The cocaine-like behavioral effects of meperidine are mediated by activity at the dopamine transporter

Meperidine has atypical opioid agonist effects and shares some structural features with the phenyltropane (WIN) analogs of cocaine. Because of these structural features, the present study was undertaken to determine if the atypical agonist actions of meperidine might be explained by cocaine-like activity. Both meperidine and the prototype u-opioid agonist, morphine, produced negligible substitution for cocaine in squirrel monkeys trained to discriminate cocaine (0.3 mg/kg) from saline. In combination with 0.1 mg/kg naltrexone, meperidine fully substituted for cocaine whereas the effectiveness of morphine was not changed. These results suggest that the cocaine-like activity of meperidine is normally not evident because of an overriding opioid action, whereas the typical opioid agonist morphine does not have these cocaine-like behavioral effects. As shown previously, cocaine inhibited over 90% of specific pHJdopamtne uptake in a biphasic manner, with both a high and a low affinity component. Meperidine inhibited only about 20% of [3H]dopamine uptake, in a monophasic manner with a potency comparable to the high affinity component of cocaine. This effect was not altered in the presence of naltrexone. Further, morphine was not active in inhibiting [³H]dopamine uptake, indicating that the effect of meperidine was not via a classic μ-opioid agonist action. Meperidine, but not morphine, displaced [³H]WIN 35,428 binding to the dopamine transporter. These data suggest that the atypical opioid agonist actions of meperidine are due to activity at the dopamine transporter. In addition, unlike other dopamine uptake inhibitors that have cocaine-like behavioral effects, meperidine appears to interact predominantly with the high-affinity, and not the low-affinity component of the dopamine transporter. Additionally, it seems that the high-affinity component of cocaine's inhibition of dopamine uptake may be the site of importance for the production of cocaine's behavioral effects.