mdl-100907 and osemozotan

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-HT(1A)-receptor agonist, and ritanserin, a 5-HT(2)-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-HT(3)-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-HT(1A)-receptor agonists and 5-HT(2)-receptor antagonists may have a potential therapeutic value for the treatment of methamphetamine abuse or psychosis.

Topics: Amphetamine-Related Disorders; Animals; Behavior, Animal; Brain; Bridged Bicyclo Compounds, Heterocyclic; Central Nervous System Stimulants; Cocaine; Cocaine-Related Disorders; Dioxanes; Dioxoles; Disease Models, Animal; Ligands; Methamphetamine; Mice; Motor Activity; Oxazines; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT3 Receptor Antagonists; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists