The Role of STEP in Cocaine-Induced Alterations in Structural Plasticity within the dmPFC

Medical University Of South Carolina, Charleston SC

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Abstract

? DESCRIPTION (provided by applicant): The goal of the proposed research is to investigate the role of striatal-enriched tyrosine phosphatase (STEP) activation in cocaine-induced structural plasticity and related signaling changes within the prelimbic prefrontal cortex (PLC) of rats during early withdrawal and how these changes are implicated in relapse. Relapse to drug- seeking remains a major obstacle in the treatment of cocaine addiction. Clinical studies suggest that relapse is precipitated by diminished prefrontal cortical activity. Thus, normalizing synaptic activity in the PLC, and downstream targets such as the nucleus accumbens core (NAcc), may be a viable approach to prevent relapse. Our lab has previously shown that cocaine self-administration (SA) in rodents results in pronounced dephosphorylation of ERK and GluN2A/B, and increased activity of STEP (an ERK and NMDA receptor phosphatase), in the PLC two hours after the final SA session (defined as early withdrawal), which underlies relapse following abstinence and extinction training. STEP-induced depression of synaptic activity is implicated in numerous neuropsychiatric disorders, but the role of STEP in cocaine-induced synaptic plasticity is relatively unknown. Furthermore, STEP activation decreases actin polymerization, causing shrinkage of dendritic spines. Evidence indicates that structural plasticity evoked by cocaine in both the dmPFC and the NAcc during prolonged abstinence is associated with altered glutamatergic signaling and promotes relapse. However, little is known about cocaine-induced structural plasticity during early withdrawal, and how this might facilitate relapse following abstinence. Thus, we propose the hypothesis that STEP activation during early withdrawal decreases synaptic activity via dephosphorylation of ERK, GluN2B, and an important regulator of actin polymerization, SPIN90, promoting altered structural plasticity in PLC neurons projecting to the NAcc. Aim 1 will determine whether cocaine-induced structural plasticity is altered in NAcc projection neurons arising from the PLC and involves STEP-mediated dephosphorylation of ERK, GluN2B, and SPIN90 in the PLC using diolistic labeling, intracellular filling, immunofluorescence, and immunoassay techniques. Aim 2 will investigate whether directly stimulating the PLC immediately after SA with Gq-coupled designer receptors exclusively activated by designer drugs (DREADDs) will reverse cocaine-induced structural plasticity and suppress relapse to drug seeking. Confirmation of our hypothesis will increase the rationale for targeting the PLC with pharmacotherapeutics that increase synaptic activity during abstinence, possibly by targeting STEP-induced synaptic depression.