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Abstract Steroids exert a profound influence on behavioral reactivity, by modulating the functions of most neurotransmitters and shaping the impact of stress and sex-related variables on neural processes. This background - as well as the observation that most neuroactive steroids (including sex hormones, glucocorticoids and neurosteroids) are synthetized and metabolized by overlapping enzymatic machineries - points to steroidogenic pathways as a powerful source of targets for neuropsychiatric disorders. Inhibitors of steroidogenic enzymes have been developed and approved for a broad range of genitourinary and endocrine dysfunctions, opening to new opportunities to repurpose these drugs for the treatment of mental problems. In line with this idea, preliminary clinical and preclinical results from our group have shown that inhibitors of key steroidogenic enzymes, such as 5α-reductase and 17,20 desmolase-lyase, may have therapeutic efficacy in specific behavioral disorders associated with dopaminergic hyperfunction. While the lack of specificity of these effects raises potential concerns about endocrine adverse events, these initial findings suggest that steroidogenesis modulators with greater brain specificity may hold significant potential for the development of alternative therapies for psychiatric problems. This article is part of the Special Issue entitled 'Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders'. Highlights • Steroids exert profound influence on behavioral regulation. • Neuroactive steroids modulate the effects of stress and sex-related variables. • Steroidogenic pathways may provide novel targets to modulate dopaminergic signaling. • Steroidogenesis inhibitors may hold potential for neuropsychiatric therapy. [ABSTRACT FROM AUTHOR]

Cannabis sativa preparations are the most consumed illicit drugs for recreational purposes worldwide, and the number of people seeking treatment for cannabis use disorder has dramatically increased in the last decades. Due to the recent decriminalization or legalization of cannabis use in the Western Countries, we may predict that the number of people suffering from cannabis use disorder will increase. Despite the increasing number of cannabis studies over the past two decades, we have gaps of scientific knowledge pertaining to the neurobiological consequences of long-term cannabis use. Moreover, no specific treatments for cannabis use disorders are currently available. In this review, we explore new research that may help fill these gaps. We discuss and provide a solution to the experimental limitation of a lack of rodent models of THC self-administration, and the importance this model can play in understanding the neurobiology of relapse and in providing a biological rationale for potential therapeutic targets. We also focus our attention on glial cells, commenting on recent preclinical evidence suggesting that alterations in microglia and astrocytes might contribute to the detrimental effects associated with cannabis abuse. Finally, due to the worrisome prevalence rates of cannabis use during pregnancy, we highlight the associations between cannabis use disorders during pregnancy and congenital disorders, describing the possible neuronal basis of vulnerability at molecular and circuit level. This article is part of the Special Issue entitled “A New Dawn in Cannabinoid Neurobiology”. [ABSTRACT FROM AUTHOR]

Neurosteroids exert diverse modulatory actions on dopamine neurotransmission and signaling. We previously documented that the enzyme 5α-reductase, which catalyzes the main rate-limiting step in neurosteroid synthesis, is required for the behavioral responses of Sprague–Dawley rats to non-selective dopaminergic agonists, such as the D 1 –D 2 receptor agonist apomorphine. Specifically, systemic and intra-accumbal administrations of the 5α-reductase inhibitor finasteride countered apomorphine-induced deficits of sensorimotor gating, as measured by the prepulse inhibition (PPI) of the startle reflex; the classes of dopamine receptors involved in these effects, however, remain unknown. Prior rodent studies have revealed that the contributions of dopamine receptors to PPI regulation vary depending on the genetic background; thus, we analyzed the effect of finasteride on the PPI deficits induced by selective dopamine receptor agonists in Long–Evans (a strain exhibiting PPI deficits in response to both D 1 and D 2 receptor agonists) and Sprague–Dawley rats (which display PPI reductions following treatment with D 2, and D 3 , but not D 1 receptor agonists). In Long–Evans rats, finasteride opposed the PPI deficits induced by activation of D 1, but not D 2 receptors; conversely, in Sprague–Dawley rats, finasteride prevented the reductions in %PPI and accumbal dopamine extracellular levels caused by selective stimulation of D 3, but not D 2 receptors; however, the effects on %PPI were not confirmed by analyses on absolute PPI values. Our findings suggest that 5α-reductase modulates the effects of D 1 , but not D 2 receptor agonists on sensorimotor gating. These data may help elucidate the role of neurosteroids in neuropsychiatric disorders featuring PPI deficits, including schizophrenia and Tourette syndrome. [ABSTRACT FROM AUTHOR]

Neurochemical, electrophysiological and behavioral evidence indicate that the potent α 2 -adrenoceptor antagonist RS 79948 is also a dopamine (DA) D 2 receptor antagonist. Thus, results from ligand binding and adenylate cyclase activity indicate that RS 79948 binds to D 2 receptors and antagonized D 2 receptor-mediated inhibition of cAMP synthesis at nanomolar concentrations. Results from microdialysis indicated that RS 79948 shared with the selective α 2 -adrenergic antagonist atipamezole the ability to increase the co-release of DA and norepinephrine (NE) from noradrenergic terminals in the medial prefrontal cortex (mPFC), except that RS 79948-induced DA release persisted after noradrenergic denervation, unlike atipamezole effect, indicating that RS 79948 releases DA from dopaminergic terminals as well. Similarly to the D 2 antagonist raclopride, but unlike atipamezole, RS 79948 increased extracellular DA and DOPAC in the caudate nucleus. Electrophysiological results indicate that RS 79948 shared with raclopride the ability to activate the firing of ventral tegmental area (VTA) DA neurons, while atipamezole was ineffective. Results from behavioral studies indicated that RS 79948 exerted effects mediated by independent, cooperative and contrasting inhibition of α 2 -and D 2 receptors. Thus, RS 79948, but not atipamezole, prevented D 2 -autoreceptor mediated hypomotility produced by a small dose of quinpirole. RS 79948 potentiated, more effectively than atipamezole, quinpirole-induced motor stimulation. RS 79948 antagonized, less effectively than atipamezole, raclopride-induced catalepsy. Future studies should clarify if the dual α 2 -adrenoceptor- and D 2 -receptor antagonistic action might endow RS 79948 with potential therapeutic relevance in the treatment of schizophrenia, drug dependence, depression and Parkinson's disease. • RS 79948 is not only an α 2 -adrenergic- but also a dopamine D 2 -receptor antagonist. • These two properties result in opposite actions on dopaminergic function. • The simultaneous α 2 -and D 2 antagonism, peculiar of atypical antipsychotics, might be of interest for psychiatric disorders. [ABSTRACT FROM AUTHOR]

Summary: Cogent evidence points to the involvement of neurosteroids in the regulation of dopamine (DA) neurotransmission and signaling, yet the neurobiological bases of this link remain poorly understood. We previously showed that inhibition of 5α-reductase (5αR), a key neurosteroidogenic enzyme, attenuates the sensorimotor gating deficits induced by DA receptor activation, as measured by the prepulse inhibition (PPI) of the acoustic startle reflex. To extend these findings, the present study was aimed at the assessment of the role of other key neurosteroidogenic enzymes in PPI, such as 17α-hydroxylase/C17,20 lyase (CYP17A1), 3α- and 3β-hydroxysteroid dehydrogenase (HSD), in Sprague-Dawley rats. The PPI deficits induced by the DAergic non-selective agonist apomorphine (APO, 0.25mg/kg, SC) were dose-dependently attenuated by the selective CYP17A1 inhibitor abiraterone (ABI, 10–50mg/kg, IP) in a fashion akin to that of the 5αR inhibitor finasteride (FIN, 100mg/kg, IP). These systemic effects were reproduced by intracerebroventricular injection of ABI (1μg/1μl), suggesting the involvement of brain CYP17A1 in PPI regulation. Conversely, the PPI disruption induced by APO was not significantly affected by the 3α- and 3β-HSD inhibitors indomethacin and trilostane. Given that CYP17A1 catalyzes androgen synthesis, we also tested the impact on PPI of the androgen receptor (AR) antagonist flutamide (10mg/kg, IP). However, this agent failed to reverse APO-induced PPI deficits; furthermore, AR endogenous ligands testosterone and dihydrotestosterone failed to disrupt PPI. Collectively, these data highlight CYP17A1 as a novel target for antipsychotic-like action, and suggest that the DAergic regulation of PPI is modulated by androgenic neurosteroids, through AR-unrelated mechanisms. [Copyright &y& Elsevier]

Abstract: The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts a multifaceted function in the modulation of information processing, through the activation of multiple receptor families. In particular, stimulation of 5-HT1A and 5-HT2A receptors leads to sensorimotor gating impairments and perceptual perturbations. Previous evidence has shown that chronic deprivation of l-tryptophan (TRP), the precursor of 5-HT, results in marked reductions of 5-HT brain levels, as well as neuroplastic alterations in 5-HT1A and 5-HT2A expression and/or signaling. Building on these premises, in the present study we tested whether a prolonged TRP deprivation may differentially impact the roles of these receptors in the regulation of the prepulse inhibition (PPI) of the acoustic startle reflex, a dependable index of gating. Male Sprague-Dawley rats were fed for 14 days with either a regimen with negligible TRP content (TR−) or the same diet supplemented of TRP (TR+). At the end of this schedule, rats were treated with the prototypical 5-HT1A receptor agonist 8-OH-DPAT (62.5–250μg/kg, subcutaneous, s.c.) or the 5-HT2 receptor agonist DOI (0.25–1mg/kg, s.c.). Notably, the PPI deficits induced by 8-OH-DPAT in TR− rats were significantly milder than those observed in their TR+ counterparts; these effects were fully prevented by the 5-HT1A antagonist WAY-100135 (10mg/kg, intraperitoneal). Conversely, TRP deprivation did not affect the PPI-disrupting properties of DOI. These findings suggest that prolonged 5-HT depletion attenuates the influence of 5-HT1A, but not 5-HT2 receptors on sensorimotor gating, confirming the distinct mechanisms of these two targets in PPI regulation. [Copyright &y& Elsevier]

Summary: Converging lines of evidence point to the involvement of neurosteroids in the regulation of dopamine (DA) neurotransmission and signaling, yet the neurobiological bases of this link remain poorly understood. We previously showed that inhibition of steroid 5α-reductase (5αR), the key rate-limiting enzyme in neurosteroidogenesis, attenuates the behavioral effects of non-selective DA receptor agonists in rats, including stereotyped responses and sensorimotor gating deficits, as measured by the prepulse inhibition (PPI) of the acoustic startle reflex. Since previous findings suggested that the role of DA D1- and D2-like receptor families in behavioral regulation may exhibit broad interspecies and interstrain variations, we assessed the impact of 5αR blockade on the behavioral effects of DAergic agonists in C57BL/6 mice. The prototypical 5αR inhibitor finasteride (FIN; 25–50mg/kg, intraperitoneally, IP) dose-dependently countered the PPI deficits and the enhancement of rearing responses induced by the full D1-like receptor agonist SKF-82958 (0.3mg/kg, IP); however, FIN did not significantly affect the hyperlocomotive and startle-attenuating effects of SKF-82958. Whereas the D2-like receptor agonist quinpirole (QUIN; 0.5mg/kg, IP) did not induce significant changes in PPI, the combination of this agent and FIN surprisingly produced marked gating and startle deficits. In contrast with previous data on rats, FIN did not affect the reductions of startle reflex and PPI produced by the non-selective DAergic agonist apomorphine (APO; 0.5mg/kg, IP). These findings collectively indicate that, in C57BL/6 mice, 5αR differentially modulates the effects of D1- and D2-like receptor agonists in behavioral regulation. [ABSTRACT FROM AUTHOR]

Summary: Cogent evidence highlights a key role of neurosteroids and androgens in schizophrenia. We recently reported that inhibition of steroid 5α-reductase (5αR), the rate-limiting enzyme in neurosteroid synthesis and androgen metabolism, elicits antipsychotic-like effects in humans and animal models, without inducing extrapyramidal side effects. To elucidate the anatomical substrates mediating these effects, we investigated the contribution of peripheral and neural structures to the behavioral effects of the 5αR inhibitor finasteride (FIN) on the prepulse inhibition (PPI) of the acoustic startle reflex (ASR), a rat paradigm that dependably simulates the sensorimotor gating impairments observed in schizophrenia and other neuropsychiatric disorders. The potential effect of drug-induced ASR modifications on PPI was excluded by measuring this index both as percent (%PPI) and absolute values (ΔPPI). In both orchidectomized and sham-operated rats, FIN prevented the %PPI deficits induced by the dopamine (DA) receptor agonists apomorphine (APO, 0.25mg/kg, SC) and d-amphetamine (AMPH, 2.5mg/kg, SC), although the latter effect was not corroborated by ΔPPI analysis. Conversely, APO-induced PPI deficits were countered by FIN infusions in the brain ventricles (10μg/1μl) and in the nucleus accumbens (NAc) shell and core (0.5μg/0.5μl/side). No significant PPI-ameliorating effect was observed following FIN injections in other brain regions, including dorsal caudate, basolateral amygdala, ventral hippocampus and medial prefrontal cortex, although a statistical trend was observed for the latter region. The efflux of DA in NAc was increased by systemic, but not intracerebral FIN administration. Taken together, these findings suggest that the role of 5αR in gating regulation is based on post-synaptic mechanisms in the NAc, and is not directly related to alterations in DA efflux in this region. [Copyright &y& Elsevier]

Abstract: Cannabis is the most common secondary illicit substance in methamphetamine (METH) users, yet the outcomes of the concurrent consumption of both substances remain elusive. Capitalizing on recent findings on the implication of CB1 cannabinoid receptors in the behavioral effects of METH, we hypothesized that METH-induced neurotoxicity may alter the brain expression of CB1, thereby affecting its role in behavioral functions. To test this possibility, we subjected rats to a well-characterized model of METH neurotoxicity (4 mg/kg, subcutaneous × 4 injections, 2 h apart), and analyzed their CB1 receptor brain expression three weeks later. METH exposure resulted in significant enhancements of CB1 receptor expression across several brain regions, including prefrontal cortex, caudate-putamen, basolateral amygdala, CA1 hippocampal region and perirhinal cortex. In parallel, a different group of METH-exposed rats was used to explore the responsiveness to the potent cannabinoid agonist WIN 55,212–2 (WIN) (0.5–1 mg/kg, intraperitoneal), within several paradigms for the assessment of emotional and cognitive functions, such as open field, object exploration and recognition, and startle reflex. WIN induced anxiolytic-like effects in METH-exposed rats and anxiogenic-like effects in saline-treated controls. Furthermore, METH-exposed animals exhibited a significantly lower impact of WIN on the attenuation of exploratory behaviors and short-term (90 min) recognition memory. Conversely, METH neurotoxicity did not significantly affect WIN-induced reductions in locomotor activity, exploration time and acoustic startle. These results suggest that METH neurotoxicity may alter the vulnerability to select behavioral effects of cannabis, by inducing distinct regional variations in the expression of CB1 receptors. [ABSTRACT FROM AUTHOR]

Abstract: Rich evidence has highlighted that stimulation of γ-amino-butyric acid (GABA)B receptors increases the occurrence of spike-and-wave discharges (SWDs), the electroencephalographic (EEG) landmark of absence epilepsy (AE). Recent findings suggest that the outcomes of GABAB activation in vivo are contingent on the chemical characteristics of the agonist. In particular, the endogenous ligand γ-hydroxybutyrate (GHB) and its precursor γ-butyro-lactone (GBL) have been shown to elicit different effects than the prototypical GABAB agonist baclofen. In view of these premises, the present study was aimed at the characterization of the effects of baclofen (0.5–10mg/kg, i.p.) and GBL (5–100mg/kg, i.p.) on the spontaneous SWDs and locomotor activity of DBA/2J mice. While both baclofen and GBL dose-dependently increased SWDs episodes, high doses of the latter (100mg/kg, i.p.) reduced the occurrence of these phenomena and increased the number of isolated spikes. Interestingly, both compounds elicited a dose-dependent reduction of locomotor activity, in comparison with their vehicle-treated controls. The GABAB selective antagonist, SCH50911 (50mg/kg, i.p.), reversed the changes in SWD occurrence and locomotion induced by baclofen and GBL, but failed to elicit intrinsic effects on either paradigm. These results indicate that GABAB receptor signaling might exert differential effects on SWDs in DBA/2J mice. [Copyright &y& Elsevier]

Abstract: Clinical evidence suggests that prenatal exposure to cannabis may be conducive to long-term neurobehavioral impairments in executive and attentional domains. Such sensorimotor alterations might be related to disorders in gating functions. Hence, the present study was undertaken to assess the effects of long-term prenatal exposure to WIN 55,212-2, a potent cannabinoid receptor agonist, on prepulse inhibition of the acoustic startle reflex, a well-validated paradigm to test sensorimotor gating. In utero exposure to WIN 55,212-2 (0.5, 1 mg/kg, from day 5 to 20 of gestation) failed to alter startle magnitude in rats in comparison with controls. Similarly, prepulse inhibition of the startle was not significantly affected by such treatment, regardless of the age when behavioral testing was carried out (40, 60 or 80 days). Interestingly, prenatal treatment with WIN 55,212-2 (0.5 mg/kg, from day 5 to 20 of gestation) induced no differences in the prepulse inhibition-disrupting effects of apomorphine (0.125, 0.25 mg/kg, s.c.) and dizocilpine (0.05, 0.1 mg/kg, s.c.), suggesting that a prenatal exposure to a cannabinoid receptor agonist is likely unable to affect sensitivity of sensorimotor gating substrates to dopaminergic agonists and NMDA receptor antagonists. Our results show that prenatal exposure to cannabis does not affect reflex reactivity to environmental stimuli, ruling out that the observed impairments in executive functions are to refer to sensorimotor gating alterations. [Copyright &y& Elsevier]

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 (MAONeo) 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). MAOANeo 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 MAOANeo 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'. • Early stress biases dopamine function and elicits aggression in MAOANeo mice. • Preadolescence is a critical developmental milestone for ontogeny of aggressiveness. • DA-D1 receptor as a molecular target for early intervention in aggressive behavior. [ABSTRACT FROM AUTHOR]

Imbalances in dopamine activity significantly contribute to the pathophysiology of several neuropsychiatric disorders, including addiction, ADHD, schizophrenia, impulse control disorders, and Parkinson's Disease. Neuro(active)steroids, comprising endogenous steroids that finely modulate neuronal activity, are considered crucial regulators of brain function and behavior, with implications in various physiological processes and pathological conditions. Specifically, subclasses of Neuro(active)steroids belonging to the 5 α reductase pathway are prominently involved in brain disorders characterized by dopaminergic signaling imbalances. This review highlights the neuromodulatory effects of Neuro(active)steroids on the dopamine system and related aberrant behavioral phenotypes. We critically appraise the role of pregnenolone, progesterone, and allopregnanolone on dopamine signaling. Additionally, we discuss the impact of pharmacological interventions targeting 5 α reductase activity in neuropsychiatric conditions characterized by excessive activation of the dopaminergic system, ranging from psychotic (endo)phenotypes and motor complications to decision-making problems and addiction. • Neuro(active)steroids modulate dopamine system. • Neuro(active) steroids contribute to the pathophysiology of dopamine-dependent disorders. • 5αR-neuro(active)steroids rescue hyperdopaminergic phenotypes. [ABSTRACT FROM AUTHOR]

On the basis of between subjects monitoring of in vivo dopamine (DA) transmission in the rat nucleus accumbens (NAc) shell and core during response-contingent and non-contingent sucrose feeding we have hypothesized that long term, daily exposure to sucrose feeding results in the acquisition of conditioned/discriminative stimuli capable of activating accumbens shell DA transmission in a non-habituating fashion. In order to verify this hypothesis we have now monitored within the same subject the changes in accumbens shell and core DA during acquisition of fixed ratio 1 (FR1) nose-poking for sucrose pellets. Once full training was obtained, dialysate DA was monitored in the same rat on three different sessions: responding for sucrose, extinction and non-contingent sucrose presentation. Dialysate DA steadily increased in the shell during operant sessions as training progressed but was activated in the core only early and transiently in training (5th session). After full training, reinforced as well as non-reinforced responding for sucrose activated DA selectively in the NAc shell. Non-contingent sucrose feeding activated DA in the shell and in the core. No habituation of shell DA responsiveness was observed under contingent and non-contingent sucrose feeding. These observations are consistent with the hypothesis that learning of FR1 nose-poking for sucrose involves acquisition of conditioned activation of DA transmission in the shell and active suppression in the core and that loss of habituation of shell DA responsiveness is related to change from primary-rewarding to conditioned/discriminative as driving stimuli of DA transmission in this area. [ABSTRACT FROM AUTHOR]

Background: Compelling evidence indicates that kappa opioid receptor (KOR) agonists produce perceptual distortions in animals and humans, yet the mechanism of action and clinical relevance of such effects remain unclear. Since abnormalities in preattentional functions and informational processing are hypothesized to underlie psychotic disorders, the present study has been designed to assess the role of KOR on sensorimotor gating. Methods: The effects of the selective KOR agonist U50488 were evaluated on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle reflex (ASR). Results: U50488 (1.25, 2.5, and 5 mg/kg, subcutaneous [SC]) induced a dose-dependent reduction of PPI, which was efficiently prevented by the selective KOR antagonist norbinaltorphimine (nor-BNI, 10 mg/kg, SC), as well as by the atypical antipsychotic clozapine (5, 8 mg/kg, intraperitoneal [IP]) but not by the typical antipsychotic haloperidol (.1, .5 mg/kg, IP). Conversely, nor-BNI (10 mg/kg, SC) failed to reverse the PPI disruption mediated by both apomorphine (.25 mg/kg, SC) and dizocilpine (.1 mg/kg, SC). Conclusions: Our results support a pivotal role of KOR in the regulation of preattentional functions and sensorimotor gating, pointing to these receptors as a possible neurobiological substrate especially relevant to the clusters of psychosis unresponsive to typical antipsychotics. [Copyright &y& Elsevier]

Vulnerability to cocaine use disorder depends upon a combination of genetic and environmental risk factors. While early life adversity is a critical environmental vulnerability factor for drug misuse, allelic variants of the monoamine oxidase A (MAOA) gene have been shown to moderate its influence on the risk of drug-related problems. However, data on the interactions between MAOA variants and early life stress (ES) with respect to predisposition to cocaine abuse are limited. Here, we show that a mouse model capturing the interaction of genetic (low-activity alleles of the Maoa gene; MAOA Neo ) and environmental (i.e., ES) vulnerability factors displays an increased sensitivity to repeated in vivo cocaine psychomotor stimulant actions associated with a reduction of GABAA receptor-mediated inhibition of dopamine neurons of the ventral tegmental area (VTA). Depolarization-induced suppression of inhibition (DSI), a 2-arachidonoylglycerol (2AG)-dependent form of short-term plasticity, also becomes readily expressed by dopamine neurons from male MAOA Neo ES mice repeatedly treated with cocaine. The activation of either dopamine D2 or CB1 receptors contributes to cocaine-induced DSI expression, decreased GABA synaptic efficacy, and hyperlocomotion. Next, in vivo pharmacological enhancement of 2AG signaling during repeated cocaine exposure occludes its actions both in vivo and ex vivo. This data extends our knowledge of the multifaceted sequelae imposed by this gene-environment interaction in VTA dopamine neurons of male pre-adolescent mice and contributes to our understanding of neural mechanisms of vulnerability for early onset cocaine use. • Gene by environment interaction is a risk factor to vulnerability to drug abuse (80). • MAOA Neo ES pre-adolescent male mice show an enhanced psychostimulant response to cocaine (89). • Repeated cocaine reduces synaptic inhibition to dopamine neurons in MAOA Neo ES pre-adolescent male mice (104). • Dopamine and 2AG are involved in cocaine-induced motor and synaptic effects (75). [ABSTRACT FROM AUTHOR]

Summary: The enzyme 5α-reductase (5αR) catalyzes the conversion of testosterone and other Δ4 -3-ketosteroids into their 5α-reduced metabolites. Of the five members of the 5αR family, the type 2 enzyme (5αR2) plays a key role in androgen metabolism, and is abundantly distributed in the urogenital system. Although 5αR2 has been reported to be highly expressed in the brain during early developmental stages, little is currently known on its anatomical and cellular distribution in the adult brain. Thus, the present study was designed to determine the detailed localization of 5αR2 in the adult rat brain, using a highly specific polyclonal antibody against this isoform. Parasagittal and coronal sections revealed 5αR2 immunoreactivity throughout most brain regions, with strong immunolabeling in the layers III and VI of the prefrontal and somatosensory cortex, olfactory bulb, thalamic nuclei, CA3 field of hippocampus, basolateral amygdala and Purkinje cell layer of cerebellum. Lower 5αR2 levels were detected in the hypothalamus and midbrain. Moreover, double labeling fluorescence with confocal laser scanning microscopy (CLSM) revealed that 5αR2 is localized in neurons, but not in glial cells. Specifically, the enzyme was documented in the pyramidal neurons of the cortex by CLSM analysis of simultaneous Golgi-Cox and immunofluorescent staining. Finally, low levels of 5αR2 expression were identified in GABAergic cells across the cortex, hippocampus and striatum. These findings show that, in the adult brain, 5αR2 is distributed in critical regions for behavioral regulation, suggesting that the functional role of this isoform is present throughout the entire lifespan of the individual. [ABSTRACT FROM AUTHOR]

Abstract: Isolation rearing (IR), a well-established rat model of early chronic psychosocial stress, engenders marked behavioral alterations related to changes of dopamine (DA) neurotransmission in cortical and subcortical brain regions. Stress-induced shifts in γ-aminobutyric acid (GABA)-ergic signaling have been implicated in the dysregulation of DA release. The neurosteroid 3α-hydroxy-5α-pregnan-20-one (allopregnanolone/AP), synthesized from progesterone by the action of the rate-limiting enzyme 5α-reductase (5AR), is a potent positive allosteric modulator of GABAA receptor function. Thus, alterations of 5AR activity/expression may impact upon DA neurotransmission. We studied the effects of IR on the 5AR expression/function and extracellular concentrations of DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC). Immediately after weaning, male rats were subjected to either IR or social rearing (SR) conditions for 5–8 weeks. Compared to SR, IR rats exhibited significantly lower protein expression of 5AR isoforms (1 and 2) in both brain regions and reduced brain, but not plasma, content of AP and allotetrahydrodeoxycorticosterone, the 5α-reduced metabolite of deoxycorticosterone. IR-exposed rats also exhibited higher levels of DA and DOPAC in the NAcc shell, but not in mPFC, when compared to SR rats. The 5AR inhibitor finasteride (FIN, 100mg/kg, i.p.) enhanced DA and DOPAC content in the NAcc shell of SR, but not IR rats. FIN, however, elicited equivalent increases in DA and DOPAC levels in the mPFC of both groups. These results show that IR induces changes in expression/activity of brain 5AR which, in a brain-region specific manner, may partially underlie the alterations in DA signaling induced by this manipulation. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’. [Copyright &y& Elsevier]

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 Δ9-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. • Prenatal THC induces an aberrant dopaminergic function in vivo. • PCE male offspring manifest a DAD2 receptor sensitivity. • PCE male progeny display maladptive responses to an acute unescapable stress. [ABSTRACT FROM AUTHOR]

The ontogeny of antisocial behavior (ASB) is rooted in complex gene-environment (G×E) interactions. The best-characterized of these interplays occurs between: a) low-activity alleles of the gene encoding monoamine oxidase A (MAOA), the main serotonin-degrading enzyme; and b) child maltreatment. The purpose of this study was to develop the first animal model of this G×E interaction, to help understand the neurobiological mechanisms of ASB and identify novel targets for its therapy. Maoa hypomorphic transgenic mice were exposed to an early-life stress regimen consisting of maternal separation and daily intraperitoneal saline injections and were then compared with their wild-type and non-stressed controls for ASB-related neurobehavioral phenotypes. Maoa hypomorphic mice subjected to stress from postnatal day (PND) 1 through 7 – but not during the second postnatal week - developed overt aggression, social deficits and abnormal stress responses from the fourth week onwards. On PND 8, these mice exhibited low resting heart rate - a well-established premorbid sign of ASB – and a significant and selective up-regulation of serotonin 5-HT 2A receptors in the prefrontal cortex. Notably, both aggression and neonatal bradycardia were rescued by the 5-HT 2 receptor antagonist ketanserin (1–3 mg kg−1, IP), as well as the selective 5-HT 2A receptor blocker MDL-100,907 (volinanserin, 0.1–0.3 mg kg−1, IP) throughout the first postnatal week. These findings provide the first evidence of a molecular basis of G×E interactions in ASB and point to early-life 5-HT 2A receptor activation as a key mechanism for the ontogeny of this condition. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'. • Antisocial behavior (ASB) is predisposed by gene x environment interactions (GEIs). • The best-known GEI occurs between low-activity MAOA alleles and child maltreatment. • We developed the first mouse model of this GEI and studied its underlying mechanism. • MAOA-hypomorphic mice subjected to early-life stress develop ASB-related phenotypes. • Our data suggest that this GEI is mediated by 5-HT2A receptors. [ABSTRACT FROM AUTHOR]