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 receptors through evaluation of cross-tolerance, particularly in the commonly affected areas. Acutely administered haloperidol (1 mg/kg, i.p.) and clozapine (20 mg/kg, i.p.) induce regionally different (e.g., the striatum, the hypothalamic paraventricular and supraoptic nuclei, and the central amygdala) and overlapping (e.g., the nucleus accumbens and the lateral septum) patterns of Fos-protein distribution in the rat forebrain. After long-term treatment, part of the acute effects of these drugs disappears in most brain areas, except in the lateral septum, the hypothalamic paraventricular and supraoptic nuclei and the amygdala following haloperidol administration. Cross-tolerance between haloperidol and clozapine was determined by administering a challenge dose of the one antipsychotic, following a 21-day pretreatment with the same or the other drug or saline. In none of the investigated brain regions was cross-tolerance towards Fos-protein induction found after haloperidol 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 responses to haloperidol and clozapine are mediated by different receptors, even in brain areas that are affected by both drugs.