There is growing interest in the possibility that drugs of abuse subvert normal learning and decision- making processes, leading to the development of compulsive, pathological drug-seeking behavior. Chronic exposure to psychostimulants, like cocaine, results in sensitization of nigrostriatal and mesolimbic dopamine pathways, which are critically involved in the acquisition of habits (i.e., rigid, stimulus-bound responses) and the expression of incentive motivation (i.e., the capacity for a reward-related cue to facilitate appetitive behaviors, or induce 'wanting'). In this project, we will evaluate two distinct (but not mutually exclusive) theories of addiction: that drug exposure allows habits to dominate the control of action selection (at the expense of deliberative, goal-directed action selection), and that drug exposure potentiates the influence of reward-related environmental cues over performance. Our plan is to use a combination of carefully controlled behavioral procedures and well-established neurochemical detection techniques to answer the following questions: (i) Does dopamine release during instrumental training match the profile of the prediction error-based reinforcement signal assumed to be responsible for governing habit formation? (ii) What are the effects of cocaine pre-exposure on the acquisition and expression of habitual performance and on reinforcement-related dopamine signaling? (iii) Does mesolimbic dopamine efflux mediate the incentive motivational processes that guide cue-based action selection? (iv) and, What are the effects of repeated cocaine exposure on cue-based action selection and on the mesolimbic dopamine response to reward-related cues? Recent studies have shown that response-contingent cocaine elicits stronger neurochemical effects and results in more dramatic and longer-lasting changes in the circuitry underlying dopamine release than noncontingent cocaine. Such findings raise questions about the validity of studies assessing the effects of experimenter-administered drugs on learning, behavioral control, and brain chemistry. Therefore, a secondary objective of the current application is to determine whether the behavioral and neurochemical effects of repeated cocaine exposure depend on the mode of drug delivery.

Public Health Relevance

Repeated exposure to drugs of abuse, including psychostimulants like cocaine, can significantly alter the neurocircuitry that supports learning and decision-making. Modern theories of addiction propose that these alterations lead to the compulsive, pathological drug-seeking behavior displayed by addicts. The current application combines well-established behavioral tests with neurochemical analysis to investigate how taking cocaine influences the way organisms acquire and select actions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA029035-04
Application #
8585046
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Lynch, Minda
Project Start
2011-02-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$277,200
Indirect Cost
$97,200
Name
University of California Los Angeles
Department
None
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Cui, Yijun; Ostlund, Sean B; James, Alex S et al. (2014) Targeted expression of ?-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward. Nat Neurosci 17:254-61
Wassum, Kate M; Greenfield, Venuz Y; Linker, Kay E et al. (2014) Inflated reward value in early opiate withdrawal. Addict Biol :
Ostlund, Sean B; Kosheleff, Alisa R; Maidment, Nigel T (2014) Differential effects of systemic cholinergic receptor blockade on Pavlovian incentive motivation and goal-directed action selection. Neuropsychopharmacology 39:1490-7
LeBlanc, Kimberly H; Maidment, Nigel T; Ostlund, Sean B (2014) Impact of repeated intravenous cocaine administration on incentive motivation depends on mode of drug delivery. Addict Biol 19:965-71
Ostlund, Sean B; LeBlanc, Kimberly H; Kosheleff, Alisa R et al. (2014) Phasic mesolimbic dopamine signaling encodes the facilitation of incentive motivation produced by repeated cocaine exposure. Neuropsychopharmacology 39:2441-9
LeBlanc, Kimberly H; Maidment, Nigel T; Ostlund, Sean B (2013) Repeated cocaine exposure facilitates the expression of incentive motivation and induces habitual control in rats. PLoS One 8:e61355
Ostlund, Sean B; Maidment, Nigel T (2012) Dopamine receptor blockade attenuates the general incentive motivational effects of noncontingently delivered rewards and reward-paired cues without affecting their ability to bias action selection. Neuropsychopharmacology 37:508-19
Wassum, Kate M; Ostlund, Sean B; Maidment, Nigel T (2012) Phasic mesolimbic dopamine signaling precedes and predicts performance of a self-initiated action sequence task. Biol Psychiatry 71:846-54
Wassum, Kate M; Ostlund, Sean B; Balleine, Bernard W et al. (2011) Differential dependence of Pavlovian incentive motivation and instrumental incentive learning processes on dopamine signaling. Learn Mem 18:475-83