The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

Abstract

The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.

Fig. 1.

NAc connectivity. The NAc receives inputs from cortical, allocortical, thalamic, midbrain, and brainstem structures. In turn, it sends projections to other basal ganglia nuclei (VP and substantia nigra pars reticulata), nuclei in the mesencephalon, the hypothalamus, and the extended amygdala. Note that many structures project from different subareas to the NAcore or NAshell. For clarity, these projections have been color coded as projecting to the NAcore (green), medial NAshell (light blue), or lateral NAshell (dark blue); in reality, many regions project to both the NAcore and NAshell along topographical gradients (e.g., dorsoventral projections from the hippocampus terminating from lateral to medial parts of the accumbens; shown as color gradients in the figure). A number of regions project uniformly throughout the accumbens and are marked white. A8, retrorubral area; ACC, anterior cingulate cortex; AId, dorsal anterior insular; AIv, ventral anterior insular; dHPC, dorsal hippocampus; dlVP, dorsolateral ventral pallidum; DRN, dorsal raphe nucleus; IL, infralimbic cortex; ILT, interlaminar nuclei of the thalamus; LC, locus coeruleus; LH, lateral hypothalamus; LPO, lateral preoptic area; NTS, nucleus of the solitary tract; PL, prelimbic cortex; PPN, pedunculopontine nucleus; PVT, paraventricular nucleus of the thalamus; vlVP, ventrolateral ventral pallidum; vmVP, ventromedial ventral pallidum; SNc, substantia nigra pars compacta; SNpr, substantia nigra pars reticulata.

Fig. 2.

NAc: the usual suspects. A general schematic of the some of the cell types discussed in this review that are present in the NAc, including MSNs (light blue), astrocytes (yellow), and various types of interneurons (purple). The accumbens receives inputs from several brain regions; examples of neurons that synapse in the accumbens are glutamatergic projection neurons (green) as well as dopaminergic projection neurons (red) (for more detail see Fig. 2).

Fig. 3.

Spine head diameter and synaptic potentiation. Synaptic plasticity involves both structural and functional changes that allow stronger or weaker synaptic connections. In LTP, spine head diameter increases to allow insertion of AMPARs at the synapse. The functional output of synaptic potentiation is an increase in the ratio between AMPA and NMDA EPSCs, with either more AMPA or less NMDA. For changes in spine morphology to occur, the actin cytoskeleton must grow and become more complex to allow structural growth or shrinkage. Actin cycling involves the formation of filamentous actin from the monomer (G-actin). These filaments have barbed ends and are organized into long stalks that cycle to expand or contract dendritic spines. In LTD, spine head diameter decreases and AMPARs are removed. In parallel with these structural changes, the functional reading of synaptic plasticity, the AMPA/NMDA ratio, is decreased.

Fig. 4.

Pharmacological targets at the glutamatergic NAcore synapse. Shown here is a schematic of a glutamate synapse in the NAcore with the pre- (green) and postsynaptic (blue) terminals as well as an astrocytic contact (yellow). Glutamate is depicted as orange spheres and cysteine is shown as gray spheres. Listed next to AMPA, NMDA, mGLuR2/3, mGluR1, mGluR5, mGluR7, x_c-, and GLT-1 are the drugs that affect these proteins, which have been shown to inhibit drug seeking.