Glutamatergic plasticity and alcohol dependence-induced alterations in reward, affect and cognition

Abstract

Introduction: Alcohol dependence is characterized by a reduction in reward threshold, development of a negative affective state, and significant cognitive impairments. Dependence-induced glutamatergic neuroadaptations in the neurocircuitry mediating reward, affect and cognitive function are thought to underlie the neural mechanism for these alterations. These changes serve to promote increased craving for alcohol and facilitate the development of maladaptive behaviors that promote relapse to alcohol drinking during periods of abstinence.

Objective: To review the extant literature on the effects of chronic alcohol exposure on glutamatergic neurotransmission and its impact on reward, affect and cognition.

Results: Evidence from a diverse set of studies demonstrates significant enhancement of glutamatergic activity following chronic alcohol exposure. In particular, up-regulation of GluN2B-containing NMDA receptor expression and function is a commonly observed phenomenon that likely reflects activity-dependent adaptive homeostatic plasticity. However, this observation as well as other glutamatergic neuroadaptations are often circuit and cell-type specific.

Discussion: Dependence-induced alterations in glutamate signaling contribute to many of the symptoms experienced in addicted individuals and can persist well into abstinence. This suggests that they play an important role in the development of behaviors that increase the probability for relapse. As our understanding of the complexity of the neurocircuitry involved in the addictive process has advanced, it has become increasingly clear that investigations of cell-type and circuit-specific effects are required to gain a more comprehensive understanding of the glutamatergic adaptations and their functional consequences in alcohol addiction.

Conclusion: While pharmacological treatments for alcohol dependence and relapse targeting the glutamatergic system have shown great promise in preclinical models, more research is needed to uncover novel, possibly circuit-specific, therapeutic targets that exhibit improved efficacy and reduced side effects.

Keywords: Addiction; Glutamate; Negative affect; Plasticity; Relapse; Withdrawal.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1. Simplified neurocircuitry illustrating the primary neural substrates for reward, negative affect and cognition

Alcohol dependence induces significant alterations in reward processing, the development of a negative affective state, and significant cognitive impairments that result in loss of behavioral flexibility and impulse control. Both dopaminergic and GABAergic projections from the VTA to the NAc play a key role in reward signaling (shown in green). This pathway is further modulated by glutamatergic input from the LHb, which in turn receives a reciprocal projection from the VTA that co-expresses both glutamate and GAB. In addition, glutamatergic projections from the LHb synapse onto GABAergic neurons of the RMTg to form a functional circuit that exerts inhibitory control over dopamine release in the VTA. Connections between nuclei of the amygdala and extended amygdala (shown in blue) mediate anxiety, anhedonia and increased sensitivity to stress. Glutamatergic inputs from the BLA impinge on neurons of both the CeA and BNST to facilitate the expression of anxiety-like behavior. Release of glutamate from BLA terminals in the BNST is further augmented by the release of corticotropin releasing factor (CRF) from neurons arising in the CeA. The PFC exerts top-down control over behavior via glutamatergic inputs to various subcortical regions including the DS, NAc, VTA and BLA (shown in red). In addition, cognitive performance is heavily controlled through network synchrony via a dense glutamatergic monosynaptic connection between the PFC and hippocampus (shown in red). Abbreviations: BLA – basolateral nucleus of the amygdala; BNST – bed nucleus of the stria terminals; CeA – central nucleus of the amygdala; DS – dorsal striatum; Hipp – hippocampus; LHb – lateral habenula; mPFC – medial prefrontal cortex; NAc – nucleus accumbens; OFC – orbitofrontal cortex; RMTg – rostrmedial tegmental nucleus; VTA – ventral tegmental area.

Figure 2. Commonly observed glutamatergic synaptic adaptations observed following chronic alcohol exposure

Chronic alcohol exposure is associated with an overall enhancement of glutamatergic signaling in the brain – a so-called hyperglutamatergic state. Many, though not all, brain regions exhibit an increase in presynaptic release of glutamate accompanied by an upregulation in receptor expression. In particular, an increase in extrasynaptic GluN2B expression has been consistently observed throughout the brain. Additional increases in GluN2A, GluA1, and GluA2 are also frequently noted. Chronic alcohol exposure is also associated with greater expression of the Group 1 mGluRs. These increases in receptor expression are driven, at least in part, by increased Homer levels, which have been observed in association with all receptor subtypes but most frequently with the mGluRs.