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 be en attributed to the activation of opioid receptors within the mesolim bic dopamine (DA) system. At present, however, it is unclear whether t he activity of DA neurons projecting to the nucleus accumbens (NAC) is necessary for the expression of these effects. The present study soug ht to address this issue in rats by examining the influence of 6-hydro xydopamine (6-OHDA) lesions of the NAC and microinjections of selectiv e DA receptor antagonists into this brain area upon the place conditio ning produced by systemically administered opioids. The mu-opioid rece ptor agonist morphine produced dose-related preferences for the drug-p aired place in control animals, whereas the kappa-opioid agonist U-695 93 produced place aversions. Bilateral 6-OHDA lesions of the NAC aboli shed the place conditioning produced by both opioids. Lesions of the c audate/putamen or medial prefrontal cortex were, however, without effe ct. Microinjection of the D-1 DA antagonist SCH-23390 into the NAC, at a dose which was as ineffective as a conditioning stimulus, attenuate d 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 modifi ed the place conditioning produced by lithium chloride, a drug of a di fferent pharmacological class. These data demonstrate that the rewardi ng and aversive effects of opioids are dependent on DA neural transmis sion within the mesolimbic system and suggest a role for NAC D-1 DA re ceptors in the mediation of both motivational effects.