GABAA Receptors Mediate the Attenuating Effects of a 5-HT3 Receptor Antagonist on Methamphetamine-Induced Behavioral Sensitization in Mice

We previously showed that 5-HT3 receptors are involved in the development and expression of methamphetamine (MAP)-induced locomotor sensitization in mice. Here, we examined whether the dopaminergic or the GABAergic systems are involved in the attenuating effects of the 5-HT3 receptor antagonist MDL72222 on MAP-induced locomotor sensitization. Quantitative autoradiography of D1 ([H-3]SCH23390), D2 ([H-3]raclopride) receptor, and GABA(A) receptor benzodiazepine ([H-3]flunitrazepam) binding was carried out in the brains of mice treated with chronic MAP and pretreatment with MDL72222. No significant differences were found in D-1 and D-2 binding between the two groups, suggesting that the attenuating effects of MDL72222 on MAP-induced locomotor sensitization is not medicated by D1 and D2 receptors. Postsynaptic dopamine (DA) receptor supersensitivity was measured by challenge with apomorphine, a dopamine D-1 and D-2 receptor agonist, after repeated MAP treatment or pretreatment with MDL72222 before MAP. Apomorphine induced an enhanced locomotor activity in both chronic MAP-treated mice and mice pretreated with MDL 72222, with no significant differences between the two groups. The binding of [H-3]flunitrazepam was significantly decreased in the motor and cingulate cortex, caudate putamen, and nucleus accumbens of mice in the repeated MAP treatment group compared with the control group, and this effect was reversed by pretreatment with MDL72222. This suggested that GABA(A) benzodiazepine binding sites are involved in the attenuating effects of a 5-HT3 receptor antagonist on MAP-induced locomotor sensitization. Synapse 64:274-279, 2010. (C) 2009 Wiley-Liss, Inc.