Involvement of 5‐HT3 receptors in the development and expression of methamphetamine‐induced behavioral sensitization: 5‐HT3A receptor channel and binding study

Methamphetamine (MAP) is one of the most commonly abused drugs in Asia, and previous studies suggest that serotonin 3 receptors (5‐HT3) are involved in MAP‐induced locomotion and reward. However, little is known about the role of 5‐HT3 receptors in MAP‐induced behavioral sensitization. Here, we measured the effects of MDL 72222, a 5‐HT3 antagonist, and SR 57227 A, a 5‐HT3 agonist, on the development and expression of MAP‐induced behavioral sensitization, and alternations of 5‐HT3 receptor binding labeled with the 5‐HT3‐selective antagonist, [3H]GR65630, in mice. In addition, we investigated the effects of MAP on 5‐HT3A receptor channel activity in Xenopus laevis oocytes expressing 5‐HT3A receptors. We found that MDL 72222 attenuated both the development and expression of behavioral sensitization to MAP (1.0 mg/kg, i.p.), and that this attenuating effect of MDL 72222 was reversed by pre‐treatment with SR 57227 A. In oocytes expressing 5‐HT3A receptor, MAP exhibited a dual modulation of 5‐HT3A receptor channel activity, i.e. pre‐treatment with a low dose of MAP (0.1 µm) enhanced 5‐HT‐induced inward peak current (I5‐HT) but a high dose of MAP (100 µm) inhibited I5‐HT. The acute administration of MDL 72222 with MAP decreased [3H]GR65630 binding versus MAP alone in the mouse striatum. Our results suggest that MDL 72222 attenuates MAP‐induced behavioral sensitization via 5‐HT3 receptors in the caudate putamen, and that 5‐HT3 receptor antagonists like MDL 72222 have potential as novel anti‐psychotic agents for the treatment of MAP dependence and psychosis.