There is an urgent need for pharmacological agents that can prevent cue-induced relapse in abstinent cocaine users. In several rat models, cocaine seeking requires glutamate-mediated excitation of medium spiny neurons (MSN) of the nucleus accumbens (NAc). In rats that are drug-nave or have had limited cocaine exposure, this excitation is mediated primarily by Ca2+-impermeable AMPA receptors (CI-AMPARs). After extended access cocaine self-administration (SA) and withdrawal, cue-induced craving intensifies (incubates). We have shown that the expression of incubated cue-induced craving is mediated by Ca2+-permeable AMPARs (CP-AMPARs), which have higher conductance than CI-AMPARs and therefore enable stronger excitation of MSN. The objective of this proposal is to determine if group I metabotropic glutamate receptors (mGluRs), which are expressed postsynaptically in MSN, can be targeted to remove CP-AMPARs from NAc synapses of incubated rats. The central hypothesis is that group I mGluRs normally exert an inhibitory influence on CP-AMPAR levels in NAc synapses, and that decreased group I mGluR signaling during withdrawal permits CP-AMPAR accumulation, whereas stimulating group I mGluRs will remove CP-AMPARs from the NAc of incubated rats and thus reduce craving. This hypothesis, formulated based on preliminary data showing that group I mGluR stimulation removes CP-AMPARs from NAc synapses in slices and cultures, will be tested by pursuing 3 Aims: 1) Determine the effect of group I mGluR activation and blockade on CP-AMPAR levels in NAc MSN in primary culture. Cultured MSN express CP-AMPARs, so this model system can be used to study acute and tonic regulation of CP-AMPAR trafficking by group I mGluRs. 2) Determine the effect of acute group I mGluR activation on AMPAR transmission in the NAc and the expression of cue-induced cocaine seeking. Slice recordings and behavioral studies in incubated rats will determine if acute group I mGluR stimulation removes CP-AMPARs from NAc synapses and reduces craving. 3) Measure group I mGluR surface expression and Homer levels in the NAc after cocaine withdrawal and determine if increasing group I mGluR signaling during withdrawal prevents CP-AMPAR accumulation and incubation. Homers are scaffolding proteins that can mediate group 1 mGluR signaling. Biochemical and behavioral experiments will test the hypothesis that group I mGluR surface expression, levels of long Homer isoforms, and/or mGluR-Homer interactions decrease in the NAc after extended access cocaine SA, permitting accumulation of CP-AMPARs, and that restoring group I mGluR signaling during withdrawal will prevent CP-AMPAR accumulation and incubation of cocaine craving. Our research plan is innovative because it challenges dogma by exploring the therapeutic utility, for addiction, of activating rather than blocking group I mGluRs and because it explores a novel form of synaptic plasticity in the NAc. The significance of our studies is that we expect them to identify a target that can be attacked with existing drugs (group I mGluR positive allosteric modulators) to reduce the risk of relapse during abstinence.
In abstinent cocaine users, environmental cues previously associated with drug use are powerful triggers for relapse. The proposed research is relevant to NIHs mission of reducing the burden of illness because it explores a novel cellular mechanism to reverse the cocaine-induced neuronal plasticity that underlies enhanced cue-induced cocaine craving during withdrawal. Because this mechanism can be targeted using a class of drugs currently under development for other disorders, our results may rapidly translate into a novel strategy for preventing relapse to cocaine use.
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