Effects of agonists with mixed efficacy profiles at the mu and kappa opioid receptor on amphetamine‐mediated dopamine release

Abstract

Although studies have demonstrated that non‐selective, mixed kappa/mu opioid agonists attenuate stimulant self‐administration with fewer side effects than selective kappa agonists, less is known about the contribution of relative mu or kappa efficacy in the effectiveness of these compounds. Consequently, a series of agonists with similar binding affinities but varying levels of efficacy in the [35S]GTPγS assay at the mu and kappa receptor were compared for ability to alter amphetamine (AMPH)‐mediated dopamine release from rat striatal slices. Addition of the selective kappa agonist U50488H to striatal slices reduced AMPH‐induced dopamine release, while addition of the selective mu agonist DAMGO enhanced the amount of dopamine released in response to AMPH. For mixed agonists the modulation of AMPH‐mediated dopamine release coincided with the predominant efficacy of the agonist at the mu or kappa receptor. However, butorphanol increased AMPH‐mediated dopamine release, despite having a relative lower efficacy at the mu vs. kappa receptor. The kappa inhibitory effect of butorphanol was only observed upon insurmountable antagonism of the mu receptor with clocinnamox. These results demonstrate that the effect of mixed compounds to modulate AMPH‐stimulated dopamine release is dependent on the balance of kappa opioid inhibitory effects and mu opioid stimulatory effects. Supported by DA 04087, 07315, 19728.