Sex-Related Differences in Voluntary Alcohol Intake and mRNA Coding for Synucleins in the Brain of Adult Rats Prenatally Exposed to Alcohol.

Maternal alcohol consumption is one of the strong predictive factors of alcohol use and consequent abuse; however, investigations of sex differences in response to prenatal alcohol exposure (PAE) are limited. Here we compared the effects of PAE throughout gestation on alcohol preference, state anxiety and mRNA expression of presynaptic proteins α-, ß- and γ-synucleins in the brain of adult (PND60) male and female Wistar rats. Total RNA was isolated from the hippocampus, midbrain and hypothalamus and mRNA levels were assessed with quantitative RT-PCR. Compared with naïve males, naïve female rats consumed more alcohol in "free choice" paradigm (10% ethanol vs. water). At the same time, PAE produced significant increase in alcohol consumption and preference in males but not in females compared to male and female naïve groups, correspondingly. We found significantly lower α-synuclein mRNA levels in the hippocampus and midbrain of females compared to males and significant decrease in α-synuclein mRNA in these brain areas in PAE males, but not in females compared to the same sex controls. These findings indicate that the impact of PAE on transcriptional regulation of synucleins may be sex-dependent, and in males' disruption in α-synuclein mRNA expression may contribute to increased vulnerability to alcohol-associated behavior.

Neurokinin-1 receptor antagonist rolapitant suppresses anxiety and alcohol intake produced by repeated withdrawal episodes.

Neurokinin-1 receptor (NK1r) antagonists have been shown to suppress operant self-administration of alcohol, voluntary alcohol consumption and stress-induced reinstatement of alcohol-seeking behaviour. Considering the long half-life and anxiolytic-like properties of NK1r antagonist rolapitant, we expected that it may be an effective option for reducing anxiety and alcohol motivation during early withdrawal. Voluntary alcohol intake (two-bottles paradigm) was recorded in male Wistar rats during the three periods: 24 days (basal level), 6-day period when rats received 5 mg·kg-1 rolapitant or vehicle and 12-h period after repeated withdrawal episodes (alcohol cessation for 36 h). We found that upon intraperitoneal (i.p.) administration, rolapitant rapidly penetrated into specific rat brain regions - amygdala, hypothalamus and neocortex - implicated in the control of anxiety and reward. Rolapitant did not affect basal voluntary alcohol intake, but significantly suppressed anxiety-like behaviour and alcohol consumption following withdrawal episodes. Our findings suggest that rolapitant should be further investigated as a novel treatment option for relapse prevention in alcohol-dependent patients.

Active immunization against serum alcohol dehydrogenase normalizes brain dopamine metabolism disturbed during chronic alcohol consumption.

Chronic ethanol consumption in high doses is associated with constitutively elevated activity of the serum alcohol dehydrogenase I (ADH I) isoform, which demonstrates a high affinity not only for ethanol but also for a number of bioamine metabolites. Such excessive ADH activity is probably associated with disruptions in the metabolism of neurotransmitters (dopamine, serotonin, and norepinephrine) and subsequent long-term changes in the activity of their receptors. Ultimately, a stable depressive-like condition contributes to the development of patients' craving for ethanol intake, frequent disruptions during therapy, and low efficacy of treatment. We applied active immunization against ADH to investigate its efficacy in the reduction of excessive serum ADH activity and regulation of ethanol consumption by chronically ethanol-fed Wistar rats (15% ethanol, 4 months, free-choice method), and we analyzed its ability to influence the levels of bioamines in the brain. Immunization (2 injections, 2-week intervals) was performed using a combination of recombinant horse ADH isozyme as an antigen and 2% aluminum hydroxide-based adjuvant. The efficacy of immunization was demonstrated by the production of high titers of ADH-specific antibodies, which was consistent with the significantly reduced ADH activity in the serum of chronically ethanol-fed rats. On the 26th day after the first vaccine injection, we registered significantly lower levels of alcohol consumption compared to ethanol-fed control animals, and the difference reached 16% on the 49th day of the experiment. These observations were accompanied by data that showed reduced levels of ethanol preference in immunized rats. Chronic alcohol drinking led to a decrease in dopamine and DOPAL (a direct dopamine metabolite and a high-affinity ADH substrate) levels in the striatum,while immunization neutralized this effect. Additionally, we observed that inhibition of serum ADH activity caused a decrease in peak dopamine levels during acute alcohol intake in chronically ethanol-fed rats during ethanol withdrawal that was associated with reduced tyrosine hydroxylase activity in the striatum. The obtained data suggest a significant contribution of ADH to the changes in neurotransmitter systems during chronic alcohol consumption and make available new prospects for developing innovative strategies for treatment of excessive alcohol intake.

Cortical Glutamate/GABA Imbalance after Combined Radiation Exposure: Relevance to Human Deep-Space Missions.

Ionizing radiation (IR) is one of the major biological limiting factors of human deep-space missions. Despite the dominant paradigm about the negative effects of IR on the CNS, the anxiolytic, antidepressant, anti-aggressive, and pro-cognitive effects have recently been discovered. The mechanisms of these phenomena remain undisclosed. Here, we study the effects of combined IR exposure (γ-rays and 12C nuclei) on the psycho-emotional state, cognitive abilities, and the metabolism of glutamate and GABA in Wistar rats, with an emphasis on the age factor. Irradiation resulted in the anxiogenic effect, reversing during maturation, and the sustained increase in spatial learning performance. A persistent decrease in the content of GABA was observed, which confirmed the hypothesis of disinhibition of the CNS under irradiation with moderate doses, proposed earlier. Glutamate/GABA imbalance was accompanied by an increase in the metabolism of these neurotransmitters: an increase in expression level of GLT-1, GAD65, GABAT and GAT1. Besides, a decrease in the expression level of NR1 subunit of the NMDA receptor was noted. Notably, the maturation of rats led not only to the rebalancing of the glutamate/GABA ratio by reducing the glutamate content, but also to leveling the differences in the expression levels of the analyzing biomolecules. Thus, the combined action of IR at moderate doses resulted in long-term changes in psycho-emotional status and, surprisingly, an increase in the efficiency of spatial learning performance. We suggest that IR (within the range of composition and doses used) can be relatively safe for the functions of the CNS.