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Methamphetamine-induced behavioral sensitization in mice: alterations in mu-opioid receptor
Chi-Tso Chiu1, Tangeng Ma, Ing K Ho
1Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Abstract:
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.
Insights
Methamphetamine-induced behavioral sensitization involves changes in mu-opioid receptors. These receptors show altered binding and enhanced signaling during sensitization, contributing to locomotor effects.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Opioid receptors are implicated in behavioral sensitization.
- Methamphetamine induces behavioral sensitization through repeated drug exposure.
Purpose of the Study:
- To investigate alterations in mu-opioid receptor during methamphetamine-induced behavioral sensitization.
- To examine changes in receptor binding and signaling at different time points.
Main Methods:
- Radioligand binding assays to measure mu-opioid receptor maximal binding.
- [(35)S]-GTPgammaS coupling assays to assess receptor signaling potency.
- Administration of naltrexone and beta-chlornaltrexamine to evaluate receptor activity.
Main Results:
- Mu-opioid receptor maximal binding was down-regulated on day 8 of methamphetamine treatment.
- Receptor binding returned to normal by day 11 and was up-regulated by day 21.
- DAMGO-stimulated GTPgammaS coupling was enhanced, indicating increased receptor potency.
- Basal GTPgammaS coupling was suppressed by opioid antagonists, suggesting elevated constitutive activity.
Conclusions:
- Mu-opioid receptor alterations, including enhanced responsiveness and constitutive activity, are involved in methamphetamine-induced behavioral sensitization.
- These changes in mu-opioid receptors contribute to the locomotor stimulating effects of methamphetamine.
