Date of Award

12-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Molecular Therapeutics and Cell Signaling

Research Advisor

Jeffrey Steketee, Ph.D.

Committee

Matthew Ennis, Ph.D. Kristin Hamre, Ph.D. Rennolds Ostrom, Ph.D. Wen Lin Sun, Ph.D.

Abstract

Cocaine sensitization is associated with cocaine-induced hyperexcitability of pyramidal projection neurons within the medial prefrontal cortex (mPFC). Such hyperexcitability presumably results in increased glutamatergic input to reward-affiliated brain regions such as the ventral tegemental area (VTA) and nucleus accumbens (NAc), consequently facilitating drugseeking behavior. Metabotropic glutamate receptor 5 (mGluR5) has been implicated in cocaine addiction and demonstrated to increase neuronal excitability, therefore, the aim of the present study was to investigate the effect of intra-mPFC mGluR5 manipulation on behavioral and neurochemical sensitization and drug-seeking. Bilateral cannulae were implanted into the mPFC of male Sprague-Dawley rats and mGluR5 antagonist MTEP (15 nmol/side) or saline was microinjected into the region five minutes prior to a challenge cocaine injection. Our data showed that intra-mPFC mGluR5 blockade via MTEP prevented late, but not early, behavioral sensitization. Further, intra-mPFC mGluR5 activation via DHPG (30 uM) increased mPFC and NAc glutamate levels in sensitized animals during early and late withdrawal, respectively. Finally, we observed a nonsignificant trend toward an MTEP-induced reduction in drug-seeking following the presentation of a cocaine-associated cue in animals that had been trained to selfadminister cocaine. Taken together, our data suggest mPFC mGluR5 plays a role in cocaine addiction, possibly through the modulation of mPFC pyramidal neuronal excitability

DOI

10.21007/etd.cghs.2012.0321

Comments

One year embargo expired December 2013

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