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.

Keywords: Addiction; Alcohol; Amygdala; Cortex; Endocannabinoid; GABA; Glutamate; Long-term depression; Striatum; Synaptic plasticity; Synaptic transmission.

Figure 1.

Molecular targets and neuromodulators involved in acute presynaptic ethanol actions at GABAergic synapses. A) Schematic diagram of a presynaptic terminal showing suspected sites of ethanol actions that enhance GABA release (*). The main suspected targets are voltage-gated calcium channels, AC, vesicle fusion, PKCε and intracellular Ca²⁺ stores. Neuropeptides, including CRF, eCBs and small molecule neurotransmitters (including feedback vesicular GABA release) can contribute to or modulate ethanol actions on presynaptic GABA release through actions on presynaptic GPCRs. Note that ethanol enhances GABA release in many brain regions, but inhibits release in others. B) Ethanol is thought to stimulate release of neuropeptides (including enkephalins and CRF) and eCBs, presumably from neurons, and these neuromodulators act on presynaptic GPCRs to alter GABA release. Arrows indicate stimulation, cross-ended lines indicate inhibition. AC = adenylyl cyclase, CB1 = cannabinoid type 1 receptor, CRF = corticotrophin-releasing factor, eCB = endocannabinoid, GABA = gamma-aminobutyric acid, GPCR = G protein-coupled receptor, Gαi/o = alpha i/o G protein subunit, Gαs/olf = alpha s/olf subunit of G protein, Gβγ = beta/gamma dimer subunit of G protein, PKA = protein kinase A, PKCε = protein kinase C epsilon,

Figure 2.

Presynaptic neuroadaptations to chronic ethanol exposure/consumption. Green arrows indicate increases in GABA and glutamate release observed in several brain regions, as well as increased CRF that drives increased GABA release in CeA. Red arrows indicate decreases in Gi/o-GPCR expression/function that occur at both GABAergic and glutamatergic synapses (including decreased GABA/GABA_BR feedback onto GABAergic terminals), as well as decreased GABA release observed in some brain regions. Decreases in GABA release are thought to compensate for ethanol-induced increases in neurotransmitter release at GABAergic synapses, while activation of GABA_B Gi/o-GPCRs participates in compensatory negative feedback that produces tolerance to the direct ethanol action on release (dashed arrow). At glutamatergic synapses, increased neurotransmitter release and decreased Gi/o-GPCR function may compensate for ethanol-induced decreases in glutamatergic transmission. Neuroadaptations that have a more allostatic role include increased GABA release and increased CRF signaling that enhances GABA release. AC = adenylyl cyclase, BLA = basolateral amygdala, CB1 = cannabinoid type 1 receptor, CeA = central amygdala, CRF = corticotrophin-releasing factor, Ctx = cortex, DS = dorsal striatum, GABA = gamma-aminobutyric acid, GABA_B = GABA type B receptor, GPCR = G protein-coupled receptor, Gαi/o = alpha i/o G protein subunit, Gαs/olf = alpha s/olf subunit of G protein, Gβγ = beta/gamma dimer subunit of G protein, Hipp = hippocampus, NAc = nucleus accumbens, DRN = dorsal raphe nucleus, PKA = protein kinase A.