Medical University of South Carolina
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Chemogenetic modulation of prelimbic cortical ouputs and their role in cocaine-seeking

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About This Project

Substance use disorder is a chronic relapsing disorder characterized by a compulsive drive for seeking drug, even if after periods of prolonged abstinence, following presentation of drug-associated contexts or cues. Patients addicted to cocaine, in particular, have high rates of relapse relative to other drugs of abuse. Our lab is particularly interested in the role of prelimbic cortical glutamatergic excitatory projection neurons in cocaine-seeking behavior following abstinence using preclinical animal models of relapse. Specifically, we are interested in how dysfunctional adaptations in prelimbic cortical neurons during early abstinence from chronic cocaine self-administration play a role in subsequent cocaine-seeking behavior (i.e. animal model of relapse), with a specific emphasis on prelimbic cortical projections to the nucleus accumbens core. Previous studies, both preclinical and clinical, have indicated that this specific pathway plays a crucial role in seeking for various drugs of abuse after abstinence. Our previous preclinical studies have indicated that prelimbic cortical glutamatergic transmission is in a quasi hypo-active state during early abstinence, when transient neuroadaptations occur that promote subsequent relapse behavior. Thus, we hypothesized that augmenting glutamatergic neurotransmission within the prelimbic cortex during early abstinence would be sufficient to prevent relapse after abstinence. Moreover, we hypothesized that specifically elevating glutamatergic neurotransmission in neurons in the prelimbic cortex that project specifically to the nucleus accumbens core would suppress cocaine-seeking after abstinence. To address this question, we used a viral-vector approach known as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in order to either; a) activate all prelimbic cortical glutamatergic neurons immediately after self-administration, or b) activate only neurons projecting to the nucleus accumbens core. Preliminary results indicate that activation of all outputs shows a non-significant trend toward suppressing relapse, which is recapitulated by specifically activating prelimbic cortical neurons projecting to the nucleus accumbens core. Overall, our results show that preferentially targeting prelimbic cortical neuron glutamatergic activity, particularly those projecting to the nucleus accumbens core, during the critical early abstinence timepoint following chronic cocaine self-administration may be a therapeutic target for preventing relapse in clinical patients diagnosed with a substance use disorder. The results from these experiments are being presented at the Society for Neuroscience annual meeting in Washington DC in November, 2017.

The Researchers

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Ben Siemsen

Graduate student

Neuroscience

Medical University of South Carolina

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Founded in 1824, The Medical University of South Carolina (MUSC) continues the tradition of excellence in education, research and patient care. MUSC educates and trains more than 3,000 students and residents in six colleges and has nearly 13,000 employees, including approximately 1,500 faculty members. As the state’s only academic health science center and largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.3 billion, with an annual economic impact of nearly $4 billion and annual research funding in excess of $250 million. MUSC operates a 700-bed medical center, which includes a nationally recognized children's hospital, the NCI-designated Hollings Cancer Center, a Level I trauma center, Institute of Psychiatry, more than 100 outreach locations across the state, and South Carolina’s only transplant center.

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