Neuropsychotoxicity of Abused Drugs: Effects of Serotonin Receptor Ligands on Methamphetamine- and Cocaine-Induced Behavioral Sensitization in Mice

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  • Ago Yukio
    Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan
  • Nakamura Shigeo
    Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan
  • Baba Akemichi
    Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan
  • Matsuda Toshio
    Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan Department of Experimental Disease Model, The Osaka-Hamamatsu Joint Research Center For Child Mental Development, Graduate School of Medicine, Osaka University, Japan

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  • Effects of serotonin receptor ligands on methamphetamine- and cocaine-induced behavioral sensitization in mice

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Abstract

Repeated administration of psychostimulants elicits a progressive enhancement of locomotor activity known as behavioral sensitization. Central dopamine (DA) neurons play key roles as the neural substrates mediating behavioral sensitization, but the role of the serotonin (5-HT) system in the sensitization is not fully elucidated. We have recently demonstrated that osemozotan, a specific 5-HT1A–receptor agonist, and ritanserin, a 5-HT2–receptor antagonist, inhibited the expression and development of both methamphetamine- and cocaine-induced behavioral sensitization in mice and that these drugs attenuated the maintenance of behavioral sensitization of methamphetamine, but not that of cocaine. We also found that azasetron, a 5-HT3–receptor antagonist, inhibited the expression and development of the sensitization induced by methamphetamine and cocaine, respectively. Neurochemical studies using a microdialysis technique showed that repeated methamphetamine enhanced the methamphetamine-induced increase in 5-HT release in the prefrontal cortex. The sensitization of 5-HT release in methamphetamine-treated mice was attenuated by osemozotan and ritanserin. These findings suggest that the 5-HT system plays an important role in methamphetamine- and cocaine-induced behavioral sensitization in mice and imply that 5-HT1A–receptor agonists and 5-HT2–receptor antagonists may have a potential therapeutic value for the treatment of methamphetamine abuse or psychosis.<br>

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