Vol. 294, Issue 2, 531-538, August 2000

Behavioral Activation Induced by D₂-Like Receptor Stimulation during Opiate Withdrawal¹

Jonathan P. Druhan, Carrie L. Walters and Gary Aston-Jones

Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

Withdrawal is a potent motivator of drug-seeking behavior in human opiate addicts. Paradoxically, opiate withdrawal reduces dopamine release and suppresses behavioral responding in several animal models of addiction. These findings pose critical questions about how a withdrawal state that depresses dopaminergic and behavioral functioning contributes to drug seeking. This study addressed this issue by investigating factors that increase behavioral activity during opiate withdrawal. Initial experiments revealed that the D₂-like agonists propylnorapomorphine HCl (NPA; 0.05-0.4 mg/kg, i.p.) and quinpirole (0.2-0.4 mg/kg, s.c.) each produced strong locomotor activating effects during opiate withdrawal that were not apparent in the absence of withdrawal. Concurrent stereotypy ratings indicated that these effects of NPA and quinpirole during withdrawal were not an indirect consequence of changes in the stereotypy-inducing effects of these drugs. Subsequent experiments showed that locomotion was not increased when opiate withdrawal was induced in the presence of the D₁-like agonist SKF 38393 (1.0-8.0 mg/kg, i.p.), that the locomotor activation produced by NPA during withdrawal could be attenuated by the D₂-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 nondependent rats. These findings indicate that opiate withdrawal regulates the behavioral impact of D₂-like receptor stimulation so that locomotion is 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.