Dissociable effects of the kappa-opioid receptor agonists bremazocine, U69593, and U50488H on locomotor activity and long-term behavioral sensitization induced by amphetamine and cocaine

Rationale: Mesolimbic dopaminergic neurotransmission plays a critical role in the locomotor effects of psychostimulant drugs, but a general involvemen t in the induction of long-term psychostimulant sensitization is questionab le. By influencing dopaminergic neurotransmission, opioid drugs can alter t he behavioral effects of psychostimulants. Objectives: The effects of the k appa-opioid receptor agonists bremazocine, U69593, and U50488H on the locom otor stimulant and the long-term sensitizing effects of amphetamine and coc aine were investigated in rats. Unlike U69593 and U50488H, bremazocine is a lso an antagonist at mu- and delta-opioid receptors, as well as an agonist at a subtype of delta-opioid receptors inhibiting dopamine D1 receptor-stim ulated adenylate cyclase. Methods: Bremazocine, U69593, and U50488H were ad ministered prior to amphetamine and cocaine, and locomotor activity was mea sured. In separate studies, the opioids were co-administered with amphetami ne and cocaine for 5 days, and locomotor sensitization was assessed 3 weeks post-treatment. Results: Bremazocine and U69593 attenuated the psychomotor stimulant effects of amphetamine and cocaine. U50488H attenuated the locom otor effect of cocaine and biphasically affected amphetamine-induced locomo tion, i.e., suppression followed by stimulation. Bremazocine prevent ed the development of amphetamine-induced but mot cocaine-induced long-term sensi tization. Neither U69593 nor U50448H affected the induction of long-term am phetamine or cocaine sensitization. Conclusions: In agreement with previous studies, the present data suggest versus the long-term sensitizing effects of psychostimulants, and the induction of long-term sensitization by amphe tamine versus cocaine. Stimulation of kappa-opioid receptors does not seem to block the induction of longterm psychostimulant sensitization. Thus, bre mazocine is likely to block the induction of amphetamine sensitization thro ugh a non-kappa-opioid receptor mechanism. We suggest that this effect of b remazocine is the result of its unique agonist action at a subtype of delta -opioid receptors, thereby acting as a functional dopamine D1 receptor anta gonist. This would be consistent with the literature showing that the induc tion of long-term amphetamine sensitization depends on the activation of do pamine D1 receptors. In addition, the present data are in keeping with stud ies showing that dopamine neurotransmission is not critical for the inducti on of long-term cocaine sensitization.