Effects of Cocaine Sensitization on Drug Self-Administration, Mesocorticolimbic SAPAP Levels, and Prefrontal Ionotropic Glutamate Receptors

Abstract

DEDICATIONTo my mother Andrea, who through her example taught me that the values of hard work, integrity, and good manners never go out of style To Karen, who taught me the true meaning of courage under the threat of certain death, and that those no longer with us physically continue to live in our thoughts iv ACKNOWLEDGEMENTS All information and data in this text was only possible due to the generous support and inexhaustible patience of my advisor Jeff Steketee and my graduate committee (which included Drs. John Boughter, Michael McDonald, Kazuko Sakata, and Wen Lin Sun). Also, instrumental to the completion of this project were the helping hands of Dr. Steve Tavalin. This project also could have never been completed without financial support from the University of Tennessee Health Science Center Neuroscience Institute and the National Institute on Drug Abuse (NIDA).v ABSTRACT Towards the goal of improving the knowledge base of how drugs of abuse function to create addicts and using currently uninvestigated areas of this knowledge base, we focused our research studies the male albino rat, and strived to explain how cocaine sensitization alters particular molecular mechanisms in the mesocorticolimbic system related to glutamate receptors, SAPAPs, and affects drug self-administration. Taking all the previously discussed research studies into consideration, we hypothesized that low-dose cocaine self-administration would yield a significant elevation in drug seeking behavior for psychostimulant sensitized animals. For specific changes at the PSD, we hypothesized that acute cocaine exposure and/or cocaine sensitization would alter iGluRs levels in the mPFC, and SAPAP levels in multiple sites of the mesocorticolimbic system. To test these hypotheses, we investigated the effects of psychostimulant sensitization on various parameters of self-administration by infusing a low-dose cocaine reward proven to not induce sensitization during self-administration (reported here as 0.3 mg/kg/infusion). Although drug exposure did not significantly alter self-administration behavior, we did find that more drug exposed subjects acquired selfadministration behavior when compared to drug naïve controls. We also investigated the effects of acute cocaine exposure and/or cocaine sensitization on iGluRs in the mPFC and SAPAPs in the entire mesocorticolimbic circuit thru western blotting, immunolabeling of proteins of interest, and comparing protein levels to those found in cocaine naïve controls. A limited self-administration protocol also tested if SAPAP levels were altered by self-administration of a low-dose cocaine reward. For these experiments, we found that SAPAP protein levels are altered in multiple regions of the mesocorticolimbic system in response to contingent and non-contingent cocaine exposure, and that iGluR receptor subunits are altered in the prefrontal cortex in response to non-contingent cocaine exposure. vi PREFACEThe Incans that first cultivated the coca plant for medicinal use five millennia ago reserved this "Elix...