While the acute effects of cocaine on brain neurochemistry have been well characterized, much less is known about the long-term changes in neurochemistry and brain function associated with chronic drug use. Clearly, a better understanding of the neurobiology underlying the progression to dependence and addiction will help direct appropriate treatment strategies. Preventing relapse is often the most difficult obstacle in treating drug addiction. It is well recognized that exposure to environmental cues associated with drug use can induce relapse in patients who have been abstinence for extended periods. Virtually nothing is known about the neurobiological underpinnings associated with extinction therapy or its enhancement by pharmacological intervention in the treatment of cocaine abuse and addiction. In the prospective studies proposed in nonhuman primates, we will evaluate changes in neurochemistry, and functional brain activity following limited- and extended-access to cocaine self-administration, drug abstinence, and extinction training with and without pharmacological intervention. Cue-induced reinstatement of cocaine self-administration will provide an abuse-related behavioral outcome to correlate with relevant neurobiological measures. We will document the effects of cocaine exposure and extinction training on 1) extracelluar neurotransmitter and metabolite levels using microdialysis, 2) in vivo binding potential of monoamine transporters and receptors using PET imaging, 3) trafficking capacity of monoamine transporters using PET imaging, 4) cocaine- and cue-induced brain activation using fMRl and, 5) resting state functional activity using fMRl. These studies will also utilize a repeated-measures experimental design, strengthening the significance ofthe results. The proposed research is highly innovative in its focus on abstinence and extinction training and the integration of multiple imaging modalities in a paradigm that models the progression of cocaine use to dependence and addiction. The long-term goals of our research are to gain a greater understanding of the mechanisms of psychostimulant addiction and to identify targets for effective treatment medications.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA010344-17
Application #
8462577
Study Section
Special Emphasis Panel (NSS)
Program Officer
Rapaka, Rao
Project Start
1997-08-15
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
17
Fiscal Year
2013
Total Cost
$584,484
Indirect Cost
$252,391
Name
Emory University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Murnane, K S; Gopinath, K S; Maltbie, E et al. (2015) Functional connectivity in frontal-striatal brain networks and cocaine self-administration in female rhesus monkeys. Psychopharmacology (Berl) 232:745-54
Howell, L L; Nye, J A; Stehouwer, J S et al. (2014) A thermostable bacterial cocaine esterase rapidly eliminates cocaine from brain in nonhuman primates. Transl Psychiatry 4:e407
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
Andersen, Monica L; Diaz, Maylen P; Murnane, Kevin S et al. (2013) Effects of methamphetamine self-administration on actigraphy-based sleep parameters in rhesus monkeys. Psychopharmacology (Berl) 227:101-7
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
Andersen, Monica L; Sawyer, Eileen K; Carroll, F Ivy et al. (2012) Influence of chronic dopamine transporter inhibition by RTI-336 on motor behavior, sleep, and hormone levels in rhesus monkeys. Exp Clin Psychopharmacol 20:77-83
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
Howell, Leonard Lee; Murnane, Kevin Sean (2011) Nonhuman primate positron emission tomography neuroimaging in drug abuse research. J Pharmacol Exp Ther 337:324-34
Sawyer, E K; Howell, L L (2011) Pharmacokinetics of fluoxetine in rhesus macaques following multiple routes of administration. Pharmacology 88:44-9
Murnane, Kevin S; Howell, Leonard L (2011) Neuroimaging and drug taking in primates. Psychopharmacology (Berl) 216:153-71

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