Date of Award

12-2007

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmacology

Research Advisor

Burt M. Sharp M.D.

Committee

Dan Goldowitz, Ph.D Shannon G. Matta, Ph.D. Jeffery D. Steketee, Ph.D. Steven J. Tavalin, Ph.D.

Abstract

The mesocorticolimbic pathway is critical in almost all aspects of drug abuse, including nicotine. Though many of the neurochemical and molecular effects of nicotine have been well studied, nicotine’s long-term neuroadaptive effects, specifically within the mesocorticolimbic pathway, are largely undefined. Thus, in current study, we determined the neuroadaptive changes in the mesocortical glutamatergic system during chronic nicotine self-administration (SA), which emulates important aspects of nicotine intake by humans, and after extinction. In the initial study, after 18 days of nicotine SA, in the medial prefrontal cortex (mPFC), NMDA receptor subunit 2A (NR2A) and NR2B were increased by 67% and 83%, respectively. In the ventral tegmental area (VTA), glutamate receptor subunit 2/3 (GluR2/3) was increased by 34%. These findings suggest the glutamate neurotransmission between mPFC and VTA may be enhanced during chronic nicotine SA. Thus, we determined the effects of nicotine SA and extinction on NMDA-induced glutamate neurotransmission between mPFC and VTA. On d 19 of ad lib access to nicotine SA, both brain regions were microdialyzed for glutamate while mPFC was sequentially perfused with: Kreb’s Ringer Buffer (KRB), 200 mM NMDA, KRB, 500 mM NMDA, KRB, 100 mM KCl. Basal glutamate levels were unaffected, but nicotine SA potentiated mPFC glutamate release to 200 mM NMDA, which was ineffective in controls. Furthermore, in VTA, nicotine SA amplified glutamate responses to both mPFC infusions of NMDA. After extinction, glutamate responses were no longer enhanced, and the expression of glutamate receptor subunits reverted to control levels. Behavioral studies showed that an mPFC microinjection of AP-5, an NMDA-R antagonist, did not affect nicotine or sucrose SA on d 19. In contrast, in VTA, NBQX, an AMPA-R antagonist, attenuated both nicotine and sucrose SA. In summary, chronic nicotine SA amplified both mPFC and VTA glutamate responses to mPFC NMDA. This hyper-responsiveness, along with the up-regulation of glutamate receptors, reverted to control levels after extinction. Blockade of VTA AMPA-R but not mPFC NMDA-R, decreased nicotine and sucrose SA. Collectively, these studies indicate that mesocortical glutamate neurotransmission adapts to chronic nicotine SA and up-regulation of VTA AMPA-R may be involved in the maintenance of nicotine SA.

DOI

10.21007/etd.cghs.2007.0340

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