LACK OF CROSS-TOLERANCE BETWEEN HALOPERIDOL AND CLOZAPINE TOWARDS FOS-PROTEIN INDUCTION IN RAT FOREBRAIN REGIONS

We investigated whether the acute effects of haloperidol and clozapine on Fos expression in the rat forebrain are mediated by the same recep tors through evaluation of cross-tolerance, particularly in the common ly affected areas. Acutely administered haloperidol (1 mg/kg, i.p.) an d clozapine (20 mg/kg, i.p.) induce regionally different (e.g., the st riatum, the hypothalamic paraventricular and supraoptic nuclei, and th e central amygdala) and overlapping (e.g., the nucleus accumbens and t he lateral septum) patterns of Fos-protein distribution in the rat for ebrain. After long-term treatment, part of the acute effects of these drugs disappears in most brain areas, except in the lateral septum, th e hypothalamic paraventricular and supraoptic nuclei and the amygdala following haloperidol administration. Cross-tolerance between haloperi dol and clozapine was determined by administering a challenge dose of the one antipsychotic, following a 21-day pretreatment with the same o r the other drug or saline. In none of the investigated brain regions was cross-tolerance towards Fos-protein induction found after haloperi dol challenge in the clozapine-treated rats. Conversely, a competitive dose of clozapine in long-term haloperidol-treated rats showed cross- tolerance in the lateral septum, while the common effect of the drugs in both the dorsomedial and the dorsolateral parts of the striatum was very small. These findings indicate that, for the major part, the res ponses to haloperidol and clozapine are mediated by different receptor s, even in brain areas that are affected by both drugs.