Partial inhibition of reverse tolerance by a high dose of ritanserin or low dose of haloperidol in methamphetamine-sensitized rat.

To clarify the implication of antagonism of serotonin (5-HT)2 receptors in the treatment of schizophrenia, the effects of ritanserin (RIT) on the development of reverse tolerance in rats repeatedly administered methamphetamine (MAP) were investigated and compared with those of low doses of haloperidol (HPD). RIT administered at a dose of 2 mg/kg and low doses of HPD (0.05, 0.1 mg/kg) shared partial inhibition of the development of reverse tolerance in MAP-sensitized rats; the drugs inhibited sniffing but not head moving and had no effect on locomotion or rearing. A combination of low doses of HPD and RIT resulted in the inhibition of head moving. These results suggested that strong antagonism for 5-HT2 receptors would be useful to some extent to treat MAP-induced psychosis and schizophrenia as well as weak antagonism of dopamine D2 receptors, and that a combination of these two actions would produce better results in these psychoses than that obtained from D2 antagonism alone. In the presence of 0.05 mg/kg of HPD, RIT caused increased locomotion and rearing, whereas it decreased them in the presence of 0.1 mg/kg of HPD. This result suggested that the interactions between 5-HT and dopamine (DA) neurons are complex, and that 5-HT2 antagonism may inhibit or disinhibit DA neurons depending on the level of D2 blockade.