Effect of acute and chronic MDL 73,147EF, a 5-HT3 receptor antagonist, on A9 and A10 dopamine neurons.

MDL 73,147EF (1H-indole-3-carboxylic acid-trans-octahydro-3-oxo-2,6- methano-2H-quinolizin-8-yl-ester methanesulphonate) is a potent and selective 5-HT3 receptor antagonist (pA2 9.8, rabbit heart; pIC50 less than 5, D-2 receptor). The effects of acutely and chronically administered haloperidol and MDL 73,147EF were compared in an electrophysiologic model for antipsychotic activity. Haloperidol, but not MDL 73,147EF, given acutely increased the number of active dopamine neurons in the substantia nigra (A9). Both haloperidol and MDL 73,147EF, given chronically, decreased the number of active ventral tegmental dopamine neurons and the number of active A9 dopamine neurons. The results indicate that MDL 73,147EF may prove useful as an antipsychotic with a unique mechanism of action.