Kappa opioid agonists alter dopamine markers and cocaine‐stimulated locomotor activity

To better understand the influence of κ‐opioid agonists on the effects of cocaine, rats were treated with daily injections of the selective κ‐opioid agonists U‐69593 or bremazocine. In combination with 10 mg/kg cocaine, both compounds, at a dose of 0.32 mg/kg, greatly diminished locomotor activity, and these effects were maintained over a period of 5 days. In addition, the response to a challenge injection of 10 mg/kg cocaine several days after the end of κ‐opioid agonist treatment with or without cocaine was markedly reduced. When naltrexone was given in combination with U‐69593, it blocked the reduction in cocaine‐induced locomotor activity after U‐69593 treatment alone. However, a single injection of either κ‐opioid agonist alone had no effect on cocaine‐induced locomotion several days later (i.e. no long‐term effects), suggesting that multiple injections of the κ‐opioid agonist are needed to reduce the locomotor activating effects of cocaine other than acutely. In addition, treatment with the κ‐opioid agonist U‐69593 (0.32 mg/kg) over a 5‐day period decreased dopamine transporter densities in the caudate putamen, and this was also blocked by co‐administration of naltrexone.