Chronic alcohol consumption and withdrawal leads to anxiety, escalated alcohol drinking behavior, and alcohol dependence. Alterations in the function of key structures within the cortico-limbic neural circuit have been implicated in underlying the negative behavioral consequences of chronic alcohol exposure in both humans and rodents. Here, we used chronic intermittent ethanol vapor exposure (CIE) in male C57BL/6J mice to evaluate the effects of chronic alcohol exposure and withdrawal on anxiety-like behavior and basal synaptic function and neuronal excitability in prefrontal cortical and extended amygdala brain regions. Forty-eight hours after four cycles of CIE, mice were either assayed in the marble burying test (MBT) or their brains were harvested and whole-cell electrophysiological recordings were performed in the prelimbic and infralimbic medial prefrontal cortex (PLC and ILC), the lateral and medial central nucleus of the amygdala (lCeA and mCeA), and the dorsal and ventral bed nucleus of the stria terminalis (dBNST and vBNST). Ethanol-exposed mice displayed increased anxiety in the MBT compared to air-exposed controls, and alterations in neuronal function were observed in all brain structures examined, including several distinct differences between subregions within each structure. Chronic ethanol exposure induced hyperexcitability of the ILC, as well as a shift toward excitation in synaptic drive and hyperexcitability of vBNST neurons; in contrast, there was a net inhibition of the CeA. This study reveals extensive effects of chronic ethanol exposure on the basal function of cortico-limbic brain regions, suggests that there may be complex interactions between these regions in the regulation of ethanol-dependent alterations in anxiety state, and highlights the need for future examination of projection-specific effects of ethanol in cortico-limbic circuitry.

Alcohol use increases across adolescence and is a concern in the United States. In humans, males and females consume different amounts of alcohol depending on the age of initiation and the long-term consequences of early ethanol consumption are not readily understood. The purpose of our work is to better understand the immediate and long-term impact of ethanol exposure during adolescence and the effects it can have on behavior and dopaminergic responsivity. We have assessed sex differences in voluntary ethanol consumption during adolescence and adulthood and the influence of binge ethanol exposure during adolescence. We have observed that males are sensitive to passive social influences that mediate voluntary ethanol consumption and early ethanol exposure induces long-term changes in responsivity to ethanol in adulthood. Exposure to moderate doses of ethanol during adolescence produced alterations in dopamine (DA) in the nucleus accumbens septi (NAcc) during adolescence and later in adulthood. Taken together, all of these data indicate the adolescent brain is sensitive to the impact of early ethanol exposure during this critical developmental period.

The purpose of this review is to present animal research models that can be used to screen and/or repurpose medications for the treatment of alcohol abuse and dependence. The focus will be on rats and in particular selectively bred rats. Brief introductions discuss various aspects of the clinical picture, which provide characteristics of individuals with alcohol use disorders (AUDs) to model in animals. Following this, multiple selectively bred rat lines will be described and evaluated in the context of animal models used to screen medications to treat AUDs. Next, common behavioral tests for drug efficacy will be discussed particularly as they relate to stages in the addiction cycle. Tables highlighting studies that have tested the effects of compounds using the respective techniques are included. Wherever possible the Tables are organized chronologically in ascending order to describe changes in the focus of research on AUDs over time. In general, high ethanol-consuming selectively bred rats have been used to test a wide range of compounds. Older studies usually followed neurobiological findings in the selected lines that supported an association with a propensity for high ethanol intake. Most of these tests evaluated the compound's effects on the maintenance of ethanol drinking. Very few compounds have been tested during ethanol-seeking and/or relapse and fewer still have assessed their effects during the acquisition of AUDs. Overall, while a substantial number of neurotransmitter and neuromodulatory system targets have been assessed; the roles of sex- and age-of-animal, as well as the acquisition of AUDs, ethanol-seeking and relapse continue to be factors and behaviors needing further study.

Binge alcohol consumption is a rising concern in the United States, especially among adolescents. During this developmental period alcohol use is usually initiated and has been shown to cause detrimental effects on brain structure and function as well as cognitive/behavioral impairments in rats. Binge models, where animals are repeatedly administered high doses of ethanol typically over a period of three or four days cause these effects. There has been little work conducted aimed at investigating the long-term behavioral consequences of repeated binge administration during adolescence on later ethanol-induced behavior in young adulthood and adulthood. The repeated four-day binge model may serve as a good approximate for patterns of human adolescent alcohol consumption as this is similar to a “bender” in human alcoholics. The present set of experiments examined the dose-response and sex-related differences induced by repeated binge ethanol administration during adolescence on sweetened ethanol (Experiment 1) or saccharin (Experiment 2) intake in young adulthood. In both experiments, on postnatal days (PND) 28–31, PND 35–38 and PND 42–45, ethanol (1.5, 3.0 or 5.0 g/kg) or water was administered intragastrically to adolescent rats. Rats underwent abstinence from PND 46–59. Subsequently, in young adulthood, ethanol and saccharin intake were assessed. Exposure to any dose of ethanol during adolescence significantly enhanced ethanol intake in adulthood. However, while female rats had higher overall g/kg intake, males appear to be more vulnerable to the impact of adolescent ethanol exposure on subsequently increased ethanol intake in young adulthood. Exposure to ethanol during adolescence did not alter saccharin consumption in young adulthood in male or female rats. Considering that adolescence is the developmental period in which ethanol experimentation and consumption is usually initiated, the present set of experiments demonstrate the importance of elucidating the impact of early binge-pattern ethanol exposure on the subsequent predisposition to drink later in life.

Background The GABAergic neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) has been studied during withdrawal from ethanol in humans, rats and mice. Serum 3α,5α-THP levels decreased and brain levels were not altered following acute ethanol administration (2 g/kg) in male C57BL/6J mice, however the effects of chronic intermittent ethanol (CIE) exposure on 3α,5α-THP levels have not been examined. Given that CIE exposure changes subsequent voluntary ethanol drinking in a time-dependent fashion following repeated cycles of ethanol exposure, we conducted a time-course analysis of CIE effects on 3α,5α-THP levels in specific brain regions known to influence drinking behavior. Methods Adult male C57BL/6J mice were exposed to four cycles of CIE to induce ethanol dependence. All mice were sacrificed and perfused at one of two time points, 8 hr or 72 hr following the final exposure cycle. Free floating brain sections (40 μm; 3-5 sections/region/animal) were immunostained and analyzed to determine relative levels of cellular 3α,5α-THP. Results Withdrawal from CIE exposure produced time-dependent and region-specific effects on immunohistochemical detection of 3α,5α-THP levels across cortical and limbic brain regions. A transient reduction in 3α,5α-THP immunoreactivity was observed in the central nucleus of the amygdala 8 hr after withdrawal from CIE (-31.4 ± 9.3). Decreases in 3α,5α-THP immunoreactivity were observed 72 hr following withdrawal in the medial prefrontal cortex (−25.0 ± 9.3%), nucleus accumbens core (−29.9 ± 6.6%), and dorsolateral striatum (−18.5 ± 6.0%), while an increase was observed in the CA3 pyramidal cell layer of the hippocampus (+42.8 ± 19.5%). Sustained reductions in 3α,5α-THP immunoreactivity were observed at both time points in the lateral amygdala (8 hr −28.3 ± 12.8%; 72 hr −27.5 ± 12.4%) and in the ventral tegmental area (8 hr −26.5 ± 9.9%; 72 hr −31.6 ± 13.8%). Conclusions These data suggest that specific neuroadaptations in 3α,5α-THP levels may be present in regions of brain that mediate anxiety, stress and reinforcement relevant to ethanol dependence. The changes that occur at different time points likely modulate neurocircuitry involved in ethanol withdrawal as well as the elevated drinking observed after CIE exposure.