Involvement of 5-HT₃ receptors in the development and expression of methamphetamine-induced behavioral sensitization: 5-HT_3A 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-HT_3A receptor channel activity in Xenopus laevis oocytes expressing 5-HT_3A 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-HT_3A receptor, MAP exhibited a dual modulation of 5-HT_3A receptor channel activity, i.e. pre-treatment with a low dose of MAP (0.1 μm) enhanced 5-HT-induced inward peak current (I_5-HT) but a high dose of MAP (100 μm) inhibited I_5-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.