EFFECTS OF YM-43611, A NOVEL DOPAMINE D-2-LIKE RECEPTOR ANTAGONIST, ON IMMEDIATE-EARLY GENE-EXPRESSION IN THE RAT FOREBRAIN

The pharmacological characteristics of two benzamides, YM-43611, a pot ent and selective dopamine D-3 and D-4 antagonist, and YM-09151-2 (nem onapride), were compared with two reference antipsychotic agents, halo peridol and clozapine, in terms of modification of c-fos and related g ene expression in the rat forebrain. After subcutaneous injection of Y M-43611 (1 or 5 mg/kg), nemonapride (4 mg/kg), haloperidol (1 mg/kg), or clozapine (25 mg/kg), Fos immunocytochemistry was employed, and the distributions of Fos-like immunoreactive neurons were compared. As wa s the case for the two reference antipsychotics, the two benzamides en hanced c-Fos immunoreactivity in a number of forebrain regions, Specif ically, like clozapine and nemonapride, YM-43611 significantly increas ed the number of immunoreactive cells in the nucleus accumbens shell a nd islands of Callejal. In contrast to clozapine and nemonapride, YM-4 3611 did not increase c-fos expression in the medial prefrontal cortex . Haloperidol and nemonapride elevated the number of positive cells in the striatum and nucleus accumbens core, whereas clozapine and YM-436 11 did not. Clozapine increased the number of Fos-like immunoreactive cells in the lateral septal nucleus and the diagonal band nucleus, but YM-43611, nemonapride and haloperidol did not. The present findings d emonstrate that in comparison with three other drugs, YM-43611 has res tricted effects on c-fos expression in the rat forebrain and is active primarily in the shell region of the nucleus accumbens and the island s of Calleja. The ability of YM-43611 to block D-3 and D-4 receptors m ay contribute to its unique actions on Fos induction. (C) 1997 America n College of Neuropsychopharmacology.