Metabotropic Glutamate Receptor 5 in the Medial Prefrontal Cortex: Role in Cocaine Sensitization and Addiction

Abstract

AcknowledgementsI would like to thank my advisor, Dr. Jeff Steketee, for his guidance and support throughout this process, as well as my outstanding committee, Drs. Matthew Ennis, Kristin Hamre, Rennolds Ostrom, and Wen Lin Sun for their input, suggestions, and evaluation. I am thankful for my lab buddy, Kyle Summers, for his exceptional conversation and collaboration on the self-administration project, and former post-doc Kun "Luke" Liu for teaching me microdialysis. I would like to thank my husband, Steve, for existing, as I could not have been this happy spending my life with anyone else. Last but absolutely not least, I would like to thank my children, Jack and Cassidy, for motivating me to complete this work.iv AbstractCocaine 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 drug-seeking 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 intramPFC 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 self-administer cocaine. Taken together, our data suggest mPFC mGluR5 plays a role in cocaine addiction, possibly through the modulation of mPFC pyramidal neuronal excitability.