Early social isolation differentially affects the glucocorticoid receptor system and alcohol-seeking behavior in male and female Marchigian Sardinian alcohol-preferring rats.

Adverse early life experiences during postnatal development can evoke long-lasting neurobiological changes in stress systems, thereby affecting subsequent behaviors including propensity to develop alcohol use disorder. Here, we exposed genetically selected male and female Marchigian Sardinian alcohol-preferring (msP) and Wistar rats to mild, repeated social deprivation from postnatal day 14 (PND14) to PND21 and investigated the effect of the early social isolation (ESI) on the glucocorticoid receptor (GR) system and on the propensity to drink and seek alcohol in adulthood. We found that ESI resulted in higher levels of GR gene and protein expression in the prefrontal cortex (PFC) in male but not female msP rats. In female Wistars, ESI resulted in significant downregulation of Nr3c1 mRNA levels and lower GR protein levels. In male and female msP rats, plasma corticosterone levels on PND35 were similar and unaffected by ESI. Wistar females exhibited higher levels of corticosterone compared with males, independently from ESI. In alcohol self-administration experiments we found that the pharmacological stressor yohimbine (0.0, 0.312, 0.625, and 1.25 mg/kg) increased alcohol self-administration in both rat lines, regardless of ESI. After extinction, 0.625 mg/kg yohimbine significantly reinstated alcohol seeking in female rats only. ESI enhanced reinstatement in female msP rats. Overall, the present results indicate that repeated social deprivation during the third week of postnatal life affects GR expression in a strain- and sex-dependent manner: such effect may contribute, at least partially, to the heightened sensitivity of female msP rats to the effects of yohimbine-induced alcohol seeking.

Psilocybin prevents reinstatement of alcohol seeking by disrupting the reconsolidation of alcohol-related memories.

BACKGROUND: For most psychiatric conditions, including alcohol use disorder (AUD), FDA-approved pharmacological treatments are limited and their efficacy is restricted to only certain subgroups of patients. Scientific interest in the potential of psychedelic drugs has dramatically increased because of clinical preliminary evidence of efficacy in treating various psychiatric disorders. One of the most promising compounds belonging to this class of molecules is psilocybin. Here, to elucidate the therapeutic potential and treatment modalities of this drug, we investigated the effect of psilocybin on alcohol drinking and seeking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, a well validated animal model of AUD characterized by excessive drinking and seeking. METHODS: Using male and female msP rats, we tested the effect of psilocybin on home cage voluntary alcohol consumption. We also tested the effect of the drug on the alcohol deprivation effect (ADE) model of relapse and on cue-induced reinstatement of alcohol seeking after a period of abstinence. Finally, we evaluated if psilocybin may disrupt the reconsolidation process of alcohol-related memory. RESULTS: Psilocybin did not reduce alcohol consumption, nor it prevented increased alcohol drinking after a period of forced abstinence and cue-induced reinstatement of alcohol-seeking. Noteworthy, in a memory retrieval-reconsolidation paradigm, psilocybin markedly attenuated resumption of alcohol seeking. CONCLUSIONS: Altogether these data suggest that, despite psilocybin does not affect alcohol drinking and relapse, it may be highly effective if used to block the reconsolidation process of alcohol-related memories. This opens to the possibility of using this psychedelic drug in clinical settings in which AUD patients undergo procedures to recall the memory of alcohol and are then treated with psilocybin during the memory reconsolidation phase.

Moderate ethanol drinking is sufficient to alter Ventral Tegmental Area dopamine neurons activity via functional and structural remodeling of GABAergic transmission.

Earlier studies have shown a major involvement of Ventral Tegmental Area (VTA) dopamine (DA) neurons in mediating the rewarding effects of ethanol (EtOH). Much less is known on the role of this system in mediating the transition from moderate to excessive drinking and abuse. Here we sought to explore the hypothesis that early stage drinking in rodents, resembling recreational EtOH use in humans, is sufficient to dysregulate VTA DA transmission thus increasing the propensity to use over time. To this purpose, midbrain slice recordings in mice previously exposed to an escalating (3, 6 and 12%) 18-day voluntary EtOH drinking paradigm was used. By recording from DA and γ-aminobutyric acid (GABA) VTA neurons in midbrain slices, we found that moderate EtOH drinking leads to a significant suppression of the spontaneous activity of VTA DA neurons, while increasing their response to acute EtOH application. We also found that chronic EtOH leads to the enhancement of GABA input frequency onto a subset of DA neurons. Structurally, chronic EtOH induced a significant increase in the number of GABA axonal boutons contacting DA neurons, suggesting deep rewiring of the GABA network. This scenario is consistent with a downmodulation of the reward DA system induced by moderate EtOH drinking, a neurochemical state defined as "hypodopaminergic" and previously associated with advanced stages of drug use in humans. In this context, increased sensitivity of DA neurons towards acute EtOH may represent the neurophysiological correlate of increased unitary rewarding value, possibly driving progression to addiction.

phMRI, neurochemical and behavioral responses to psychostimulants distinguishing genetically selected alcohol-preferring from genetically heterogenous rats.

Alcoholism is often associated with other forms of drug abuse, suggesting that innate predisposing factors may confer vulnerability to addiction to diverse substances. However, the neurobiological bases of these factors remain unknown. Here, we have used a combination of imaging, neurochemistry and behavioral techniques to investigate responses to the psychostimulant amphetamine in Marchigian Sardinian (msP) alcohol-preferring rats, a model of vulnerability to alcoholism. Specifically, we employed pharmacological magnetic resonance imaging to investigate the neural circuits engaged by amphetamine challenge, and to relate functional reactivity to neurochemical and behavioral responses. Moreover, we studied self-administration of cocaine in the msP rats. We found stronger functional responses in the extended amygdala, alongside with increased release of dopamine in the nucleus accumbens shell and augmented vertical locomotor activity compared with controls. Wistar and msP rats did not differ in operant cocaine self-administration under short access (2 hours) conditions, but msP rats exhibited a higher propensity to escalate drug intake following long access (6 hours). Our findings suggest that neurobiological and genetic mechanisms that convey vulnerability to excessive alcohol drinking also facilitate the transition from psychostimulants use to abuse.

Role of gonadotropin-releasing hormone (GnRH) in the regulation of gonadal differentiation in the gilthead seabream (Sparus aurata).

It has been proposed that gonadotropin-releasing hormone (GnRH) plays an autocrine/paracrine regulatory role in mammalian and fish ovaries. The marine teleost gilthead seabream is an interesting model since, during the life span of the fish, gonadal tissues develop first as testes, which then regress allowing the development of ovarian follicles. Recent studies carried out in ovaries of the gilthead seabream have demonstrated that various GnRH transcripts as well as GnRH splicing variants are expressed. The mRNA level of several GnRH forms in the female and male areas of the switching gonad, and their possible role in this process, were further investigated. The results here reported show that sGnRH, cGnRH-II, and sbGnRH transcripts are locally expressed during gilthead seabream gonadal differentiation; the expression of the three GnRH forms was found to differ among the morphologically defined areas of the switching gonad, as demonstrated by applying reverse transcription-polymerase chain reaction (RT-PCR), together with in situ hybridization, and semiquantitative PCR analyses. Moreover, the hypothesis that GnRH forms may regulate testicular regression via an apoptotic mechanism was investigated by analyzing the different areas of switching gonads for caspase-3 activity as a measure of apoptosis. Our results showed a marked increase of caspase-3 activity in the area corresponding to the regressing testes in which a significant decrease of testosterone production was also found. The present findings demonstrate that the changes in the endogenous GnRH transcripts could be related with the gonadal differentiation in gilthead seabream, and that exogenous GnRH plays a role by stimulating apoptosis in the degenerating testis.

The circadian rhythm of guanylate cyclase and its interrelationship to rat liver chalone.

Guanylate cyclase [E.C.4.6.1.2], the enzyme that catalyzes the production of cyclic GMP, was found to have a circadian rhythm in chick embryo livers with peak levels of basal activity at 9 p.m. and with another peak of activity at 6 a.m. The lowest levels of basal activity were at 3 a.m. and 3 p.m. Liver contains an inhibitor of cellular mitosis, i.e., chalone, which has its maximal inhibitory effect on mitosis when isolated at 9 p.m. Utilizing this 9 p.m. liver chalone in vivo reinforced the endogenous rhythm of guanylate cyclase but reset it at a higher level 4 hours after injection. This maximally effective hepatic chalone inhibited guanylate cyclase activity in vitro approximately 50 percent in rat liver, kidney, small intestine, heart and pancreas.