Synaptic effects induced by alcohol

Abstract

Ethanol (EtOH) has effects on numerous cellular molecular targets, and alterations in synaptic function are prominent among these effects. Acute exposure to EtOH activates or inhibits the function of proteins involved in synaptic transmission, while chronic exposure often produces opposing and/or compensatory/homeostatic effects on the expression, localization, and function of these proteins. Interactions between different neurotransmitters (e.g., neuropeptide effects on release of small molecule transmitters) can also influence both acute and chronic EtOH actions. Studies in intact animals indicate that the proteins affected by EtOH also play roles in the neural actions of the drug, including acute intoxication, tolerance, dependence, and the seeking and drinking of EtOH. This chapter reviews the literature describing these acute and chronic synaptic effects of EtOH and their relevance for synaptic transmission, plasticity, and behavior.

Fig. 1

Acute and chronic EtOH effects on GABAergic and glutamatergic synaptic transmission. a Schematic diagram of a GABAergic synapse, including presynaptic GPCRs that modulate neurotransmitter release, and postsynaptic ionotropic receptors (located both at synapses and extrasynaptically) that mediate fast synaptic transmission. The predominant presynaptic effect of acute EtOH is potentiation of GABA release (most likely by increasing the probability of vesicle fusion). This presynaptic potentiation may involve neuromodulators such as CRF, and activation of presynaptic GPCRs and downstream signaling pathways. Postsynaptically, EtOH potentiates ionotropic GABA_A receptor function. Increases in synaptic GABA_AR function prolong synaptic responses, while potentiation of extrasynaptic receptors increases tonic current that affects neuronal excitability, b Changes in GABAergic synapses following chronic EtOH exposure. Presynaptically, the release of GABA is decreased. Alterations in levels of neuromodulators that act on GPCRs, as well as altered function of presynaptic GPCRs may contribute to these changes. Postsynaptically, the subunit composition of GABA_ARs is altered, often including increased synaptic α4-containing receptors, and fewer α1-containing synaptic receptors. Synaptic α4-containing receptors may be less sensitive to acute EtOH, promoting tolerance to synaptic effect of the drug, c Schematic diagram of a glutamatergic synapse on a dendritic spine, including postsynaptic ionotropic receptors that mediate fast synaptic transmission. The predominant effect of acute EtOH is to inhibit ionotropic glutamate receptor function, and all subclasses of these receptors are sensitive to EtOH inhibition. The most potent effects have been observed at kainate and NMDA receptor subtypes, d Changes in glutamatergic synapses following chronic EtOH exposure. Presynaptically, the release of glutamate is enhanced. Postsynaptically, NMDAR function is increased, most likely due to increased receptor density at the synapse. There is also evidence for increased numbers of NR2B-containing NMDARs. There is also evidence of increased volume of the dendritic spine.