Behavioral activation induced by D-2-like receptor stimulation during opiate withdrawal

Withdrawal is a potent motivator of drug-seeking behavior in human opiate a ddicts. Paradoxically, opiate withdrawal reduces dopamine release and suppr esses behavioral responding in several animal models of addiction. These fi ndings pose critical questions about how a withdrawal state that depresses dopaminergic and behavioral functioning contributes to drug seeking. This s tudy addressed this issue by investigating factors that increase behavioral activity during opiate withdrawal. Initial experiments revealed that the D -2-like agonists propylnorapomorphine HCl (NPA; 0.05-0.4 mg/kg, i.p.) and q uinpirole (0.2-0.4 mg/kg, s.c.) each produced strong locomotor activating e ffects during opiate withdrawal that were not apparent in the absence of wi thdrawal. Concurrent stereotypy ratings indicated that these effects of NPA and quinpirole during withdrawal were not an indirect consequence of chang es in the stereotypy-inducing effects of these drugs. Subsequent experiment s showed that locomotion was not increased when opiate withdrawal was induc ed in the presence of the D-1-like agonist SKF 38393 (1.0-8.0 mg/kg, i.p.), that the locomotor activation produced by NPA during withdrawal could be a ttenuated by the D-2-like antagonist eticlopride (0.1-0.2 mg/kg, i.p.), and that locomotor activating effects of NPA could be observed when withdrawal was induced by extracting the implanted morphine pellets, but not when the NPA was given after naltrexone antagonism of acute morphine treatment in n ondependent rats. These findings indicate that opiate withdrawal regulates the behavioral impact of D-2-like receptor stimulation so that locomotion i s markedly increased when these receptors are stimulated during periods of withdrawal. This potentiation may be important for facilitating behavioral responses during periods of opiate detoxification.