Mechanisms of Neuroplasticity and Ethanol's Effects on Plasticity in the Striatum and Bed Nucleus of the Stria Terminalis

Abstract

Long-lasting changes in synaptic function (i.e., synaptic plasticity) have long been thought to contribute to information storage in the nervous system. Although synaptic plasticity mainly has adaptive functions that allow the organism to function in complex environments, it is now clear that certain events or exposure to various substances can produce plasticity that has negative consequences for organisms. Exposure to drugs of abuse, in particular ethanol, is a life experience that can activate or alter synaptic plasticity, often resulting in increased drug seeking and taking and in many cases addiction.Two brain regions subject to alcohol's effects on synaptic plasticity are the striatum and bed nucleus of the stria terminalis (BNST), both of which have key roles in alcohol's actions and control of intake. The specific effects depend on both the brain region analyzed (e.g., specific subregions of the striatum and BNST) and the duration of ethanol exposure (i.e., acute vs. chronic). Plastic changes in synaptic transmission in these two brain regions following prolonged ethanol exposure are thought to contribute to excessive alcohol drinking and relapse to drinking. Understanding the mechanisms underlying this plasticity may lead to new therapies for treatment of these and other aspects of alcohol use disorder.

Figure 1

Schematic illustration of neuronal circuits in the dorsomedial striatum (DMS) and of the effects of acute and chronic ethanol exposure on plasticity in this region. (A) Simplified diagram of the circuits in the DMS, showing glutamatergic cortical inputs to the major projection neurons in the striatum (i.e., medium spiny neurons [MSNs]). Also indicated is GABAergic microcircuitry involving MSN–MSN synapses that tend to innervate dendrites and synapses made by fast-spiking interneurons (FSIs) on MSN cell bodies. These MSNs project out of the striatum to the globus pallidus external segement (GPe) and the substantia nigra pars reticulata (SNr). Boxed areas indicate the predominate sites of synapses on the MSNs. (B) Effects of acute ethanol exposure on plasticity at synapses onto DMS MSNs. The net effects are prevention of normal plasticity (i.e., inhibition of long-term potentiation [LTP]) at excitatory cortical glutamatergic inputs, while a new form of NMDA receptor (NMDAR)-dependent long-term facilitation (LTF) occurs. Increased synaptic inhibition also occurs. Thus, the net signal output from the DMS may be dampened, while responses to associative cortical input may become aberrant. (C) Effects of chronic ethanol exposure on plasticity at synapses in the DMS. Net effects include prolonged LTF and LTP-like increase in AMPA receptor function at glutamatergic synapses, accompanied by net decreases in inhibition. These changes may alter goal-directed ethanol-related behaviors, particularly those controlled by the prefrontal cortex and related associative cortices.

Figure 2

Schematic illustration of neuronal circuits in the dorsolateral striatum (DLS) and of the effects of acute and chronic ethanol exposure on plasticity in this region. (A) Simplified diagram of the circuits in the DLS, showing glutamatergic cortical inputs to the major projection neurons in the striatum (i.e., medium spiny neurons [MSNs]). Also indicated is GABAergic microcircuitry involving MSN–MSN synapses that tend to innervate dendrites and synapses made by fast-spiking interneurons (FSIs) on MSN cell bodies. These MSNs project out of the striatum to the globus pallidus external segement (GPe) and the substantia nigra pars reticulata (SNr). Boxed areas indicate the predominate sites of synapses on the MSNs. (B) Effects of acute ethanol exposure on plasticity at synapses onto DLS MSNs. The major net effect described to date is decreased inhibition, which would increase net output from sensorimotor striatum and perhaps initiate habit formation. (C) Effects of chronic ethanol exposure on plasticity at synapses in the DLS. The net effects are decreased presynaptic endocannabinoid (eCB)-dependent long-term depression (LTD), increased MSN excitability, and decreased inhibitory GABAergic transmission onto MSN. These changes should foster greater DLS output in response to a given set of inputs from sensorimotor cortex, potentially facilitating habit formation.