Effects of JO 1784, A selective sigma ligand, on the autoradiographic localization of M 2 and M 2 muscarinic receptor subtypes in trimethyltin treated rats

Abstract

The distribution patterns of M 1 and M 2 muscarinic receptor subtypes following TMT and JO 1784 administration in the male Sprague-Dawley rat were investigated. In the present study, JO 1784 was injected in doses of 1, 4 and 16 mg/kg i.p. for one week prior to the single injection of TMT (8 mg/kg i.p.) and subsequently for 33 days. The effects of JO 1784 on the density of muscarinic receptor sub-types (M 1 and M 2) in the control and trimethyltin (TMT) treated rats were then evaluated. The topographic distribution and changes in muscarinic (M 1 and M 2) receptor densities were determined by means of autoradiography using [ 3H]quinuclidinylbenzilate (QNB). Both sub-types of muscarinic receptors contributed to the observed decrease in total muscarinic receptor binding in TMT-treated rats. In control rats, JO 1784 alone decreased M 1 receptor density in the amygdaloid nuclei, basal ganglia, cortex and hippocampus and decreased M 2 receptor density in the amygdaloid nuclei, basal ganglia, cortex, hippocampus, hypothalamus and septal regions. In TMT treated rats, chronic JO 1784 administration has a “neuroprotective effect” on both M 1 and M 2 receptors subtypes. Thus, following chronic administration of JO 1784 to TMT treated rats, both increases and decreases in M 1 receptor density were observed relative to TMT animals. A significant increase in M 1 receptor density was found in the cortex, olfactory regions, septum, thalamus and basal forebrain nuclei. In the hippocampus (CA 2 and CA 3), a significant decrease in M 1 receptor density was observed. In TMT-treated rats, JO 1784 produced a significant increase in M 2 receptor density in several brain regions with the most marked effects occurring in the amygdaloid nuclei, basal ganglia, cortex, hippocampus and hypothalamus. The ability of the selective sigma ligand, JO 1784, to attenuate the loss of muscarinic receptors in TMT treated rats could be of importance in the development of novel neuroprotective drugs.