These data suggest that stimulation of mGluR5s in the mPFC is sufficient to induce cocaine sensitization and is necessary for the expression of this sensitized response.
Cocaine sensitization is associated with increased excitability of pyramidal projection neurons in the medial prefrontal cortex. Such hyperexcitability is presumed to increase glutamatergic input to the nucleus accumbens and ventral tegmental area. This study examined the effects of medial prefrontal cortex Group I metabotropic glutamate receptor activation on glutamate levels in the medial prefrontal cortex, nucleus accumbens, and ventral tegmental area in sensitized and control animals. Male Sprague-Dawley rats received four daily injections of cocaine (15 mg/kg, i.p.) or saline (1 mL/kg i.p.). One, 7, or 21 days from the fourth injection, dual-probe microdialysis experiments were performed wherein Group I metabotropic glutamate receptor agonist DHPG was infused into the medial prefrontal cortex and glutamate levels in this region as well as the nucleus accumbens or ventral tegmental area were examined. Intra-mPFC DHPG infusion increased glutamate levels in the medial prefrontal cortex at 1 and 7 days withdrawal, and in the nucleus accumbens at 21 days withdrawal in sensitized rats. These results suggest Group I metabotropic glutamate receptor activation may contribute to the increased excitability of medial prefrontal cortex pyramidal neurons in sensitized animals.
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.
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