The goal of this research is to broaden our understanding of the neural and behavioral mechanisms that mediate the transition from recreational cocaine use to cocaine addiction. More specifically, this application proposes a series of studies using models of cocaine self-administration in monkeys, with the brain imaging procedure positron emission tomography (PET), in an effort to better understand the consequences of long-term cocaine use and cocaine abstinence on dopamine (DA) receptor function. In PET studies with monkeys self-administering cocaine, we have observed 20 percent reductions in D2 binding potentials throughout 1 year of cocaine use. We also found that baseline D2 receptor levels correlated with rates of cocaine self-administration, suggesting that D2 receptor levels were associated with """"""""vulnerability."""""""" These studies are the first to use a within-subjects design and PET imaging to examine long-term changes in the brains of monkeys self-administering cocaine and during abstinence. The studies proposed in this application are designed to extend our understanding of DA receptor function and compulsive cocaine seeking in male rhesus monkeys (M. mulatta) self-administering cocaine, in an effort to identify a transition """"""""switch"""""""" for addiction. Specifically, we propose to study how the DA system, in particular D1, D2 and DA transporters (DAT): 1) is differentially influenced by pattern of cocaine use, comparing cocaine-maintained responding under a second-order schedule to a binge pattern of self-administration; 2) recovers during abstinence and how lifetime cocaine intake modifies the rate of recovery; and 3) is correlated with cocaine seeking in a model of craving that does not involve extinction of cocaine-maintained responding. We hypothesize that the """"""""switch"""""""" is a functional interaction between D1, and D2 receptors with cocaine-induced increases in extracellular DA via DAT. Combining PET imaging with our monkey models of cocaine abuse, we will be able to characterize DA receptor function, as it pertains to cocaine seeking, over long periods of time. A better understanding of the neuroadaptation of the DA neurotransmitter system correlated with behavioral outcomes of cocaine use and abstinence will lead to a better understanding of the mechanisms that mediate the transition from drug use to addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA014637-01
Application #
6425001
Study Section
Special Emphasis Panel (ZDA1-MXG-S (01))
Program Officer
Wetherington, Cora Lee
Project Start
2001-09-30
Project End
2006-08-31
Budget Start
2001-09-30
Budget End
2002-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$360,938
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Gould, Robert W; Duke, Angela N; Nader, Michael A (2014) PET studies in nonhuman primate models of cocaine abuse: translational research related to vulnerability and neuroadaptations. Neuropharmacology 84:138-51
Czoty, Paul W; Gage, H Donald; Garg, Pradeep K et al. (2013) Effects of repeated treatment with the dopamine D2/D3 receptor partial agonist aripiprazole on striatal D2/D3 receptor availability in monkeys. Psychopharmacology (Berl) :
Gould, Robert W; Porrino, Linda J; Nader, Michael A (2012) Nonhuman primate models of addiction and PET imaging: dopamine system dysregulation. Curr Top Behav Neurosci 11:25-44
Newman, Amy Hauck; Blaylock, Brandi L; Nader, Michael A et al. (2012) Medication discovery for addiction: translating the dopamine D3 receptor hypothesis. Biochem Pharmacol 84:882-90
Gould, Robert W; Gage, H Donald; Banks, Matthew L et al. (2011) Differential effects of cocaine and MDMA self-administration on cortical serotonin transporter availability in monkeys. Neuropharmacology 61:245-51
Banks, Matthew L; Czoty, Paul W; Gage, H Donald et al. (2008) Effects of cocaine and MDMA self-administration on serotonin transporter availability in monkeys. Neuropsychopharmacology 33:219-25
Nader, Michael A; Czoty, Paul W; Gould, Robert W et al. (2008) Review. Positron emission tomography imaging studies of dopamine receptors in primate models of addiction. Philos Trans R Soc Lond B Biol Sci 363:3223-32
Nader, Michael A; Czoty, Paul W (2008) Brain imaging in nonhuman primates: insights into drug addiction. ILAR J 49:89-102
Czoty, Paul W; Reboussin, Beth A; Calhoun, Tonya L et al. (2007) Long-term cocaine self-administration under fixed-ratio and second-order schedules in monkeys. Psychopharmacology (Berl) 191:287-95
Nader, Michael A; Morgan, Drake; Gage, H Donald et al. (2006) PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys. Nat Neurosci 9:1050-6

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