The proposed research will establish a nonhuman primate model to characterize drug-induced changes in brain neurochemistry during cocaine self-administration. The primary objective is to evaluate the effectiveness of selective dopamine and serotonin transporter inhibitors to attenuate cocaine self-administration and cocaine-induced changes in neurochemistry. Behavioral studies of intravenous cocaine self- administration will be complemented by in vivo microdialysis and pharmacokinetic studies. The proposed use of in vivo microdialysis techniques in conscious monkeys trained to self-administer cocaine will characterize neurochernical changes associated with the reinforcing or addictive properties of cocaine, and will identify neurochemical mechanisms that mediate drug effects on behavior. Experiments will be conducted in squirrel monkeys surgically prepared with chronically- indwelling venous catheters for drug administration. Stereotaxic procedures will be employed in conjunction with magnetic resonance imaging (MRI) to implant guide cannulae into selected target areas and to verify the accuracy of probe placement. A major focus of the research plan will involve the pharmacological manipulation of monoamine transporter function to access changes in sensitivity to the behavioral and neurochemical effects of cocaine. Accordingly, experiments will determine the effectiveness of acutely and chronically administered transporter inhibitors selective for the dopamine and serotonin transporters to attenuate the reinforcing effects of cocaine and cocaine-induced changes in neurochemistry. in addition, serum blood levels of cocaine and its primary metabolite, benzoylecgonine, will be assayed to characterize the pharmacokinetics of cocaine, and to determine whether altered sensitivity to the behavioral and neurochernical effects of cocaine may involve changes in cocaine metabolism or clearance. Collectively, the proposed studies will enhance our understanding of the neurochemical substrates that underlie cocaine self-administration in nonhuman primates, and will evaluate the potential utility of monoamine transporters as targets for the pharmacotherapy of cocaine abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA012514-05S1
Application #
6862437
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Aigner, Thomas G
Project Start
2000-02-03
Project End
2005-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
5
Fiscal Year
2004
Total Cost
$17,111
Indirect Cost
Name
Emory University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Pitts, Elizabeth G; Minerva, Adelaide R; Chandler, Erika B et al. (2017) 3,4-Methylenedioxymethamphetamine Increases Affiliative Behaviors in Squirrel Monkeys in a Serotonin 2A Receptor-Dependent Manner. Neuropsychopharmacology 42:1962-1971
Cooper, Debra A; Kimmel, Heather L; Manvich, Daniel F et al. (2014) Effects of pharmacologic dopamine ?-hydroxylase inhibition on cocaine-induced reinstatement and dopamine neurochemistry in squirrel monkeys. J Pharmacol Exp Ther 350:144-52
Murnane, Kevin S; Andersen, Monica L; Rice, Kenner C et al. (2013) Selective serotonin 2A receptor antagonism attenuates the effects of amphetamine on arousal and dopamine overflow in non-human primates. J Sleep Res 22:581-8
Murnane, Kevin S; Winschel, Jake; Schmidt, Karl T et al. (2013) Serotonin 2A receptors differentially contribute to abuse-related effects of cocaine and cocaine-induced nigrostriatal and mesolimbic dopamine overflow in nonhuman primates. J Neurosci 33:13367-74
Kimmel, Heather L; Nye, Jonathon A; Voll, Ronald et al. (2012) Simultaneous measurement of extracellular dopamine and dopamine transporter occupancy by cocaine analogs in squirrel monkeys. Synapse 66:501-8
Manvich, Daniel F; Kimmel, Heather L; Cooper, Debra A et al. (2012) The serotonin 2C receptor antagonist SB 242084 exhibits abuse-related effects typical of stimulants in squirrel monkeys. J Pharmacol Exp Ther 342:761-9
Bauzo, Rayna M; Kimmel, Heather L; Howell, Leonard L (2012) The cystine-glutamate transporter enhancer N-acetyl-L-cysteine attenuates cocaine-induced changes in striatal dopamine but not self-administration in squirrel monkeys. Pharmacol Biochem Behav 101:288-96
Manvich, Daniel F; Kimmel, Heather L; Howell, Leonard L (2012) Effects of serotonin 2C receptor agonists on the behavioral and neurochemical effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 341:424-34
Andersen, Monica L; Sawyer, Eileen K; Howell, Leonard L (2012) Contributions of neuroimaging to understanding sex differences in cocaine abuse. Exp Clin Psychopharmacol 20:2-15
Sawyer, E K; Howell, L L (2011) Pharmacokinetics of fluoxetine in rhesus macaques following multiple routes of administration. Pharmacology 88:44-9

Showing the most recent 10 out of 23 publications