Animal models of alcohol use disorder and the brain: From casual drinking to dependence.

Abstract

Alcohol use disorder (AUD) is a chronically relapsing disorder, characterized by a shift from casual to compulsive intake of alcohol that is driven by changes in multiple regions throughout the brain. Animal models, long recognized for their utility in elucidating the biological underpinnings of human diseases, have enabled key advances in our understanding of the risk, development, and treatment of AUD. Here, we provide an overview of animal models used in the study of AUD, including both voluntary consumption and forced exposure models that reflect the range from casual drinking to alcohol dependence. We also review recent updates in the neurobiology across stages of AUD using these models, which have elucidated the profound changes in cellular physiology and molecular markers in key brain regions that are involved in regulation of reward seeking and emotions. Currently available pharmacotherapies as well as emerging treatments informed by the animal literature are also detailed.

Forced Abstinence From Alcohol Induces Sex-Specific Depression-Like Behavioral and Neural Adaptations in Somatostatin Neurons in Cortical and Amygdalar Regions

“…Our results corroborate previous preclinical animal studies on sex differences in voluntary alcohol drinking (Almeida et al, 1998;Priddy et al, 2017;Crowley et al, 2019a;Peltier et al, 2019) in which female mice consistently consumed more alcohol than male mice across 6 weeks of access, despite both sexes showing similar alcohol preference over water (Figures 1B,C). In humans, while women historically tend to consume less alcohol than men (Rehm et al, 2010), this gap is rapidly closing with substantial increases in the prevalence of alcohol use and binge drinking among women and not men (White et al, 2015;Grucza et al, 2018).…”

“…Interestingly, this model of alcohol exposure disrupts inhibitory transmission in layer 5/6 pyramidal neurons in both sexes (Hughes et al, 2019), likely via an uncharacterized microcircuit mechanism. Excitatory transmission in PL layer 2/3 pyramidal neurons is decreased following four cycles of DID via distinct cellular mechanisms between the sexes (Crowley et al, 2019a), in which DID targeted cell-surface expression of NMDA and AMPA receptors alterations occur in female PL only. Sex also modulates the effects of stress on the cortical circuitry.…”

“…Alcohol use disorder and major depressive disorder (MDD) are highly comorbid disorders with overlapping etiology. Novel fast acting antidepressants are able to reduce both binge drinking (Crowley et al, 2019a) and depressive-like behavior following alcohol exposure (Holleran et al, 2016;Vranjkovic et al, 2018) further highlighting the potential overlapping neural circuitry involved in AUD and MDD. Importantly, both the clinical and preclinical depression literature has continuously pointed to a novel subpopulation of gamma aminobutyric acidergic (GABAergic) neurons as a protective, resiliencyconferring population.…”

Bi-directional control of a prelimbic somatostatin microcircuit decreases binge alcohol consumption

“…In separate complementary studies, male C57BL6/J mice exposed to the chronic intermittent ethanol vapor (CIE) model of alcohol dependence exhibited elevated intrinsic excitability in layer 2/3 pyramidal neurons (21,22), increased dendritic spine density (22,38), and upregulated NMDA receptor expression (38). The DID paradigm, in contrast to the CIE model, models a binge drinking pattern that produces a highly intoxicated state without inducing dependence symptomologies (28), and changes seen in this model could be considered precursors to those that occurring following CIE. Previously, we demonstrated that four cycles of DID reduced glutamatergic transmission onto female pyramidal neurons in the PL via a reduction in cell-surface AMPA and NMDA receptors (20), which is not evident in males.…”

“…Adult male and female C57BL/6J (stock #000664, The Jackson Laboratory), hemizygous SST-IRES-Cre mice (stock #013044, The Jackson Laboratory) and Ai9 reporter mice (stock #007909, The Jackson Laboratory) on C57BL6/J background were bred in-house and genotyped by standard PCR protocol. All mice were single-housed on a 12 hr reverse light cycle for the entirety of the experiments (lights off at 7:00am), as is consistent with choice alcohol consumption paradigms (28,29). Mice had ad libitum access to food and water (except for during the DID procedure, described below, when water was removed).…”