Alcohol and the Brain: Neuronal Molecular Targets, Synapses, and Circuits

Abstract

Ethanol is one of the most commonly abused drugs. Although environmental and genetic factors contribute to the etiology of alcohol use disorders, it is ethanol's actions in the brain that explain (1) acute ethanol-related behavioral changes, such as stimulant followed by depressant effects, and (2) chronic changes in behavior, including escalated use, tolerance, compulsive seeking, and dependence. Our knowledge of ethanol use and abuse thus relies on understanding its effects on the brain. Scientists have employed both bottom-up and top-down approaches, building from molecular targets to behavioral analyses and vice versa, respectively. This review highlights current progress in the field, focusing on recent and emerging molecular, cellular, and circuit effects of the drug that impact ethanol-related behaviors. The focus of the field is now on pinpointing which molecular effects in specific neurons within a brain region contribute to behavioral changes across the course of acute and chronic ethanol exposure.

The endocannabinoid‐alcohol crosstalk: Recent advances on a bi‐faceted target

“…Alcohol produces its effects through actions on multiple brain circuits and involves neuroadaptive changes not only in adulthood but especially in critical periods of development …”

“…Alcohol produces its effects through actions on multiple brain circuits and involves neuroadaptive changes not only in adulthood but especially in critical periods of development. 22,[25][26][27][28][29][30][31] The past 2 decades of clinical research and data derived from preclinical models of alcohol addiction point to the glutamatergic and the GABAergic systems as the main target of alcohol activity in the mesocorticolimbic system, [32][33][34][35][36][37][38] where alcohol intake results in increased dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Notwithstanding, alcohol's mechanism of action at the molecular level is fairly unknown.…”

Nicotine and alcohol: the role of midbrain dopaminergic neurons in drug reinforcement

“…Acute ethanol potentiates the firing of DA neurons, but has differing effects on GABA release at DA synapses and inhibitory transmission within the VTA (Fig. ; Burkhardt & Adermark, ; Abrahao et al., ). Approximately 20–40% of VTA neurons are GABAergic and regulate VTA DA neuron activity (Carr et al., ; Margolis et al., ).…”

“…The magnitude of ethanol's impact within specific neural circuits and cells is dictated by concentration, route of administration, and exposure frequency (i.e., acute vs. chronic). Therefore, it is imperative to take into account network modulations occurring throughout the brain during chronic use (Seo & Sinha, ; Abrahao et al., ). Optogenetics and novel tracing viral strategies have now made it possible to assess behaviorally relevant inputs and anatomical connectivity between brain structures and how the function and sensitivity of these circuits change in the context of drug addiction (Osakada et al., ; Tye & Deisseroth, ).…”

Identification of alcohol‐binding site(s) in proteins using diazirine‐based photoaffinity labeling and mass spectrometry

“…Further, to develop newer drugs with minimum side‐effects, it is imperative to understand the molecular mechanism of alcohol action and define molecular targets (receptors, enzymes, and ion channels) of ethanol in the brain, so that drugs can be designed based on the alcohol‐binding site(s). Ethanol has multiple targets and affects many neuronal circuitries in the brain . For example, ion channels such as GABA A , glycine, and glutamate; enzymes such as adenylyl cyclase, phosphodiesterase type 4, protein kinase C (PKC), etc., are some of the well‐characterized targets of ethanol.…”