Dopaminergic mechanisms mediating the incentive to seek cocaine and heroinfollowing long-term withdrawal of IV drug self-administration

Rationale: The neurobiological mechanisms underlying the persistence of dru g craving in detoxified addicts are still poorly understood. Objective: The present study was designed to evaluate dopaminergic mechanisms in drug-see king behaviour following long-term (>3 weeks) extinction of IV drug self-ad ministration in rats. Methods: To that end, we studied the effects of direc t and indirect dopamine (DA) agonists on reinstatement of previously exting uished responding for heroin (50 mu g/kg per injection; 14-15 daily 3-h ses sions) and cocaine (500 mu g/kg per injection; 10-11 daily 2-h sessions). R esults: In animals with a cocaine history, priming with cocaine, the select ive DA reuptake inhibitor GBR-12909 and the DA D-2 receptor agonist quinpir ole resulted in robust and selective reinstatement of non-reinforced nose p oking behaviour in the previously drug-paired hole. In contrast, the D-1 ag onist SKF-82958 failed to reinstate responding and the non-selective DA ago nist apomorphine even suppressed responding in these animals. In heroin-tra ined rats, heroin and GBR-12909 strongly reinstated responding, whereas all direct DA agonists were ineffective. Again, the two highest doses of apomo rphine decreased responding in these animals. In a parallel study, the abil ity of DA ligands to express behavioural sensitization in animals pretreate d with amphetamine or morphine was evaluated. Interestingly, all agonists t hat reinstated responding in the present study caused expression of locomot or sensitization and vice verse. Conclusions: The differences between direc t and indirect agonists indicate a clear, but complex, involvement of DA in drug-seeking behaviour long after detoxification. Moreover, the results sh ow an important role of D-2 receptor activation in the persistence of cocai ne- but not heroin-seeking behaviour. Finally, the results from both studie s suggest a relationship between drug-induced reinstatement and drug hyperr esponsiveness in long-term abstinent rats.