Further Evidence that Behavioral Tests and Neuropeptide mRNA and Tissue Level Alterations Can Differentiate between Typical and Atypical Antipsychotic Drugs

Abstract

This study was designed to compare some behavioral and biochemical effects of chronic treatment with a range of antipsychotic drugs. Gene expression of enkephalin, chromogranin A, chromogranin B, and secretogranin II and their respective peptide products were studied with in situ hybridization and radioimmunoassays after daily oral administration of haloperidol, clozapine, risperidone, or zotepine for 21 days. In behavioral tests, significant catalepsy was induced by haloperidol only. All four antipsychotic drugs increased hind paw retraction time but only haloperidol also increased forelimb retraction time. In the caudate putamen, haloperidol increased both enkephalin mRNA expression and enkephalin tissue levels. Neither of these parameters was altered by the other three drugs. In the prefrontal cortex, antipsychotic drugs generated a distinct pattern of gene expression in two regards. First, the dopamine D2 receptor antagonist, haloperidol, did not significantly alter synaptic protein levels or their encoding mRNAs. Secondly, there was a differential change in tissue levels and mRNA expression since secretogranin II was not affected by any tested antipsychotic drug. This study shows that different types of antipsychotic drug induce distinct behavioural effects as well as differential changes in the biosynthesis of synaptic proteins and their encoding mRNAs. The data reinforce the notion that haloperidol can be classed as a typical antipsychotic drug whilst clozapine, zotepine, and risperidone reflect their atypical classification.