (0.3-0.6 mg/kg, SC). SKF82958 did not elevate mPFC levels of AP but enhanced the content of its precursor progesterone. The PPI deficits caused by SKF82958 in combination with AP were opposed by the AP antagonist isoallopregnanolone (10 mg/kg, IP) and the glutamate NMDA receptor positive modulator CIQ (5 mg/kg, IP)., Conclusion: These results suggest that AP enables the detrimental effects of D 1 receptor activation on sensorimotor gating. AP antagonism or glutamatergic modulation counters these effects and may have therapeutic potential for neuropsychiatric disorders characterized by gating deficits., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Alcohol and other xenobiotics may limit the therapeutic effects of medications. We aimed at investigating alcohol-medication interactions (AMI) after the exclusion of confounding effects related to other xenobiotics. We performed a systematic review and meta-analysis of controlled studies comparing the effects induced by alcohol versus placebo on pharmacodynamic and/or pharmacokinetic parameters of approved medications. Certainty in the evidence of AMI was assessed when at least 3 independent studies and at least 200 participants were available. We included 107 articles (3097 participants): for diazepam, cannabis, opioids, and methylphenidate, we found significant AMI and enough data to assign the certainty of evidence. Alcohol consumption significantly increases the peak plasma concentration of diazepam (low certainty; almost 290 participants), cannabis (high certainty; almost 650 participants), opioids (low certainty; 560 participants), and methylphenidate (moderate certainty; 290 participants). For most medications, we found some AMI but not enough data to assign them the certainty grades; for some medications, we found no differences between alcohol and placebo in any outcomes evaluated. Our results add further evidence for interactions between alcohol and certain medications after the exclusion of confounding effects related to other xenobiotics. Physicians should advise patients who use these specific medications to avoid alcohol consumption. Further studies with appropriate control groups, enough female participants to investigate sex differences, and elderly population are needed to expand our knowledge in this field. Short phrases suitable for indexing terms., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cannabis is the illicit drug most widely used by pregnant women worldwide. Its growing acceptance and legalization have markedly increased the risks of child psychopathology, including psychotic-like experiences, which lowers the age of onset for a first psychotic episode. As the majority of patients with schizophrenia go through a premorbid condition long before this occurs, understanding neurobiological underpinnings of the prodromal stage of the disease is critical to improving illness trajectories and therapeutic outcomes. We have previously shown that male rat offspring prenatally exposed to Δ 9 -tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), exhibit extensive molecular and synaptic changes in dopaminergic neurons of the ventral tegmental area (VTA), converging on a hyperdopaminergic state. This leads to a silent psychotic-like endophenotype that is unmasked by a single exposure to THC. Here, we further characterized the VTA dopamine neuron and sensorimotor gating functions of PCE rats exposed to acute stress or a challenge of the D2 receptor agonist apomorphine, by using in vivo single-unit extracellular recordings and Prepulse Inhibition (PPI) analyses. At pre-puberty, PCE male rat offspring display a reduced population activity of VTA dopamine neurons in vivo, the majority of which are tonically active. PCE male progeny also exhibit enhanced sensitivity to dopamine D2 (DAD2) receptor activation and a vulnerability to acute stress, which is associated with compromised sensorimotor gating functions. This data extends our knowledge of the multifaceted sequelae imposed by PCE in the mesolimbic dopamine system of male pre-adolescent rats, which renders a neural substrate highly susceptible to subsequent challenges that may trigger psychotic-like outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular, and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase in dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure.

Despite great efforts to warn pregnant women that drugs of abuse impact development of the embryo and the fetus, the use of legal and illegal drugs by childbearing women is still a major public health concern. In parallel with well-established teratogenic effects elicited by some drugs of abuse, epidemiological studies show that certain psychoactive substances do not induce birth defects but lead to subtle neurobehavioral alterations in the offspring that manifest as early as during infancy. Although gender differences in offspring susceptibility have not been fully investigated, a number of longitudinal studies indicate that male and female progeny exposed in utero to drugs of abuse show different vulnerabilities to deleterious effects of these substances in cognitive, executive, and behavioral domains. Here, we briefly review the existing literature focusing on gender differences in the neurobehavioral consequences of maternal exposure to drugs of abuse. Overall, the data strongly indicate that male exposed progeny are more susceptible than female to dysfunctions in cognitive processing and emotional regulation. However, insights into the mechanisms determining this natural phenomenon are not currently available. Our analysis prompts future investigations to implement clinical studies including the influence of gender/sex as a biological variable in the outcome of offspring prenatally exposed to drugs of abuse., (Copyright © 2020 Traccis, Frau and Melis.)

Sleep deprivation (SD) is associated with a broad spectrum of cognitive and behavioural complications, including emotional lability and enhanced stress reactivity, as well as deficits in executive functions, decision making and impulse control. These impairments, which have profound negative consequences on the health and productivity of many individuals, reflect alterations of the prefrontal cortex (PFC) and its connectivity with subcortical regions. However, the molecular underpinnings of these alterations remain elusive. Our group and others have begun examining how the neurobehavioural outcomes of SD may be influenced by neuroactive steroids, a family of molecules deeply implicated in sleep regulation and the stress response. These studies have revealed that, similar to other stressors, acute SD leads to increased synthesis of the neurosteroid allopregnanolone in the PFC. Whereas this up-regulation is likely aimed at counterbalancing the detrimental impact of oxidative stress induced by SD, the increase in prefrontal allopregnanolone levels contributes to deficits in sensorimotor gating and impulse control, signalling a functional impairment of PFC. This scenario suggests that the synthesis of neuroactive steroids during acute SD may be enacted as a neuroprotective response in the PFC; however, such compensation may in turn set off neurobehavioural complications by interfering with the corticolimbic connections responsible for executive functions and emotional regulation., (© 2019 British Society for Neuroendocrinology.)

The increased legal availability of cannabis has led to a common misconception that it is a safe natural remedy for, among others, pregnancy-related ailments such as morning sickness. Emerging clinical evidence, however, indicates that prenatal cannabis exposure (PCE) predisposes offspring to various neuropsychiatric disorders linked to aberrant dopaminergic function. Yet, our knowledge of how cannabis exposure affects the maturation of this neuromodulatory system remains limited. Here, we show that male, but not female, offspring of Δ 9 -tetrahydrocannabinol (THC)-exposed dams, a rat PCE model, exhibit extensive molecular and synaptic changes in dopaminergic neurons of the ventral tegmental area, including altered excitatory-to-inhibitory balance and switched polarity of long-term synaptic plasticity. The resulting hyperdopaminergic state leads to increased behavioral sensitivity to acute THC exposure during pre-adolescence. The neurosteroid pregnenolone, a US Food and Drug Administration (FDA) approved drug, rescues synaptic defects and normalizes dopaminergic activity and behavior in PCE offspring, thus suggesting a therapeutic approach for offspring exposed to cannabis during pregnancy.

Aggressive behavior (AB) is a multifaceted disorder based on the interaction between genetic and environmental factors whose underlying mechanisms remain elusive. The best-characterized gene by environment (GxE) interaction for AB is the relationship between child neglect/abuse and low-activity alleles of the monoamine-oxidase A (MAOA) gene. MAOA oxidizes monoamines like serotonin and dopamine, whose aberrant signaling at discrete developmental ages plays a pivotal role in the ontogeny of AB. Here, we investigated the impact of this GxE on dopamine function at pre-adolescence by exposing hypomorphic MAOA (MAO Neo ) mice to early life stress (ES) and by performing behavioral and ex vivo electrophysiological analyses in the ventral tegmental area (VTA) and the prefrontal cortex (PFC). MAOA Neo ES mouse dopamine neurons exhibited an enhanced post-synaptic responsiveness to excitatory inputs, aberrant plasticity in the PFC, and an AB. Systemic administration of the selective antagonist at dopamine D1 receptors SCH23390 fully restored PFC function and rescued AB. Collectively, these findings reveal that dysfunctional mesocortical dopamine signaling at pre-adolescence ties to AB in the MAOA Neo ES mouse, and identify dopamine D1 receptor as a molecular target to be exploited for an age-tailored therapy. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: The extraction of salient information from the environment is modulated by the activation of dopamine receptors. Using rodent models, we previously reported that gating deficits caused by dopamine receptor activation - as measured by the prepulse inhibition (PPI) of startle - are effectively opposed by inhibitors of the steroidogenic enzyme 5α-reductase (5αR). The specific 5αR isoenzyme and steroids implicated in these effects, however, remain unknown., Methods: The effects of the selective D 1 dopamine receptor agonist SKF-82958 (SKF, 0.3 mg/kg, IP) and D 2 receptor agonist quinpirole (QUIN, 0.5 mg/kg, IP) were tested in the startle reflex and PPI of knockout (KO) mice for either 5αR type 1 (5αR1) or type 2 (5αR2). Furthermore, we established whether these effects may be modified by the 5α-reduced steroids dihydroprogesterone (DHP), allopregnanolone (AP), dihydrotestosterone (DHT), 5α-androstane-3α,17β-diol (3α-diol), or androsterone. To test the mechanisms whereby 5αR products may alter the PPI-disrupting properties of D 1 agonists, we studied the involvement of GABA-A and PXR, two receptors targeted by neuroactive steroids. Specifically, we tested the effects of SKF in combination with the GABA-A antagonist bicuculline, as well as in KO mice for the GABA-A δ subunit and PXR., Results: 5αR1, but not 5αR2, knockout (KO) mice were insensitive to the PPI-disrupting effects of SKF. This sensitivity was reinstated by AP (3 mg/kg, IP), but not other 5α-reduced steroids. The PPI deficits induced by SKF were not modified by bicuculline, δ-subunit KO mice and PXR KO mice., Conclusions: These results collectively suggest that 5αR1 enables the negative effects of D 1 dopamine receptor activation on information processing via production of AP. The contribution of AP to the PPI-disrupting mechanisms of D 1 receptor agonists, however, do not appear to be mediated by either GABA-A or PXR receptors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Although 1-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay therapy for treating Parkinson's disease (PD), its long-term administration is accompanied by the development of motor complications, particularly L-DOPA induced dyskinesia (LID), that dramatically affects patients' quality of life. LID has consistently been related to an excessive dopamine receptor transmission, particularly at the down-stream signaling of the striatal D 1 receptors (D 1 R), resulting in an exaggerated stimulation of cAMP-dependent protein kinase and extracellular signal-regulated kinase (ERK) pathway. We previously reported that pharmacological blockade of 5alpha-reductase (5AR), the rate-limiting enzyme in neurosteroids synthesis, attenuates the severity of a broad set of behavioral alterations induced by D 1 R and D 3 R activation, without inducing extrapyramidal symptoms. In line with this evidence, in a recent study, we found that inhibition of 5AR by finasteride (FIN) produced a significant reduction of dyskinesia induced by L-DOPA and direct dopaminergic agonists in 6-OHDA-lesioned rats. In the attempt to further investigate the effect of 5AR inhibitors on dyskinesia and shed light on the mechanism of action, in the present study we compared the effect of FIN and dutasteride (DUTA), a potent dual 5AR inhibitor, on the development of LID, on the therapeutic efficacy of L-DOPA, on the molecular alterations downstream to the D 1 R, as well as on D 1 R-D 3 R interaction. The results indicated that both FIN and DUTA administration significantly reduced development and expression of LID; however, DUTA appeared more effective than FIN at a lower dose and produced its antidyskinetic effect without impacting the ability of L-DOPA to increase motor activation, or ameliorate forelimb use in parkinsonian rats. Moreover, this study demonstrates for the first time that 5AR inhibitors are able to prevent key events in the appearance of dyskinesia, such as L-DOPA-induced upregulation of striatal D 1 R-related cAMP/PKA/ERK signaling pathways and D 1 R-D 3 R coimmunoprecipitation, an index of heteromer formation. These findings are relevant as they confirm the 5AR enzyme as a potential therapeutic target for treatment of dyskinesia in PD, suggesting the first ever evidence that neurosteroidogenesis may affect functional interaction between dopamine D 1 R and D 3 R., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Sardinia, the second largest Mediterranean island has long been considered a privileged observatory for the study of several medical conditions. The peculiar epidemiology of mood disorders and suicide across Sardinian sub-regions has long intrigued clinicians and researchers., Objective: The principal aim of the present study was to test whether the geographical distribution of suicides committed in Sardinian over the last three decades are comparable with the geographical origin of patients hospitalized up to half a century ago., Method: The distribution of the municipalities of origin of the patients hospitalized in Sardinia between 1901 and 1964 for schizophrenia, bipolar disorder, and depression was reanalyzed and compared with the distribution of municipalities where suicides were committed between 1980 and 2013. Data were also analyzed by the altitude above the sea level and by the population size of the municipalities., Results: There was a significant variation of hospitalization and suicide rates across Sardinian sub-regions. The sub-regions of origin of the patients hospitalized for schizophrenia and bipolar disorder correlated with each other ( P = 0.047). Both hospitalizations and suicides were more incident in municipalities with a higher altitude and a smaller population size. The incidence of hospitalizations and suicides correlated significantly with each other both at the municipality ( P = 1.86 x 10 -7 ) and at the sub-region level ( P = 1.71 x 10 -7 )., Conclusion: The present study confirms the peculiar geographical distribution of major psychoses and suicide in Sardinia. The two phenomena appear to have been correlated for as long as one century.

Mood disorders and circulating thyroid antibodies are very prevalent in the population and their concomitant occurrence may be due to chance. However, thyroid antibodies have been repeatedly hypothesized to play a role in specific forms of mood disorders. Potentially related forms include treatment-refractory cases, severe or atypical depression, and depression at specific phases of a woman's life (early gestation, postpartum depression, perimenopausal). With regard to bipolar disorder, studies of specific subgroups (rapid cycling, mixed, or depressive bipolar) have reported associations with thyroid antibodies. Offspring of bipolar subjects were found more vulnerable to develop thyroid antibodies independently from the vulnerability to develop psychiatric disorders. A twin study suggested thyroid antibodies among possible endophenotypes for bipolar disorder. Severe encephalopathies have been reported in association with Hashimoto's thyroiditis. Cases with pure psychiatric presentation are being reported, the antithyroid antibodies being probably markers of some other autoimmune disorders affecting the brain. Vasculitis resulting in abnormalities in cortical perfusion is one of the possible mechanisms.