VTA Ionotropic Glutamate Receptors in Cocaine Addiction

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Cocaine addiction is thought to involve neuroplasticity in mesolimbic dopamine neurons. Previous studies have found that repeated "passive" cocaine administration transiently increases dopamine neuron excitability in the ventral tegmental area (VTA), and this effect may induce long-term sensitization to drugs and other stimuli that trigger craving and relapse. Some studies suggest that increased dopamine neuron excitability is caused by cocaine-induced up-regulation in GluR1 and NR1 subunits of AMPA and NMDA glutamate receptors, while others suggest these changes are related to PKA- and PKC/CaMKII-mediated phosphorylation processes that facilitate AMPA and NMDA receptor insertion into synaptic membranes, and enhance receptor function. Our preliminary results suggest that chronic cocaine "self'-administration produces a -90% up- regulation in GluR1 levels in the VTA at early (1 day) withdrawal. Thus, studies in Aim I will further characterize GluR1 up-regulation and other AMPA and NMDA receptor subunits following chronic cocaine self-administration, including PKA- and PKC/CaMKII-mediated phosphorylation of GluR1 and NR1, and the persistence of neuroadaptive changes in cocaine withdrawal. These studies also will determine whether passive and self-administration differentially regulates AMPA and NMDA receptor subunits, and whether changes are specifically related to "addicted" vs. "non-addicted" phenotypes based on individual differences in preferred levels of cocaine intake. Given functional and anatomical heterogeneity in VTA neurons, Aim II will measure GluR1 up-regulation in distinct VTA subregions, and in dopaminergic and GABAergic cell types, following chronic cocaine self-administration. Aims III and IV will determine the functional role of GuR1 and NR1 up-regulation in addiction-like changes in cocaine self-administration, and both the direct (short-term) and indirect (long-term) effects on reinstatement of cocaine seeking in withdrawal. In these studies, viral vectors will be infused into the VTA to produce highly localized over-expression of AMPA and NMDA receptor subunits in vivo prior to behavioral tests. Dominant negative GluR1 and NR1 mutants will determine the effects of down-regulating AMPA and NMDA receptor-mediated excitatory input to VTA neurons on self-administration and reinstatement. Similarly, phosphorylation-resistant mutants will study the role of PKA- and PKC/CaMKII-mediated phosphorylation of GluR1 and NR1 in regulating addictive behavior. Together, these studies will test the hypothesis that cocaine-induced up-regulation in GluR1 and NR1 in the VTA contributes to addiction-related changes in cocaine self-administration, and the propensity for relapse to cocaine seeking in withdrawal.