Behavioral sensitization, the enhanced motor-stimulant response that occurs with repeated, intermittent exposure to cocaine, has been proposed to play a role in drug craving and relapse. An increased understanding of the mechanisms involved in the development of sensitization may lead to improved pharmacotherapies for drug addiction. It has been suggested that cocaine-induced changes in the ventral tegmental area (VIA) and nucleus accumbens are involved in the initiation and expression of sensitization, respectively. However, recent studies do not entirely support this hypothesis. Thus, the present proposal will test the hypothesis that sensitization results from a decrease in dopamine-mediated glutamate transmission from the medial prefrontal cortex (mPFC). We have reported that depletion of dopamine in the mPFC by 6-hydroxydopamine lesions enhances the motor-stimulant response to cocaine. Follow up studies will determine whether these lesions also enhance glutamate transmission in the mPFC and dopamine and glutamate transmission in regions innervated by the mPFC such as the VTA and nucleus accumbens. A second set of studies will determine whether sensitization to cocaine is associated with changes in dopamine and glutamate transmission in the mPFC using in vivo microdialysis. The temporal relation of neurochemical changes in the mPFC, compared with those previously shown in the nucleus accumbens, will also be assessed. The role of mPFC dopamine in the development of sensitization will be further examined by determining the effects of site specific injections of dopamine receptor agonists or antagonists into the mPFC on behavioral and neurochemical responses to cocaine. Preliminary data suggest that sensitization to cocaine may result from a decrease in dopamine receptor function in the mPFC. To determine this, the effects of repeated cocaine exposure on dopamine receptor regulation of adenylyl cyclase activity in the mPFC will be examined. Results of these studies should provide a better understanding of the role the mPFC plays in the development of sensitization to cocaine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013470-05
Application #
6727637
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Lin, Geraline
Project Start
2001-03-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2006-03-31
Support Year
5
Fiscal Year
2004
Total Cost
$250,250
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Jayaram, Prathiba; Steketee, Jeffery D (2006) Cocaine-induced increases in medial prefrontal cortical GABA transmission involves glutamatergic receptors. Eur J Pharmacol 531:74-9
Williams, Jason M; Steketee, Jeffery D (2005) Effects of repeated cocaine on the release and clearance of dopamine within the rat medial prefrontal cortex. Synapse 55:98-109
Jayaram, Prathiba; Steketee, Jeffery D (2005) Effects of cocaine-induced behavioural sensitization on GABA transmission within rat medial prefrontal cortex. Eur J Neurosci 21:2035-9
Williams, Jason M; Steketee, Jeffery D (2005) Time-dependent effects of repeated cocaine administration on dopamine transmission in the medial prefrontal cortex. Neuropharmacology 48:51-61
Steketee, Jeffery D; Walsh, Timothy J (2005) Repeated injections of sulpiride into the medial prefrontal cortex induces sensitization to cocaine in rats. Psychopharmacology (Berl) 179:753-60
Williams, Jason M; Stafford, David; Steketee, Jeffery D (2005) Effects of repeated inhalation of toluene on ionotropic GABA A and glutamate receptor subunit levels in rat brain. Neurochem Int 46:1-10
Steketee, Jeffery D (2005) Cortical mechanisms of cocaine sensitization. Crit Rev Neurobiol 17:69-86
Steketee, Jeffery D; Beyer, Chad E (2005) Injections of baclofen into the ventral medial prefrontal cortex block the initiation, but not the expression, of cocaine sensitization in rats. Psychopharmacology (Berl) 180:352-8
Williams, Jason M; Steketee, Jeffery D (2004) Characterization of dopamine transport in crude synaptosomes prepared from rat medial prefrontal cortex. J Neurosci Methods 137:161-5
Jayaram, Prathiba; Steketee, Jeffery D (2004) Effects of repeated cocaine on medial prefrontal cortical GABAB receptor modulation of neurotransmission in the mesocorticolimbic dopamine system. J Neurochem 90:839-47

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