Drug addiction arises from aberrant synaptic plasticity that is induced by cocaine or other drugs of abuse. Our studies examine the molecular and cellular basis of this plasticity, and focus on adaptations mediated by cellular immediate early genes (IEG). The IEG termed Homer1a functions at excitatory synapses, and controls a newly identified signaling pathway that integrates aspects of dopamine and glutamate receptor signaling, reward-dependent synaptic plasticity, and drug addiction (1). Studies to date reveal that cocaine induces dopamine receptor-dependent intracellular signaling events that result in the transcriptional induction of Homer1a, together with the phosphorylation of group 1 metabotropic glutamate receptor type 5 (mGluR5). These coordinated events result in the binding of a prolyl isomerase termed Pin1 to mGluR5, which mediates a conformational switch that enhances the ability of mGluR5 to activate the NMDA receptor. We term this the mGluR5-Pin1 signaling pathway. Using a combination of approaches, we find that this pathway mediates synaptic plasticity that underlies cocaine motor sensitization. We hypothesize this pathway contributes to several forms of neuromodulator-dependent synaptic plasticity, and is a fundamental mechanism to modulate NMDA receptor function. The renewal application will examine the molecular basis of mGluR5-Pin1 coupling to NMDA receptor. Studies will assess the role of mGluR directed scaffolding proteins and the role of intracellular Ca2+ stores. We will also define how the Pin1 mechanism regulates mGluR1 gating to TRPC ion channels, and assess the contribution of mGluR-Pin1 signaling to cocaine-induced plasticity.
This proposal examines the molecular and cellular basis of drug addiction. The work focuses on a novel signaling pathway that is controlled by the immediate early gene Homer1a, and that involves group 1 metabotropic glutamate receptors to mediate dopamine receptor-dependent synaptic plasticity. Proposed studies will define the molecular mechanism of signal transduction and the impact on behavioral models important for understanding addiction.
Showing the most recent 10 out of 33 publications
