The effect of typical and atypical antipsychotic drugs on the mRNA expression of rat mesencephalic D2 receptor

Shon, Young Ho; Kim, Jin Soo

Abstract

Recently various types of dopamine receptors have been proved to exist in human central nervous system. And the understanding of the of specific function is expected to improve therapeutic effect as well as to reduce undesirable side-effect of current antipsychotic and antiparkinson treatment. Since the dopamine autoreceptor is known to be more sensitive to dopaminergic drugs, there is a growing concern about its functional role in neuropsyhiatric disease. Besides ligand binding studies, recent advances in molecular biology make it possible to quantitate mRNA coding for specific receptors which gives more direct information about its rate of synthesis at the gene level. It is documented that chronic antipsychotics treatment enhances the sensitivity of dopamine autoreceptor, but changes in its mRNA expression have never been investigated yet. Using male Sprague-Dawley rats, 6-hydroxydopamine was injected into left median forebrain bumdle to test whether D2 receptoe mRNA found in midbrain is coding for autoreceptors. And antipsychotic drugs, haloperidol, sulpiride, and clozapine, were administered daily for 2 weeks in order to evaluate their effect on dopamine autoreceptor mRNA, expression. The quantitation of mRNA expression was performed using ribonuclease protection assay. After 6-hydroxydopamine injection, significant reduction in D2, both D2L and D2S, receptor mRNA expression was observed in left midbrain compared with right side. The ratios of D2L/beta-actin and D2S/beta-actin- mRNA in left midbrain were 23.3% and 21.6% of that in right side respectively. Significant expression was demonstrated after repetitive haloperidol and sulpiride, but not after clozapine treatment ; D2S mRNA was increased after haloperidol treatment, while sulpiride enhanced D2L mRNA expression. However, the relative ratio of D2L and D2S mRNA expression in rat midbrain was not changed after repetitive administration of antipsychotic drugs used in this study. These result suggest ; first, the major proportion of mesencephalic D2 receptor mRNA is coding for autoreceptor ; second, the D2 receptor mRNA expression is increases after chronic haloperidol and sulpiride, ut not after clozapine treatment, which may be related to development of extrapyramidal side to alter the relative ratio of D2L and D2S mRNA expression in rat midbrain.