The proposed research will characterize behavioral and in vivo neurochemical interactions between serotonin and cocaine in the context of self-administration behavior in nonhuman primates. It is well recognized that dopamine plays a fundamental role in the behavioral pharmacology of cocaine associated with its addictive properties. However, a substantial literature has documented that serotonergic function also plays a significant role in the abuse-related effects of cocaine and other psychomotor stimulants. Specifically, selective serotonin transporter (SERT) inhibitors can effectively attenuate cocaine self-administration and cocaine-induced increases in extracellular dopamine, suggesting that drug interactions on behavior are mediated through neurochemical interactions between serotonin and dopamine. However, the mechanistic basis for these drug interactions on behavior and neurochemistry has not been adequately established. The proposed studiesin squirrel monkeys will investigate the involvement of specific receptor mediated mechanisms, and extend drug interactions on self-administration to other abuse-related effects including drug-induced reinstatement and cue-mediated behavior. Pharmacological targets for the manipulation of serotonergic activity will include the SERT and the 5HT2C and 5HT2A receptor subtypes.
The Specific Aims are: 1) to establish the effectiveness of SERT inhibitors to attenuate the abuse-related effects of cocaine across multiple behavioral paradigms including i.v. drug self-administration, drug-induced reinstatement and, cue-induced behavior;2) to correlate the behavioral effects of SERT inhibitors with in vivo neurochemistry including SERT occupancy with PET neuroimaging, and extracellular serotonin and dopamine with in vivo microdialysis;and 3) to define the role of 5HT2C and 5HT2A receptor subtypes in the interactions observed between SERT inhibitors and cocaine. The innovative design employed effectively integrates behavioral pharmacology and sophisticated in vivo neurochemistry in a nonhuman primate model. The results obtained will evaluate the effectiveness of serotonergic systems as potential targets for cocaine medications development. Moreover, serotonin has significant therapeutic potential in the treatment of a variety of psychiatric disorders. Accordingly, the elucidation of basic neurochemical interactions between serotonin and dopamine in vivo in nonhuman primates should have significant impact on the development of therapeutics outside the field of drug addiction.

Public Health Relevance

The objective of the present proposal is to identify potential therapeutic targets for the treatment of cocaine abuse and dependence. These translational studies in nonhuman primates will determine the effectiveness of the serotonin system to modulate the behavioral and neurochemical effects cocaine. Moreover, the documentation of basic neurochemical interactions between serotonin and dopamine in vivo in nonhuman primates should have significant impact on the development of therapeutics outside the field of drug addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA012514-13
Application #
8245819
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Aigner, Thomas G
Project Start
2000-02-03
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
13
Fiscal Year
2012
Total Cost
$412,995
Indirect Cost
$178,339
Name
Emory University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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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
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