Compulsive behaviors, including excessive eating, gambling, shopping, exercising, or drug-taking, can develop over time in individuals without other psychopathology. Although compulsive behavior is marked by excessive engagement in a particular behavior, animal models of compulsive behavior suggest that another defining feature is behavior that is disconnected from reinforcer delivery. Thus, people may gamble compulsively even though they do not win often, or shop excessively even when they may not use what they have purchased. Our hypothesis is that these types of reinforcer- disconnected behaviors result when both operant (instrumental, goal-tracking) and respondent (Pavlovian, classical, sign-tracking) conditioning processes converge on the same behavior. In addition, individuals must be sensitized to dopamine, and the compulsive behavior is more likely to occur in the presence of a D3/D2 agonist acting on the sensitized dopamine receptors. We will test this hypothesis in three behavioral models: 1) quinpirole-induced responding for stimuli associated with cocaine;2) quinpirole-induced responding for water in the presence of water;and 3) quinpirole as an occasion setter for either cocaine or water-reinforced behavior. The behavioral pharmacology of these models will be tested with various dopamine agonists and antagonists, and the roles of sensitization, goal-tracking, and sign-tracking will be studied. Understanding the environmental, behavioral, neurochemical, and pharmacological aspects of compulsive disorders will hopefully contribute to the development of treatments for these debilitating disorders.

Public Health Relevance

The purpose of this proposal is to determine various environmental and neurochemical contributors to compulsive behavior (e.g., excessive gambling, shopping, eating, sexual behavior, and drug-taking). Our hypothesis, that compulsions result when the same classically conditioned and operantly conditioned behavior is established in the presence of sensitized dopamine receptors and stimulation of dopamine receptors, will be tested in three rat models in this research effort. Evaluation of the ability of selective dopamine receptors, as well as silencing the RNA for the D3 receptor, to modify the compulsive behavior should help point towards possible pharmacological treatment of these disorders, and understanding of the setting conditions will suggest behavioral therapy and prevention approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA024897-03
Application #
8107619
Study Section
Special Emphasis Panel (ZRG1-BBBP-T (02))
Program Officer
Thomas, David A
Project Start
2009-09-30
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$460,317
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Bertz, Jeremiah W; Jackson, Emily L; Barron, Davina R et al. (2016) Effects of sex and remifentanil dose on rats' acquisition of responding for a remifentanil-conditioned reinforcer. Behav Pharmacol 27:137-47
Bertz, Jeremiah W; Chen, Jianyong; Woods, James H (2015) Effects of pramipexole on the acquisition of responding with opioid-conditioned reinforcement in the rat. Psychopharmacology (Berl) 232:209-21
Bertz, Jeremiah W; Woods, James H (2013) Acquisition of responding with a remifentanil-associated conditioned reinforcer in the rat. Psychopharmacology (Berl) 229:235-43
Podlesnik, Christopher A; Jimenez-Gomez, Corina (2013) Punishing and cardiovascular effects of intravenous histamine in rats: pharmacological selectivity. J Exp Anal Behav 100:333-54
Koffarnus, Mikhail N; Collins, Gregory T; Rice, Kenner C et al. (2012) Self-administration of agonists selective for dopamine D2, D3, and D4 receptors by rhesus monkeys. Behav Pharmacol 23:331-8
Collins, Gregory T; Cunningham, Alyssa R; Chen, Jianyong et al. (2012) Effects of pramipexole on the reinforcing effectiveness of stimuli that were previously paired with cocaine reinforcement in rats. Psychopharmacology (Berl) 219:123-35
Collins, Gregory T; Truong, Yen Nhu-Thi; Levant, Beth et al. (2011) Behavioral sensitization to cocaine in rats: evidence for temporal differences in dopamine D3 and D2 receptor sensitivity. Psychopharmacology (Berl) 215:609-20
Li, Su-Min; Collins, Gregory T; Paul, Noel M et al. (2010) Yawning and locomotor behavior induced by dopamine receptor agonists in mice and rats. Behav Pharmacol 21:171-81
Collins, Gregory T; Truccone, Andrew; Haji-Abdi, Faiza et al. (2009) Proerectile effects of dopamine D2-like agonists are mediated by the D3 receptor in rats and mice. J Pharmacol Exp Ther 329:210-7
Collins, Gregory T; Woods, James H (2009) Influence of conditioned reinforcement on the response-maintaining effects of quinpirole in rats. Behav Pharmacol 20:492-504