Date of Award

12-2007

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmacology

Research Advisor

Jeffery D.Steketee, Ph.D.

Committee

Andrea J. Elberger, Ph.D. Burt M. Sharp, M.D. Fu-Ming Zhou, Ph.D. Steven J. Tavalin, Ph.D.

Abstract

The current studies examined the role of medial prefrontal cortical (mPFC) group II metabotropic glutamate receptors (mGluR2/3) in the development of cocaine sensitization. Initial studies demonstrated that intra-mPFC injection of the mGluR2/3 receptor agonist, APDC, dose-dependently reduced acute behavioral response to cocaine (0.015-15 nmol/side with significant effects starting at 1.5nmol/side). The effects of APDC were prevented by intra-mPFC co-injections of an mGluR2/3 antagonist, LY341495 (1.5 nmol/side). Repeated intra-mPFC APDC (1.5 nmol/side) injections also prevented the initiation of behavioral and neurochemical sensitization, which is defined as enhanced nucleus accumbens (NAc) dopamine response to cocaine. Once sensitization was induced, however, intra-mPFC administration of APDC did not block cocaine-induced behavioral and neurochemical responses in sensitized animals after 7 days and 30 days withdrawal. In contrast, intra-mPFC injections of APDC were found to block the expression of behavioral and neurochemical sensitization in sensitized animals after 1 day withdrawal. Additional microdialysis studies demonstrated that intra-mPFC infusions of LY341495 increased glutamate levels in the mesocorticolimbic brain regions of control animals, while this response was enhanced in sensitized animals following short term withdrawal from repeated cocaine exposure. The mesocorticolimbic brain regions examined in these studies include the mPFC, NAc and VTA, which are well known brain regions involved in cocaine sensitization. Nonetheless, this effect was no longer apparent in animals after prolonged withdrawal (7 days and 30 days). Furthermore, additional results demonstrated that repeated cocaine exposure enhanced the vesicular (K+ evoked) and non-vesicular (cystine evoked) glutamate release in the mPFC. It was shown that LY379268, an mGluR2/3 receptor agonist, inhibited the K+ induced glutamate release and cystine induced glutamate release in the mPFC of animals following 1 day of withdrawal from repeated cocaine injections. In contrast to these data, LY 379268 did not inhibit the release of glutamate from one of these sources in the mPFC of animals following 7 day of withdrawal. Collectively, these data suggested that the mPFC mGluR2/3 receptor can reduce the motor response to cocaine. The development of cocaine sensitization may be associated with an initial increased responsiveness of the mPFC mGluR2/3 receptor, coupled with enhanced glutamate transmission in the mPFC. Following prolonged withdrawal, loss of inhibitory control of the glutamate release within mPFC by the mGluR2/3 receptor thereafter may result in the enhanced excitatory drive, which in turn generates increased excitatory output from mPFC to subcortical regions including NAc and VTA.

DOI

10.21007/etd.cghs.2007.0360