Effects of JO 1784, a selective sigma ligand, on the autoradiographic localization of M1 and M2 muscarinic receptor subtypes in trimethyltin treated rats.

The distribution patterns of M1 and M2 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 (M1 and M2) in the control and trimethyltin (TMT) treated rats were then evaluated. The topographic distribution and changes in muscarinic (M1 and M2) 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 M1 receptor density in the amygdaloid nuclei, basal ganglia, cortex and hippocampus and decreased M2 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 M1 and M2 receptors subtypes. Thus, following chronic administration of JO 1784 to TMT treated rats, both increases and decreases in M1 receptor density were observed relative to TMT animals. A significant increase in M1 receptor density was found in the cortex, olfactory regions, septum, thalamus and basal forebrain nuclei. In the hippocampus (CA2 and CA3), a significant decrease in M1 receptor density was observed. In TMT-treated rats, JO 1784 produced a significant increase in M2, 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.