Behavioural and neurochemical effects of antipamezole, a novel alpha 2-adrenoceptor antagonist.

The effects of antipamezole (MPV-1248), a novel selective and specific alpha 2-adrenoceptor antagonist, were studied on monoamine metabolism in rat brain and CSF. In addition, the ability of the drug to antagonize the behavioural and neurochemical effects of two alpha 2-adrenoceptor agonists, detomidine and medetomidine, was assessed. Atipamezole, 0.03-3.0 mg/kg, had no gross behavioral effects on the rats. Above 3 mg/kg, the rats showed increased vocalization and some hostility, rapid breathing and piloerection. The drug caused dose-dependent, rapid and relatively long-lasting increase in the central turnover of noradrenaline (NA) as reflected by increases in the levels of the major metabolites of NA in brain and CSF and an increase in the depleting effect of alpha-methyl-para-tyrosine on brain NA levels. An increase in the turnover of serotonin (5-HT) in brain was indicated by a decrease in the concentration of 5-HT and a corresponding increase in the level of its metabolite, 5-hydroxyindoleacetic acid. Atipamezole was able to antagonize the sedative, hypothermic and neurochemical effects of two potent alpha 2-agonists, detomidine and medetomidine. These results give support for the characterization of atipamezole as a potent antagonist at central alpha 2-adrenoceptors with a rapid onset of action.