Chronic, but not acute, dosing of antipsychotic drugs alters neurotensin binding in rat brain regions.

The present study compared high affinity neurotensin (NT) binding in rat brain following acute or chronic treatment with the classical antipsychotic, haloperidol, and the newer antipsychotic drugs, clozapine and zotepine. Drugs were given orally, as an acute treatment (1 dose) or chronically (21 day dosing) and binding to the NT high affinity receptor was examined in three brain regions; striatum, nucleus accumbens/olfactory tubercle and frontal cortex. Acute dosing with either vehicle, haloperidol, clozapine or zotepine produced no significant changes in NT binding from controls (naïve rats). Chronic (21 day) dosing resulted in an increase in the K:(D:) and B(max) of high affinity receptors in the striatum following haloperidol, but not clozapine, zotepine or vehicles. In contrast, the newer antipsychotics, clozapine and zotepine but not haloperidol or vehicles, significantly altered NT binding in the nucleus accumbens/olfactory tubercle by decreasing the K:(D:) and B(max). Further differentiation between the two newer antipsychotic drugs occurred in the frontal cortex. Clozapine had no significant effect on NT binding, whereas zotepine significantly reduced the K:(D:) of the high affinity receptor with no alteration in B(max). The antipsychotic drugs tested did not interact directly with the NT high affinity receptor. Therefore, they must be acting indirectly via an alternative receptor mechanism to alter NT high affinity binding. In accordance with previously reported NT/dopamine receptor interactions, this would suggest cross-talk between these systems. Overall, these data demonstrate that chronic, but not acute, administration of antipsychotic drugs alters NT binding in the rat brain. In addition, anatomical differences in NT binding arise according to the antipsychotic drug under test. This may be predictive of drug side-effect profile, antipsychotic efficacy or atypicality.