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AbstractThis study investigated the relationship between stress exposure and subsequent ethanol use, focusing on individual differences among male rats. We combined operant self-administration with behavioral economics to assess how intermittent swim stress affects ethanol consumption. This approach allowed for a nuanced analysis of the transition from regular ethanol intake to stress-induced escalation in economic demand. Results showed a consistent rise in ethanol demand post-stress among subjects, irrespective of exposure to actual swim stress or a sham procedure. This increase may result from a two-week abstinence or an inherent rise in demand over time. Significantly, we identified a direct link between post-stress corticosterone levels and the demand for ethanol, considering baseline levels. This correlation was particularly pronounced when examining the shifts in both corticosterone levels and demand for ethanol post-stress. However, neither post-stress corticosterone levels nor their change over time correlated significantly with changes in ethanol demand following a forced swim test that was administered 24 hours after the intermittent swim stress test. This suggests potential context-specific or stressor-specific effects. Importantly, pre-stress ethanol demand did not significantly predict the corticosterone response to stress, indicating that high ethanol-demand rats do not inherently exhibit heightened stress sensitivity. Our research brings to light the complex interplay between stress and ethanol consumption, highlighting the critical role of individual differences in this relationship. This research introduces a nuanced perspective, underscoring the need for future studies in the realm of stress and substance use to give greater consideration to individual variability.

Platelet aggregation, secretion of serotonin, and formation of thromboxane B2 induced by platelet-activating factor (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) were studied in plasma containing physiological concentrations of ionized calcium in eight alcoholics after cessation of heavy drinking. Responses of platelets of four nonalcoholic volunteers, matched with a subgroup of the alcoholics by age and sex, were also investigated. Aggregation of platelets from alcoholics was significantly less throughout the 6-day detoxification period compared with controls. Secretion of serotonin (5-hydroxy-tryptamine) was negligible and the production of thromboxane B2 was not detectable. Decreased platelet aggregability in response to aggregating agents, including platelet-activating factor, may be important in the development of hemorrhagic complications in alcoholics.

BackgroundVentral tegmental area (VTA) GABA neurons have been heavily implicated in alcohol reinforcement and reward. In animals that self‐administer alcohol, VTA GABA neurons exhibit increased excitability that may contribute to alcohol's rewarding effects. The present study investigated the effects of acute and chronic ethanol exposure on glutamate (GLU) synaptic transmission to VTA GABA neurons.MethodsWhole‐cell recordings of evoked, spontaneous, and miniature excitatory postsynaptic currents (eEPSCs, sEPSCs, and mEPSCs, respectively) were performed on identified GABA neurons in the VTA of GAD67‐GFP+ transgenic mice. Three ethanol exposure paradigms were used: acute ethanol superfusion; a single ethanol injection; and chronic vapor exposure.ResultsAcute ethanol superfusion increased the frequency of EPSCs but inhibited mEPSC frequency and amplitude. During withdrawal from a single injection of ethanol, the frequency of sEPSCs was lower than saline controls. There was no difference in α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/N‐methyl‐d‐aspartate (NMDA) ratio between neurons following withdrawal from a single exposure to ethanol. However, following withdrawal from chronic ethanol, sEPSCs and mEPSCs had a greater frequency than air controls. There was no difference in AMPA/NMDA ratio following chronic ethanol.ConclusionsThese results suggest that presynaptic mechanisms involving local circuit GLU neurons, and not GLU receptors, contribute to adaptations in VTA GABA neuron excitability that accrue to ethanol exposure, which may contribute to the rewarding properties of alcohol via their regulation of mesolimbic dopamine transmission.

The effect of ethanol in vitro on inositol lipid metabolism in brain slices was investigated under nonstimulating and stimulating conditions. In cerebral cortical slices 100 microM norepinephrie (NE), 1 mM carbachol, 100 microM serotonin, 20 mM KCl, 1 mM glutamate and 30 microM A23187 stimulated inositide hydrolysis as measured by the release of [3H]inositol phosphates from [3H]myoinositol labeled slices. Ethanol (500 mM) inhibited nonstimulated inositide hydrolysis but had variable effects on stimulated inositide breakdown. NE-, KCl- and glutamate-stimulated [3H]inositol phosphate release was inhibited by 500 mM ethanol in the cortex. The inhibitory effect of ethanol on NE-stimulated inositide hydrolysis was concentration dependent and significant at concentrations as low as 100 mM. Inhibition by ethanol appeared to be noncompetitive. A similar pattern of inhibition by ethanol was observed when KCl was the stimulant. In hippocampal and hypothalamic slices, similar to cortical slices. NE- and KCl-stimulated inositide breakdown was significantly inhibited by ethanol. However, in brain stem slices, only KCl-stimulated [3H]inositol phosphate release was inhibited. Striatal slices stimulated by carbachol, NE and KCl were sensitive to the inhibitory effects of ethanol on inositol lipid breakdown. These results suggest that ethanol in vitro has specific effects on inositol lipid metabolism depending on the brain region studied and the type of stimulation. Moreover, the differential sensitivity to ethanol of stimulated inositide hydrolysis in the brain may contribute, at least in part, to some of the pharmacological effects of ethanol in vivo.

Background:  Ethanol (ETOH) consumption by pregnant women can result in Fetal Alcohol Spectrum Disorder (FASD). To date, the cellular targets and mechanisms responsible for FASD are not fully characterized. Our aim was to determine if ETOH can affect fetal human brain‐derived neural progenitor cells (NPC).Methods:  Neural progenitor cells were isolated by positive selection from normal second trimester fetal human brains (n = 4) and cultured, for up to 72 hours, in mitogenic media containing 0, 1, 10, or 100 mM ETOH. From 48 to 72 hours in culture, neurospheres generated in these conditions were filmed using time‐lapse video microscopy. At the end of 72 hours, neurosphere diameter and roundness were measured using videographic software. Mitotic phase analysis of cell‐cycle activity and apoptotic cell count were also performed at this time, by flow cytometry using propidium iodide (PI) staining. Real‐time PCR was used to estimate expression of genes associated with cell adhesion pathways.Results:  Neurosphere diameter correlated positively (r = 0.87) with increasing ETOH concentrations. There was no significant difference in cell‐cycle activity and no significant increase in apoptosis with increasing ETOH concentrations. Time‐lapse video microscopy showed that ETOH (100 mM) reduced the time for neurosphere coalescence. Real‐time PCR analysis showed that ETOH significantly altered the expression of genes involved in cell adhesion. There was an increase in the expression of α and β Laminins 1, β Integrins 3 and 5, Secreted phosphoprotein1 and Sarcoglycan ε. No change in the expression of β Actin was observed while the expression of β Integrin 2 was significantly suppressed.Conclusions:  ETOH had no effect on NPC apoptosis but, resulted in more rapid coalescence and increased volume of neurospheres. Additionally, the expression of genes associated with cell adhesion was significantly altered. ETOH induced changes in NPC surface adhesion interactions may underlie aspects of neurodevelopmental abnormalities in FASD.

Although cocaine use may induce/accelerate HIV-associated comorbidities in HIV-infected individuals on antiretroviral therapy (ART), and that HIV itself may accelerate aging, the issue of whether cocaine use plays a role in HIV-associated aging in HIV-infected cocaine users has not been reported. The goals of this study were (1) to explore factor(s) associated with peripheral blood leukocyte telomere length, a marker of cellular replicative history, and telomere shortening in HIV-infected individuals, and (2) to assess whether cocaine use plays a role in accelerating telomere shortening in cocaine users with HIV infection.Between June 2010 and December 2016, 147 HIV-infected participants in Baltimore, Maryland, were enrolled in a cross-sectional study investigating factor(s) associated with telomere length. Of these 147, 93 participated in a follow-up study to examine factor(s) associated with telomere shortening. Robust regression model was used to analyze cross-sectional data and the generalized estimating equation approach was used to analyze follow-up data.Cross-sectional analyses demonstrated that (1) both daily alcohol consumption and use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were independently associated with telomere length, and cocaine use modified the associations of daily alcohol use and NNRTI use with telomere length. Longitudinal analyses suggested that both daily alcohol consumption and duration of NNRTI use were independently associated with telomere shortening, and (2) cocaine use induced/accelerated telomere shortening in HIV-infected individuals.Our findings suggest that cocaine use may promote premature aging in HIV-infected individuals who are on ART. Our results emphasize the importance of cocaine abstinence/reduced use, which may retard HIV-associated premature aging.

Neuronal death is an active process that results in the upregulation of antigens recognized by ALZ-50 and p53. Since prenatal exposure to ethanol can induce the postnatal death of cortical neurons, we examined the effects of ethanol on the in vivo expression of both the ALZ-50-positive antigen and p53. Pregnant rats were fed one of three diets, a liquid diet containing ethanol (Et), an isocaloric and isonutritive diet (Ct), or chow and water (Ch). Segments of frontoparietal cortex from fetuses and pups were examined for ethanol-induced changes (a) in the expression of ALZ-50 and p53 immunoreactivity using a quantitative immunoblotting assay and (b) in the distribution of ALZ-50- and p53-positive cells using immunohistochemistry. In control rats, ALZ-50 identified a 56-kDa peptide that was transiently expressed postnatally and peak expression occurred on postnatal day (P) 6 to P12. In Et-treated rats, peak expression was attained earlier (on P3) and was about three times of that achieved in the controls. The anti-p53 antibody identified three proteins (28, 56, and 58 kDa). Peak expression in control rats occurred during the second postnatal week and only the 58-kDa protein was expressed in appreciable amounts in adult cortex. Each p53-positive protein was affected by ethanol exposure. The 28- and 56-kDa p53-positive proteins were affected by ethanol much in the same way as was the ALZ-50-positive antigen. That is, the timing and amount of peak expression were earlier and lower, respectively, in the Et-treated rats. The postnatal expression of the 58-kDa protein was halved following prenatal exposure to ethanol. Both ALZ-50 and anti-p53 immunoprecipitated proteins are p53- and ALZ-50-positive, respectively. Thus, ethanol alters the expression of the ALZ-50- and p53-positive proteins and presumably the timing of neuronal death in the developing cortex. The parallel effects of prenatal ethanol exposure on the 56-kDa ALZ-50-positive antigen and the 28- and 56-kDa p53-positive proteins and the coprecipitation of the proteins are consistent with the notion that ALZ-50 recognizes a form of p53.

Ethanol exposure to rodents during postnatal day 7 (P7), which is comparable to the third trimester of human pregnancy, induces long-term potentiation and memory deficits. However, the molecular mechanisms underlying these deficits are still poorly understood.In the present study, we explored the potential role of epigenetic changes at cannabinoid type 1 (CB1R) exon1 and additional CB1R functions, which could promote memory deficits in animal models of fetal alcohol spectrum disorder.We found that ethanol treatment of P7 mice enhances acetylation of H4 on lysine 8 (H4K8ace) at CB1R exon1, CB1R binding as well as the CB1R agonist-stimulated GTPγS binding in the hippocampus and neocortex, two brain regions that are vulnerable to ethanol at P7 and are important for memory formation and storage, respectively. We also found that ethanol inhibits cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and activity-regulated cytoskeleton-associated protein (Arc) expression in neonatal and adult mice. The blockade or genetic deletion of CB1Rs prior to ethanol treatment at P7 rescued CREB phosphorylation and Arc expression. CB1R knockout mice exhibited neither ethanol-induced neurodegeneration nor inhibition of CREB phosphorylation or Arc expression. However, both neonatal and adult mice did exhibit enhanced CREB phosphorylation and Arc protein expression. P7 ethanol-treated adult mice exhibited impaired spatial and social recognition memory, which were prevented by the pharmacological blockade or deletion of CB1Rs at P7.Together, these findings suggest that P7 ethanol treatment induces CB1R expression through epigenetic modification of the CB1R gene, and that the enhanced CB1R function induces pCREB, Arc, spatial, and social memory deficits in adult mice.