Differential effects of typical and atypical antipsychotics on nerve growth factor and choline acetyltransferase expression in the cortex and nucleus basalis of rats

Previously we reported that chronic exposure to haloperidol (HAL), but not the atypical antipsychotics risperidone (RISP) or clozapine (CLOZ), resulted in reductions in brain choline acetyltransferase (ChAT) immunoreactivity and impaired water maze task performance in rats. In the present study, we compared the effects of these antipsychotic drugs on the expression of nerve growth factor (NGF) as well ChAT the in the rat cortex and nucleus basalis of Meynert (NBM) in an effort to determine the underlying mechanism for the differential drug effects observed previously. We also evaluated the effects of these compounds in a crossover design to evaluate specific neurochemical consequences of switching between typical and atypical antipsychotics, a common practice observed in the clinical setting. Male Wistar rats (250-300 g) were exposed to HAL (2.0 mg/kg/day), RISP (2.5 mg/kg/day), or CLOZ (20 mg/kg/day) for 45 days or a pre-treatment regimen consisting of administering either RISP/HAL (i.e., RISP followed by HAL) or CLOZ/HAL, or a post-treatment regimen consisting of administering: HAL/RISP or HAL/CLOZ. The duration of each treatment in the crossover study was also 45 days. NGF and ChAT immunoreactivity were measured by quantitative immunohistochemistry in some sub-cerebral cortical regions and NBM after drug exposures. NGF protein was also measured by an enzyme-linked ImmunoSorbent assay (ELISA) in rat sensorimotor cortex. The results indicated that HAL (but not RISP or CLOZ) significantly reduced NGF levels in some sub-cortical regions and ChAT immunoreactivity in both cortex and NBM. However, pre-treatment with CLOZ prevented the HAL-associated decreases in NGF and ChAT, while post-treatment with either RISP or CLOZ (i.e., after the administration of HAL) appeared to restore NGF and ChAT to control levels. These data indicate that antipsychotic drugs exert dissimilar effects on the levels of NGF and ChAT in the brain, which may contribute to their differential effects on cognitive function. The crossover data further suggest that certain atypical antipsychotic drugs (e.g., clozapine) may have the potential to prevent or reverse the deleterious effects of HAL on important neurochemical substrates of cognitive function.