Addiction-related alterations in D1 and D2 dopamine receptor behavioral responses following chronic cocaine self-administration

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 D-1 and D-2 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 D-1 and D-2 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 D-1 agonist SKF 81297 to inhibit cocaine-seeking behavior elicited by cocaine priming, but supersensitive to cocaine seeking triggered by the D-2 agonist quinpirole, when compared to low intake rats. Additionally, high intake rats developed profound increases in locomotor responses to D-2 receptor challenge from early to late withdrawal times, whereas low intake rats developed increased responsiveness to D-1 receptor challenge. In a second experiment, responses to the mixed D-1/D-2 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 D-1 and D-2 receptors and their ability to modulate cocaine-seeking behavior.