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Adolescent binge drinking in humans is associated with adverse outcomes, here we examined sex- and withdrawal-dependent changes in affective behaviors and metabolomic profiles in male and female mice following AIE exposure. Male and female C57BL/6 J mice were exposed to intermittent ethanol vapor inhalation from postnatal (PND) 28–42, a model of intermittent binge-like ethanol exposure during adolescence. Affective behavior was assessed using the open field test (OFT), light/dark test (LDT), and tail suspension test (TST) during short-term withdrawal (PND 49–53) and again during long-term withdrawal (PND 91–95). Serum samples were collected 24 h after the final exposure cycle (PND 43), fecal samples were collected during each OFT, and liver samples were collected at euthanasia (PND 119; ~80 days after exposure) for metabolomic analysis. Ethanol sensitivity in adulthood was additionally assessed using loss of righting reflex (LORR) on PND 116. Overall, AIE produced modest, sex- and withdrawal-dependent behavioral effects, whereas metabolomic differences were most pronounced in males shortly after exposure and diminished with longer withdrawal. These findings support future work testing whether early metabolomic shifts track later behavioral vulnerability.

Rationale Nicotine and alcohol co-use is highly prevalent, and as such, individuals experience the interoceptive effects of both substances together. Therefore, examining sensitivity to a compound nicotine and alcohol (N + A) interoceptive cue is critical to broaden our understanding of mechanisms that may contribute to nicotine and alcohol co-use. Objectives This work assessed the ability of a N + A interoceptive cue to gain control over goal-tracking behavior and determined the effects of the α4β2 nicotinic partial agonist and smoking cessation compound varenicline on sensitivity to N + A. Methods Two groups of male Long Evans rats were trained to discriminate N + A (0.4 mg/kg nicotine + 1 g/kg alcohol, intragastric gavage (IG)) from water under two different training conditions using a Pavlovian drug discrimination task. The effects of varenicline (0, 1, 3 mg/kg, intraperitoneally (IP)) administered alone and on sensitivity to N + A and the components were determined. Results Under both training conditions, N + A rapidly gained control over behavior, with a greater contribution of nicotine to the N + A compound cue. Varenicline fully substituted for the N + A training dose, and varenicline (1 mg/kg) enhanced sensitivity to the lowest N + A dose (0.1 N + 0.1 A). Given the high selectivity of varenicline for the α4β2 receptor, this finding suggests a functional role for α4β2 nicotinic acetylcholine receptors (nAChRs) in modulating sensitivity to N + A. Conclusions The N + A compound cue is a unique cue that is modulated, in part, by activity at the α4β2 nAChR. These findings advance understanding of the interoceptive effects of nicotine and alcohol in combination and may have implications in relation to their co-use.

Escalations in alcohol drinking associated with experiencing stressful life events and chronic life stressors may be related to altered sensitivity to the interoceptive/subjective effects of alcohol. Indeed, through the use of drug discrimination methods, rats show decreased sensitivity to the discriminative stimulus (interoceptive) effects of alcohol following exposure to the stress hormone corticosterone (CORT). This exposure produces heightened elevations in plasma CORT levels (eg, as may be experienced by an individual during stressful episodes). We hypothesized that decreased sensitivity to alcohol may be related, in part, to changes in metabotropic glutamate receptors-subtype 5 (mGluR5) in the nucleus accumbens, as these receptors in this brain region are known to regulate the discriminative stimulus effects of alcohol. In the accumbens, we found reduced mGluR5 expression (immunohistochemistry and Western blot) and decreased neural activation (as measured by c-Fos immunohistochemistry) in response to a moderate alcohol dose (1 g/kg) following CORT exposure (7 days). The functional role of these CORT-induced adaptations in relation to the discriminative stimulus effects of alcohol was confirmed, as both the systemic administration of 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) an mGluR5 positive allosteric modulator and the intra-accumbens administration of (R,S)-2-Amino-2-(2-chloro-5-hydroxyphenyl)acetic acid sodium salt (CHPG) an mGluR5 agonist restored sensitivity to alcohol in discrimination-trained rats. These results suggest that activation of mGluR5 may alleviate the functional impact of the CORT-induced downregulation of mGluR5 in relation to sensitivity to alcohol. Understanding the contribution of such neuroadaptations to the interoceptive effects of alcohol may enrich our understanding of potential changes in subjective sensitivity to alcohol during stressful episodes.

Small-conductance Ca(2+)-activated K(+) (KCa2) channels control neuronal excitability and synaptic plasticity, and have been implicated in substance abuse. However, it is unknown if genes that encode KCa2 channels (KCNN1-3) influence alcohol and drug addiction. In the present study, an integrative functional genomics approach shows that genetic datasets for alcohol, nicotine, and illicit drugs contain the family of KCNN genes. Alcohol preference and dependence QTLs contain KCNN2 and KCNN3, and Kcnn3 transcript levels in the nucleus accumbens (NAc) of genetically diverse BXD strains of mice predicted voluntary alcohol consumption. Transcript levels of Kcnn3 in the NAc negatively correlated with alcohol intake levels in BXD strains, and alcohol dependence enhanced the strength of this association. Microinjections of the KCa2 channel inhibitor apamin into the NAc increased alcohol intake in control C57BL/6J mice, while spontaneous seizures developed in alcohol-dependent mice following apamin injection. Consistent with this finding, alcohol dependence enhanced the intrinsic excitability of medium spiny neurons in the NAc core and reduced the function and protein expression of KCa2 channels in the NAc. Altogether, these data implicate the family of KCNN genes in alcohol, nicotine, and drug addiction, and identify KCNN3 as a mediator of voluntary and excessive alcohol consumption. KCa2.3 channels represent a promising novel target in the pharmacogenetic treatment of alcohol and drug addiction.

Metabotropic glutamate receptor subtypes (mGlu2/3) regulate a variety of alcohol-associated behaviors, including alcohol reinforcement, and relapse-like behavior. To date, the role of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol has not been examined. Given that the discriminative stimulus effects of drugs are determinants of abuse liability and can influence drug seeking, we examined the contributions of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol. In male Long-Evans rats trained to discriminate between alcohol (1 g/kg, IG) and water, the mGlu2/3 agonist LY379268 (0.3–10 mg/kg) did not produce alcohol-like stimulus effects. However, pretreatment with LY379268 (1 and 3 mg/kg; in combination with alcohol) inhibited the stimulus effects of alcohol (1 g/kg). Systemic LY379268 (3 mg/kg, i.p.) was associated with increases in neuronal activity within the amygdala, but not the nucleus accumbens, as assessed by c-Fos immunoreactivity. Intra-amygdala activation of mGlu2/3 receptors by LY379268 (6 μg) inhibited the discriminative stimulus effects of alcohol, without altering response rate. In contrast, intra-accumbens LY379268 (3 μg) profoundly reduced response rate; however, at lower LY379268 doses (0.3, 1 μg), the discriminative stimulus effects of alcohol and response rate were not altered. These data suggest that amygdala mGlu2/3 receptors have a functional role in modulating the discriminative stimulus properties of alcohol and demonstrate differential motor sensitivity to activation of mGlu2/3 receptors in the amygdala and the accumbens. Understanding the neuronal mechanisms that underlie the discriminative stimulus effects of alcohol may prove to be important for future development of pharmacotherapies for treating alcoholism.

Chronic exposure to forced swim stress (FSS), results in a stress-induced enhancement of voluntary ethanol consumption in mice with a history of alcohol exposure. Morphological analyses of dendritic spines revealed CIE and CIE-FSS treated mice show an increase in long thin spine density and total spine density.

Rationale and objective Repeated and/or heightened elevations in glucocorticoids (e.g., repeated stress) can promote escalated drug-taking behaviors and induce compromised HPA axis function. Given that interoceptive/subjective drug cues are a fundamental factor in drug-taking behavior, we sought to determine the effects of exposure to repeated elevations in the glucocorticoid corticosterone (CORT) on the interoceptive effects of alcohol in rats using drug discrimination techniques. Methods Male Long Evans rats trained to discriminate alcohol (1 g/kg, IG) vs. water were exposed to CORT (300 μg/ml) in the home cage drinking water for 7 days. The interoceptive effects of experimenter- and self-administered alcohol were assessed and HPA axis function was determined. Results The interoceptive effects of experimenter- and self-administered alcohol were blunted following CORT. Control experiments determined that this decreased sensitivity was unrelated to discrimination performance impairments or decreased CORT levels at the time of testing and was dependent on repeated CORT exposure. Susceptibility to compromised HPA axis function following CORT exposure was suggested by an altered pattern of CORT secretion and blunted CORT response following injection of the synthetic glucocorticoid dexamethasone. Conclusions These findings present a possible behavioral mechanism for escalated alcohol drinking during episodes of heightened elevations in glucocorticoids (e.g., stress). That is, during these episodes, individuals may consume more alcohol to achieve the desired interoceptive effects. Understanding these behavioral mechanisms may lead to a better understanding of factors that promote alcoholism and alcohol abuse in at risk populations.

Small-conductance Ca super(2+)-activated K super(+) (K sub(Ca)2) channels control neuronal excitability and synaptic plasticity, and have been implicated in substance abuse. However, it is unknown if genes that encode K sub(Ca)2 channels (KCNN1-3) influence alcohol and drug addiction. In the present study, an integrative functional genomics approach shows that genetic datasets for alcohol, nicotine, and illicit drugs contain the family of KCNN genes. Alcohol preference and dependence QTLs contain KCNN2 and KCNN3, and Kcnn3 transcript levels in the nucleus accumbens (NAc) of genetically diverse BXD strains of mice predicted voluntary alcohol consumption. Transcript levels of Kcnn3 in the NAc negatively correlated with alcohol intake levels in BXD strains, and alcohol dependence enhanced the strength of this association. Microinjections of the K sub(Ca)2 channel inhibitor apamin into the NAc increased alcohol intake in control C57BL/6J mice, while spontaneous seizures developed in alcohol-dependent mice following apamin injection. Consistent with this finding, alcohol dependence enhanced the intrinsic excitability of medium spiny neurons in the NAc core and reduced the function and protein expression of K sub(Ca)2 channels in the NAc. Altogether, these data implicate the family of KCNN genes in alcohol, nicotine, and drug addiction, and identify KCNN3 as a mediator of voluntary and excessive alcohol consumption. K sub(Ca)2.3 channels represent a promising novel target in the pharmacogenetic treatment of alcohol and drug addiction.

Mechanisms underlying excessive alcohol drinking behavior and relapse are not fully understood and are critical for mapping the pathological course of alcohol use disorders (AUD). Long-term ethanol consumption results in strengthened excitatory neurotransmission and increased AMPA receptor signaling in animal models. However, the mechanistic role of enhanced AMPA receptor activity in ethanol-reinforcement and alcohol-seeking behavior remains unclear. Thus, the experiments in this dissertation sought to elucidate the behavioral and molecular mechanisms that underlie AMPA receptor-mediated ethanol reinforcement processes and relapse to ethanol-seeking behavior using a preclinical model of high alcohol preference, the alcohol-preferring (P-) rat. Enhancement of AMPA receptor signaling by systemically administered aniracetam (AMPA receptor positive allosteric modulator) significantly increased ethanol self-administration in a reinforcer-specific manner. Moreover, aniracetam potentiated cue-induced reinstatement in P-rats, which suggest that enhanced activity at AMPA receptors promotes reinforcement and ethanol-seeking behavior. Experiments further characterized enhanced AMPA receptor signaling in modulating operant self-administration and relapse-like behavior by examining neuroanatomical contributions to AMPA receptor-mediated alterations in ethanol reinforcement. Since AMPA receptor activity is potentiated by post-translational modification (e.g. phosphorylation of GluA1subunits), immunohistochemistry was used to examine neuroadaptive changes in pGluA1 in limbic brain regions after a history of ethanol self-administration. Increased pGluA1 immunoreactivity was observed in sub-nuclei of the amygdala and nucleus accumbens of ethanol self-administering P-rats relative to the sucrose controls. Guided by immunohistochemistry results, the effects of aniracetam on ethanol self-administration were examined via site-specific microinjections in the amygdala and nucleus accumbens. Intra-amygdala, but not intra-accumbens, aniracetam increased ethanol self-administration in a reinforcer-specific manner. Furthermore, coadministration of intra-amygdala aniracetam and myristolated AIP (CaMKII peptide inhibitor) blocked aniracetam-induced increased ethanol self-administration; which demonstrates a critical role for amygdala CaMKII activity in AMPA receptor-mediated potentiation of ethanol reinforcement. These data suggest that enhanced amygdala AMPA receptor activity promotes drinking and ultimately could contribute to alcohol use disorders. In contrast, intra-amygdala aniracetam did not significantly alter cue-induced reinstatement; which suggest that enhanced AMPA receptor activity in this region may not significantly contribute to promoting cue-induced ethanol-seeking. Collectively, key experimental results provide novel insight into AMPA receptor-related mechanisms in excessive alcohol drinking behavior and vulnerability to relapse.

Given the adverse effects of adolescent binge alcohol consumption in humans, the present work explores the lasting behavioral and metabolomic impacts following adolescent binge ethanol exposure. Here we determine short- and long-term changes in affective behaviors and metabolomic profiles in male and female adolescent binge ethanol-exposed mice. Male and female C57BL/6J mice were exposed to adolescent intermittent ethanol (AIE) as a model of binge ethanol exposure using intermittent vapor inhalation from postnatal day (PND) 28-42. Mice were tested in a battery of behavioral tests and metabolomic analyses were conducted following short-term and long-term withdrawal from AIE exposure. Mice were tested for affective behaviors using the open field test (OFT), the light/dark test (LDT), and the tail suspension test (TST) one week following AIE exposure from PND 49-53 and again from PND 91-95. Serum samples were collected on PND 43, corresponding to 24 hours after the last exposure, fecal samples were collected during each OFT, and liver samples were collected approximately 80 days after AIE exposure for metabolomic analysis. We show modest incubation of behavioral differences in anxiety-like behavior in males after adolescent binge ethanol exposure; an effect that was absent in female mice. In contrast, metabolomic differences in male mice that were more pronounced shortly after adolescent binge ethanol exposure waned as time progressed since last exposure. Male mice appear to be more susceptible to the persistent changes in adolescent binge ethanol exposure that varies over time. It is possible that short-term metabolomic changes may predict long-term behavioral changes in affective behaviors. Adolescent binge alcohol exposure causes long-lasting changes in behavior, however the underlying biology mediating these changes have not readily been assessed in a sex-specific manner. Metabolomic assays are a powerful tool that can be used as biomarkers to determine changes in biological pathways that are linked to specific behavioral phenotypes. Here we explored the relationship between adolescent binge alcohol exposure, changes in anxiety-like behavior, and metabolomic profiles in male and female C57BL/6J mice. We find robust changes in metabolomic profiles following short-term withdrawal in male mice exposed to binge alcohol during adolescence. We also see modest changes in anxiety-like behavior following long-term withdrawal. Although female mice did not show any robust changes in anxiety-like behavior nor global changes in metabolomic profiles, in both sexes we do observe persistent changes in some amino acids, which may serve as specific biomarkers associated with changes in alcohol-induced behavioral changes. These data add to the field by conducting a novel longitudinal study following male and female mice from adolescence to early adulthood and measuring physiological biomarkers (metabolomics) coupled with behavioral changes following binge ethanol exposure.