Presynaptic Ethanol Actions: Potential Roles in Ethanol Seeking

Abstract

Ethanol produces intoxication through actions on numerous molecular and cellular targets. Adaptations involving these and other targets contribute to chronic drug actions that underlie continued and problematic drinking. Among the mechanisms involved in these ethanol actions are alterations in presynaptic mechanisms of synaptic transmission, including presynaptic protein function and excitation-secretion coupling. At synapses in the central nervous system (CNS), excitation-secretion coupling involves ion channel activation followed by vesicle fusion and neurotransmitter release. These mechanisms are altered by presynaptic neurotransmitter receptors and prominently by G protein-coupled receptors (GPCRs). Studies over the last 20-25 years have revealed that acute ethanol exposure alters neurotransmitter secretion, with especially robust effects on synapses that use the neurotransmitter gamma-aminobutyric acid (GABA). Intracellular signaling pathways involving second messengers such as cyclic AMP and calcium are implicated in these acute ethanol actions. Ethanol-induced release of neuropeptides and small molecule neurotransmitters that act on presynaptic GPCRs also contribute to presynaptic potentiation at synapses in the amygdala and hippocampus and inhibition of GABA release in the striatum. Prolonged exposure to ethanol alters neurotransmitter release at many CNS GABAergic and glutamatergic synapses, and changes in GPCR function are implicated in many of these neuroadaptations. These presynaptic neuroadaptations appear to involve compensation for acute drug effects at some synapses, but "allostatic" effects that result in long-term resetting of synaptic efficacy occur at others. Current investigations are determining how presynaptic neuroadaptations contribute to behavioral changes at different stages of alcohol drinking, with increasing focus on circuit adaptations underlying these behaviors. This chapter will discuss the acute and chronic presynaptic effects of ethanol in the CNS, as well as some of the consequences of these effects in amygdala and corticostriatal circuits that are related to excessive seeking/drinking and ethanol abuse.

Female-specific decreases in alcohol binge-like drinking resulting from GABAA receptor delta-subunit knockdown in the VTA

“…While there have been conflicting reports 29 , it has been suggested that low alcohol concentrations influence the activity of δ-containing GABA A receptors in recombinant receptor systems as well as in slices 9–11,30,31 . However, it is also likely that the well-documented effects of ethanol on presynaptic GABA release 15–17 and/or increases in neurosteroid levels 18–20,32 may indirectly mediate the effects of ethanol on these receptors. Regardless, global deletion of the Gabrd gene was found to be associated with reduced 24 hr alcohol consumption and preference in males and females 12 .…”

“…GABA receptors containing the γ2 subunit, which mediate phasic inhibition, respond to high alcohol concentrations; whereas, δ-containing GABA A receptors, which mediate tonic inhibition, have been suggested to respond to low/moderate alcohol concentrations 11–13 . The role of extrasynaptic GABA A Rs in conferring sensitivity to alcohol has been proposed to be due to direct effects on these receptors 14 , but may also be mediated indirectly via changes in presynaptic GABA release 15–17 or ethanol-induced increases in neurosteroids 18–20 that potentiate the effects of GABA on these extrasynaptic receptor subtypes 21 . Whether the δ subunit is necessary for the behavioral effects of alcohol concentrations achieved in an active binge drinking session remains unknown, although the global loss of these receptors has been shown to reduce alcohol intake and alcohol preference 12 .…”

Gabapentin for alcohol use disorder: A good option, or cause for concern?

“…20 Acutely, alcohol promotes GABA release and may also reduce GABA degradation, producing sedative and anxiolytic effects. 21 Chronic alcohol use leads to a decrease in the number of GABA A receptors. Clinically, this downregulation manifests as tolerance to alcohol's sedating effects.…”

“…Clinically, this downregulation manifests as tolerance to alcohol's sedating effects. 21 Alcohol affects the signaling of glutamatergic interaction with the N-methyl-d-aspartate (NMDA) receptor. 22 Glutamate activates this receptor as well as the voltage-gated ion channels, modifying calcium infl ux and increasing neuronal excitability.…”

Synaptic plasticity mechanisms common to learning and alcohol use disorder

“…For example, loss of endocannabinoid-dependent LTD is observed following exposure to several drugs in addition to ethanol (Mato et al 2005;Xia et al 2006;Adermark et al 2011;Atwood et al 2014a). However, the mechanisms underlying these effects are likely to be different, as cannabinoid drugs down-regulate receptor function, while EtOH may have a more general effect on intraterminal signaling mechanisms involved in presynaptic LTD (Hoffman et al 2003;Mato et al 2005;Lovinger 2017). Given the different primary molecular targets of ethanol and other drugs of abuse, it is likely that compensatory plasticity involving changes in these target molecules would also differ for the different substances.…”