Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats

Haloperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experimentshave even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypicalantipsychotics may actually improve cognitive function in somepatients, although this assertion requires further investigation. The purpose ofthis study was to comparethe effects of prior chronic (45-or 90-day) oralexposure to HAL and the a typical antipsychoticsrisperidone (RISP) and clozapine (CLOZ) on cognitive performance andcentralcholinergic markers in rats. Allanalyses were done after 4 days of drug washout in orderto minimize direct drug effects. Learningperformance and choline acetyl transferase (ChAT) levels were assessed in a water maze task and with immunofluorescence staining, respectively. HAL significantly impaired learning performance after 90 but not after 45 days of treatment when compared to both vehicle controls and the atypicalagents, while RISP slightly improved task performance. Both 45 and 90 days of previous HAL exposure reduced ChAT staining in severalbrain regions, includingthe cortex, caudate-putamen, and hippo campus. ChAT staining in the caudate-putamenand hippocampus was also decreased after 90 days of RISP exposure, raisingthe possibility of deleterious cognitive effects after exposureto this dosage for longer periods of time. The results suggest that antipsychotic drugs exert differential and temporally dependent effectson central cholinergic neurons and learning performance.