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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 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.

More importantly, these early-life exposures shape the pathophysiological trajectory of major psychiatric disorders in a sex-dependent manner, underscoring the prominent role of sex hormones in the interplay between early-life events and mental health. [...]to achieve a profound understanding of the biological basis of psychiatric diseases and to pave the way for the development of effective prevention and intervention strategies, it is imperative to consider the contributions of sex and environmental factors in both clinical investigations and experimental models. [...]VPA treatment decreased the number of AVPV TH positive cells in males only and elicited a lower quality of parental behavior in males than females. Importantly, a protective effect of communal nesting was observed on both the sensorimotor gating deficit and compulsive burying behavior, with significant differences between males and females.

More and more scientists are now systemically including sex-related variables in experimental studies to unravel the influence of sex (and its hormonal components) on the development of psychiatric diseases. [...]we implemented animal models based on etiological validities (homologies between the etiologies in the animal model and the psychiatric condition) and “multiple hits” hypotheses, where stress, prenatal exposure to drugs of abuse and infections were the most-used environmental risk factors able to unveil a psychopathological phenotype. Unique sex-specific vulnerabilities have also been detected in the consequences of prenatal drug exposure on the brain and behavior of newborns during infancy, adolescence, and adulthood. [...]as the second contribution of this collection, the mini-review by Sikic et al. revisits clinical and pre-clinical studies on prenatal nicotine exposure (PNE) and discusses the modulating role of sex in the manifestation of PNE-related outcomes. Since the methodology used in the different studies resulted in outcomes that were too inconsistent to define the role of sex in this context, the authors recommended the inclusion of sex as a discriminating factor in PNE research along with the increased use of vapor exposure models in preclinical research to more accurately model the parameters of human nicotine intake. By combining behavioral and electrophysiological characterization of the dopamine system in the MIA model across generations, the authors showed that maternal infections during pregnancy in female rats of the first (F0) generation influence in a sex-dependent manner the dopamine system integrity not only in their offspring (F1) but also in the F2 progeny, confirming that MIA influences the neurodevelopmental trajectories in the dopamine function across generations.

Ethanol, like other substances of abuse, preferentially increases dopamine (DA) transmission in the rat nucleus accumbens (NAc) following passive administration. It remains unclear, however, whether ethanol also increases NAc DA transmission following operant oral self-administration (SA). The NAc is made-up of a ventro-medial compartment, the shell and a dorso-lateral one, the core, where DA transmission responds differentially following exposure to drugs of abuse. Previous studies from our laboratory investigated changes in dialysate DA in the NAc shell and core of rats responding for sucrose pellets and for drugs of abuse. As a follow up to these studies, we recently investigated the changes in NAc shell and core DA transmission associated to oral SA of a 10% ethanol solution. For the purpose of comparison with literature studies utilizing sucrose + ethanol solutions, we also investigated the changes in dialysate DA associated to SA of 20% sucrose and 10% ethanol + 20% sucrose solutions. Rats were trained to acquire oral SA of the solutions under a Fixed Ratio 1 (FR1) schedule of nose-poking. After training, rats were monitored by microdialysis on three consecutive days under response contingent (active), reward omission (extinction trial) and response non-contingent (passive) presentation of ethanol, sucrose or ethanol + sucrose solutions. Active and passive ethanol administration produced a similar increase in dialysate DA in the two NAc subdivisions, while under extinction trial DA increased preferentially in the shell compared to the core. Conversely, under sucrose SA and extinction DA increased exclusively in the shell. These observations provide unequivocal evidence that oral SA of 10% ethanol increases dialysate DA in the NAc, and also suggest that stimuli conditioned to ethanol exposure contribute to the increase of dialysate DA observed in the NAc following ethanol SA. Comparison between the pattern of DA changes detected in the NAc subdivisions under sucrose and ethanol SA likewise suggests that the NAc shell and core DA play different roles in sucrose as compared to ethanol reinforcement.

The enzyme monoamine oxidase A (MAOA) catalyzes the degradation of several neurotransmitters, including serotonin. A large body of evidence has shown that genetic MAOA deficiency predisposes humans and mice to aggression and antisocial behavior. We previously documented that the aggression of male MAOA-deficient mice is contributed by serotonin 5-HT2 and glutamate N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC). Indeed, blocking either receptor reduces the aggression of MAOA knockout (KO) mice; however, 5-HT2 receptor antagonists, such as ketanserin (KET), reduce locomotor activity, while NMDA receptor blockers are typically associated with psychotomimetic properties. To verify whether NMDA receptor blockers induce psychotomimetic effects in MAOA KO mice, here we tested the effects of these compounds on prepulse inhibition (PPI) of the acoustic startle reflex. We found that male MAOA KO mice are hypersensitive to the PPI-disrupting properties of NMDA receptor antagonists, including the non-competitive antagonist dizocilpine (DIZ; 0.1, 0.3 mg/kg, IP) and the NR2B subunit-specific blocker Ro-256981 (5, 10 mg/kg, IP). Since KET has been previously shown to counter the PPI deficits caused by NMDA receptor antagonists, we tested the behavioral effects of the combination of KET (2 mg/kg, IP) and these drugs. Our results show that the combination of KET and DIZ potently reduces aggression in MAOA KO mice without any PPI deficits and sedative effects. While the PPI-ameliorative properties of KET were also observed after infusion in the medial PFC (0.05 μg/side), KET did not counter the PPI-disruptive effects of Ro-256981 in MAOA KO mice. Taken together, these results point to the combination of non-subunit-selective NMDA and 5-HT2 receptor antagonists as a potential therapeutic approach for aggression and antisocial behavior with a better safety and tolerability profile than each monotherapy.

Early social isolation (ESI) disrupts neurodevelopmental processes, potentially leading to longlasting emotional and cognitive changes in adulthood. Communal nesting (CN), i.e., the sharing of parental responsibilities between multiple individuals in a nest, creates a socially enriching environment known to impact social and anxiety-related behaviors. This study examines the effects of (i) the CN condition and of (ii) ESI during the 3 rd week of life (i.e., pre-weaning ESI) on motor, cognitive, and emotional domains during adolescence and adulthood in male and female rats reared in the two different housing conditions, as well as (iii) the potential of CN to mitigate the impact of ESI on offspring. We found that in a spontaneous locomotor activity test, females exhibited higher activity levels compared to males. In female groups, adolescents reared in standard housing (SH) condition spent less time in the center of the arena, suggestive of increased anxiety levels, while the CN condition increased the time spent in the center during adolescence, but not adulthood, independently from ESI. The prepulse inhibition (PPI) test showed a reduced PPI in ESI adolescent animals of both sexes and in adult males (but not in adult females), with CN restoring PPI in males, but not in adolescent females. Further, in the marble burying test SH-ESI adolescent males exhibited more marble burials than all other groups, suggestive of obsessive-compulsive traits. CN completely reversed this stress-induced effect. Interestingly, ESI and CN did not have a significant impact on burying behavior in adult animals of both sexes. Overall, our findings (i) assesses the effects of ESI on locomotion, sensorimotor gating, and compulsive-like behaviors, (ii) reveal distinct vulnerabilities of males and females within these domains, and (iii) show how early-life social enrichment may successfully counteract some of the behavioral alterations induced by earlylife social stress in a sex-dependent manner. This study strengthens the notion that social experiences during early-life can shape emotional and cognitive outcomes in adulthood, and points to the importance of social enrichment interventions for mitigating the negative effects of early social stress on neurodevelopment.

Abnormal consumption of ethanol, the ingredient responsible for alcoholic drinks’ addictive liability, causes millions of deaths yearly. Ethanol’s addictive potential is triggered through activation, by a still unknown mechanism, of the mesolimbic dopamine (DA) system, part of a key motivation circuit, DA neurons in the posterior ventral tegmental area (pVTA) projecting to the ipsilateral nucleus accumbens shell (AcbSh). The present in vivo brain microdialysis study, in dually-implanted rats with one probe in the pVTA and another in the ipsilateral or contralateral AcbSh, demonstrates this mechanism. As a consequence of the oral administration of a pharmacologically relevant dose of ethanol, we simultaneously detect a) in the pVTA, a substance, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), untraceable under control conditions, product of condensation between DA and ethanol’s first by-product, acetaldehyde; and b) in the AcbSh, a significant increase of DA release. Moreover, such newly generated salsolinol in the pVTA is responsible for increasing AcbSh DA release via μ opioid receptor (μOR) stimulation. In fact, inhibition of salsolinol’s generation in the pVTA or blockade of pVTA μORs prevents ethanol-increased ipsilateral, but not contralateral, AcbSh DA release. This evidence discloses the long-sought key mechanism of ethanol’s addictive potential and suggests the grounds for developing preventive and therapeutic strategies against abnormal consumption.

Background:In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia.Methods:Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in ventral tegmental area were studied by in vivo electrophysiology.Results:Polyriboinosinic-polyribocytidilic acid-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory, and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In polyriboinosinic-polyribocytidilic acid rats, dopamine neurons showed reduced spontaneously firing rate and population activity.Conclusions:These results confirm that maternal immune activation severely impairs dopamine system and that the polyriboinosinic-polyribocytidilic acid model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human pathology.

The endocannabinoids anandamide and 2-arachidonoyglycerol (2-AG) may contribute to the regulation of mood and emotion. In this study, we investigated the impact of the endocannabinoid transport inhibitor AM404 on three rat models of anxiety: elevated plus maze, defensive withdrawal and separation-induced ultrasonic vocalizations. AM404 (1-5 mg kg(-1), intraperitoneal (i.p.)) exerted dose-dependent anxiolytic-like effects in the three models. These behavioral effects were associated with increased levels of anandamide, but not 2-AG, in the prefrontal cortex and were prevented by the CB(1) cannabinoid antagonist rimonabant (SR141716A), suggesting that they were dependent on anandamide-mediated activation of CB(1) cannabinoid receptors. We also evaluated whether AM404 might influence motivation (in the conditioned place preference (CPP) test), sensory reactivity (acoustic startle reflex) and sensorimotor gating (prepulse inhibition (PPI) of the startle reflex). In the CPP test, AM404 (1.25-10 mg kg(-1), i.p.) elicited rewarding effects in rats housed under enriched conditions, but not in rats kept in standard cages. Moreover, AM404 did not alter reactivity to sensory stimuli or cause overt perceptual distortion, as suggested by its lack of effect on startle or PPI of startle. These results support a role of anandamide in the regulation of emotion and point to the anandamide transport system as a potential target for anxiolytic drugs.

Morphine- and ethanol-induced stimulation of neuronal firing of ventral tegmental area (VTA) dopaminergic neurons and of dopamine (DA) transmission in the shell of the nucleus accumbens (AcbSh) represents a crucial electrophysiological and neurochemical response underlying the ability of these compounds to elicit motivated behaviors and trigger a cascade of plasticity-related biochemical events. Previous studies indicate that the standardized methanolic extract of roots (WSE) prevents morphine- and ethanol-elicited conditioned place preference and oral ethanol self-administration. Aim of the present research was to investigate whether WSE may also interfere with the ability of morphine and ethanol to stimulate VTA dopaminergic neurons and thus AcbSh DA transmission as assessed in male Sprague-Dawley rats by means of patch-clamp recordings in mesencephalic slices and brain microdialysis, respectively. Morphine and ethanol significantly stimulated spontaneous firing rate of VTA neurons and DA transmission in the AcbSh. WSE, at concentrations (200-400 μg/ml) that significantly reduce spontaneous neuronal firing of VTA DA neurons via a GABA - but not GABA -mediated mechanism, suppressed the stimulatory actions of both morphine and ethanol. Moreover, administration of WSE at a dose (75 mg/kg) that fails to affect basal DA transmission, significantly prevented both morphine- and ethanol-elicited increases of DA in the AcbSh. Overall, these results highlight the ability of WSE to interfere with morphine- and ethanol-mediated central effects and suggest a mechanistic interpretation of the efficacy of this extract to prevent the motivational properties of these compounds.