¹Department of Psychiatry and the Neuroscience Graduate Program, The Seay Center for Basic and Applied Research in Psychiatric Illness, University of Texas Southwestern Medical Center, Dallas, TX, USA

Correspondence: Dr DW Self, Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9070, USA. Tel: +1 214 648 1237; Fax: +1 214 648 4947; E-mail: david.self@utsouthwestern.edu

Received 13 September 2005; Revised 3 February 2006; Accepted 9 February 2006; Published online 15 March 2006.

Abstract

The cocaine-addicted phenotype can be modeled in rats based on individual differences in preferred levels of cocaine intake and a propensity for relapse in withdrawal. These cocaine-taking and -seeking behaviors are strongly but differentially regulated by postsynaptic D₁ and D₂ receptors in the mesolimbic dopamine system. Thus, we determined whether addiction-related differences in cocaine self-administration would be related to differential sensitivity in functional D₁ and D₂ receptor responses. Using a population of 40 outbred Sprague–Dawley rats trained to self-administer cocaine for 3 weeks, we found that animals with higher preferred levels of cocaine intake exhibited a vertical and rightward shift in the self-administration dose–response function, and were more resistant to extinction from cocaine self-administration, similar to phenotypic changes reported in other models of cocaine addiction. After 3 weeks of withdrawal from cocaine self-administration, high intake rats were subsensitive to the ability of the D₁ agonist SKF 81297 to inhibit cocaine-seeking behavior elicited by cocaine priming, but supersensitive to cocaine seeking triggered by the D₂ agonist quinpirole, when compared to low intake rats. Additionally, high intake rats developed profound increases in locomotor responses to D₂ receptor challenge from early to late withdrawal times, whereas low intake rats developed increased responsiveness to D₁ receptor challenge. In a second experiment, responses to the mixed D₁/D₂ agonist apomorphine and the NMDA glutamate receptor antagonist MK-801 failed to differ between low and high intake rats. These findings suggest that cocaine addiction is related specifically to differential alterations in functional D₁ and D₂ receptors and their ability to modulate cocaine-seeking behavior.