Examination of the neurochemical substrates mediating the motivational effects of opioids: role of the mesolimbic dopamine system and D-1 vs. D-2 dopamine receptors.

Both the reinforcing and aversive effects of exogenous opioids have been attributed to the activation of opioid receptors within the mesolimbic dopamine (DA) system. At present, however, it is unclear whether the activity of DA neurons projecting to the nucleus accumbens (NAC) is necessary for the expression of these effects. The present study sought to address this issue in rats by examining the influence of 6-hydroxydopamine (6-OHDA) lesions of the NAC and microinjections of selective DA receptor antagonists into this brain area upon the place conditioning produced by systemically administered opioids. The mu-opioid receptor agonist morphine produced dose-related preferences for the drug-paired place in control animals, whereas the kappa-opioid agonist U-69593 produced place aversions. Bilateral 6-OHDA lesions of the NAC abolished the place conditioning produced by both opioids. Lesions of the caudate/putamen or medial prefrontal cortex were, however, without effect. Microinjection of the D-1 DA antagonist SCH-23390 into the NAC, at a dose which was as ineffective as a conditioning stimulus, attenuated the place conditioning produced by low doses of morphine and U-69593. Over the dose range tested, the D-2 DA antagonist (-)-sulpiride was without effect. Neither SCH-23390 nor 6-OHDA lesions of the NAC modified the place conditioning produced by lithium chloride, a drug of a different pharmacological class. These data demonstrate that the rewarding and aversive effects of opioids are dependent on DA neural transmission within the mesolimbic system and suggest a role for NAC D-1 DA receptors in the mediation of both motivational effects.