Cocaine-induced neuroadaptations in glutamate transmission: potential therapeutic targets for craving and addiction

Abstract

A growing body of evidence indicates that repeated exposure to cocaine leads to profound changes in glutamate transmission in limbic nuclei, particularly the nucleus accumbens. This review focuses on preclinical studies of cocaine-induced behavioral plasticity, including behavioral sensitization, self-administration, and the reinstatement of cocaine seeking. Behavioral, pharmacological, neurochemical, electrophysiological, biochemical, and molecular biological changes associated with cocaine-induced plasticity in glutamate systems are reviewed. The ultimate goal of these lines of research is to identify novel targets for the development of therapies for cocaine craving and addiction. Therefore, we also outline the progress and prospects of glutamate modulators for the treatment of cocaine addiction.

Figure 1

Proposed neuronal circuitry mediating cocaine priming–induced reinstatement of drug-seeking behavior. The medial prefrontal cortex (mPFC) sends segregated glutamatergic afferents to the nucleus accumbens (NA). These include excitatory projections from the dorsal mPFC (anterior cingulated cortex and dorsal prelimbic cortex) and ventral mPFC (ventral prelimbic cortex and infralimbic cortex) to the NA core and shell, respectively. The core and shell subregions of the accumbens also receive excitatory glutamatergic projections from both cortical (hippocampus) and subcortical (basolateral amygdala [BLA]) nuclei. Dopaminergic projections from the ventral tegmental area (VTA) and substantia nigra (SN) modulate the flow of emotional, declarative, and procedural memories through circuits centered on the NA, mPFC, BLA, and hippocampus. The activity of VTA and SN dopamine cells is regulated by excitatory glutamatergic projections from the pedunculopontine tegmental nucleus (PPTg)/laterodorsal tegmental nucleus (LDT), mPFC, hippocampus, and BLA, as well as inhibitory GABAergic/peptidergic projections from the NA and ventral pallidum (VP). Excitatory cholinergic afferents from the PPTg/LDT also synapse on midbrain dopamine neurons. The NA functions to translate the rewarding/reinforcing effects of drugs of abuse into drug-seeking behavior by processing, consolidating, and integrating information from limbic nuclei with motor functions of basal ganglia structures including the VP, thalamus, and motor cortex. (In color in Annals online.)

Figure 2

Glutamate receptor–mediated signaling. Glutamate released into the synaptic cleft binds to and activates ionotropic glutamate receptors (NMDA, AMPA, and kainate [KA] receptors) on postsynaptic membranes. Extracellular glutamate also binds to and activates perisynaptic metabotropic glutamate receptors located on presynaptic (mGluR2/3 autoreceptors) or postsynaptic (mGluR1/5s heteroreceptors) membranes. Influx of Na⁺, Ca²⁺, and K⁺ ions through activated AMPA/KA receptors depolarizes a neuron and subsequently relieves the Mg²⁺ block from voltage-sensitive NMDA receptors and activates voltage-gated Ca²⁺ channels (not shown). In addition to propagating action potentials, influx of cations through ionotropic glutamate receptors activates several intracellular signaling pathways including, but not limited to, Ras, CaMKII, and protein kinase A (PKA). Group I (mGluR1/5) and group II (mGluR2/3) metabotropic glutamate receptors are coupled via G_q and G_i/o, respectively, to intracellular enzymes. Stimulation of mGluR1/5s activates phospholipase C (PLC), which catalyzes the production of inositol-1,4,5-triphosphate (IP₃) and diacylglycerol (DAG) from phosphatidylinositol-4,5-bisphosphate (PIP_s). The resulting increase in cytoplasmic IP₃ triggers release of Ca²⁺ from intracellular stores, including the endoplasmic reticulum (ER). Stimulation of mGluR2/3s inhibits adenylyl cyclase (AC) activity, thus decreasing intracellular levels of cAMP and PKA. The cytoplasmic proteins PSD-95, glutamate receptor–interacting protein (GRIP), and Homer anchor glutamate receptors to the PSD complex. For example, Shank–Homer interactions link mGluR1/5s to NMDA receptors through PSD-95 and guanylate kinase–associated protein (GKAP). GluR1-containing AMPA receptors may be linked to mGluR1/5s through interactions between Homer and phosphoinositide 3 kinase (PI3-K) enhancer (PIKE-L). Metabotropic glutamate receptor–mediated signaling is influenced by regulators of G protein signaling (RGS), including activator of G protein signaling 3 (AGS3). AGS3 binds to and stabilizes the inactive guanosine diphosphate (GDP)–bound G_i conformation, preventing GDP release and thereby inhibiting G_i-mediated signaling. PKA phosphorylates dopamine- and cyclic AMP–regulated phosphoprotein (DARPP-32) at Thr34, which enhances extracellular signal–regulated kinase (ERK) signaling by inhibiting phosphatase activity. Activation of ionotropic and metabotropic glutamate receptors ultimately leads to phosphorylation of transcription factors, including cAMP response element–binding protein (CREB) at Ser133, changes in gene expression, and persistent changes in synaptic plasticity. See text for more detail on how repeated cocaine administration influences glutamate receptor–mediated signaling in the nucleus accumbens. (In color in Annals online.)

Figure 3

Link between nucleus accumbens shell dopamine and glutamate systems, via L-type Ca²⁺ channels and Ca²⁺/calmodulin kinase II (CaMKII), which is proposed to underlie the reinstatement of cocaine seeking. In brief: stimulation of D1-like dopamine receptors serially activates L-type Ca²⁺ channels and CaMKII. In addition to phosphorylation of CaMKII, reinstatement of cocaine seeking is associated with phosphorylation of GluR1 AMPA receptor subunits at Ser831, a known CaMKII and protein kinase C (PKC) phosphorylation site, as well as increased surface expression of GluR1-containing AMPA receptors in the nucleus accumbens shell. However, cocaine priming–induced reinstatement was not associated with an increase in GluR1 phosphorylation on Ser845, a known protein kinase A (PKA) phosphorylation site. Interfering with PDZ domain–containing proteins, such as synapse-associated protein (SAP) 97, and GluR1 subunits impairs trafficking of GluR1-containing AMPA receptors to the cell surface and attenuates cocaine seeking. Reinstatement of drug seeking is also associated with increased phosphorylation of GluR2 subunits at Ser880, a known PKC phosphorylation site that promotes internalization of GluR2-containing AMPA receptors. Although the receptor systems that activate PKC signaling during the reinstatement are unknown, one possibility is mGluR1/5s that are coupled to PKC via PLC. Consistent with the theory that PKC phosphorylation promotes internalization of GluR2-containing AMPA receptors after a priming injection of cocaine, disruption of accumbens shell protein interacting with C kinase (PICK1) function, which involves binding to GluR2 subunits and their rapid internalization, attenuates the reinstatement of cocaine seeking. Taken together, these results suggest that the reinstatement of cocaine-seeking behavior is associated with dynamic trafficking of AMPA receptor subunits between the cell surface and cytoplasmic compartments within the accumbens and that these molecular adaptations underlie cocaine-induced synaptic plasticity. (In color in Annals online.)