Methamphetamine-induced behavioral sensitization in mice: alterations in mu-opioid receptor.

We had previously demonstrated that opioid receptors contribute to the induction and expression of behavioral sensitization induced by repeated daily injection with 2.5 mg/kg of methamphetamine for 7 days. Using the same regimen, the present study investigated the alterations in mu-opioid receptor during the induction (on days 2, 5, and 8) and expression (on days 11 and 21) periods of behavioral sensitization. Radioligand binding revealed that the maximal binding of mu-opioid receptor was not changed on days 2 and 5, but down-regulated on day 8. After cessation of drug treatment, the maximal binding of mu-opioid receptor gradually and time-dependently returned to normal level on day 11 and up-regulated on day 21. In contrast, no changes in delta- and kappa-opioid receptors were detectable on any given day examined. The potency of DAMGO for [(35)S]-GTPgammaS coupling was enhanced on days 2, 5, 11, and 21. Moreover, 1 muM of naltrexone or beta-chlornaltrexamine significantly suppressed the basal [(35)S]-GTPgammaS coupling on days 2, 11, and 21. These findings indicate enhanced responsiveness and elevated constitutive activity of mu-opioid receptor. In summary, our data clearly demonstrate that alterations in mu-opioid receptor are involved in and may contribute to the sensitization to locomotor stimulating effect of methamphetamine.