Effects of some selective muscarinic M1 and M2 receptor agonists and antagonists on rat brain dopaminergic activity

Abstract

In this study, the effects of some selective muscarinic M1 and M2 receptor agonists on rat brain levels of dopamine (DA), and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), was investigated using a high pressure liquid chromatographic (HPLC) technique. The rat brain DA, DOPAC and HVA levels in uncannulated and ip saline-administered control animals was not significantly different from their intracerebroventricular (i.c.v.) cannulated artificial cerebrospinal fluid-administered counterparts. The muscarinic M1 receptor agonists, arecholine (i.p.) and McN-343 (i.c.v.) increased DA concentrations while decreasing that of DOPAC and HVA. A similar feature was noted with the M2 receptor antagonists gallamine (i.c.v.) and AF-DX 116 (i.p.). On the contrary, the M1 receptor antagonists pirenzepine (i.c.v.) and scopolamine (i.p.) induced a decrease in DA levels with increase in DOPAC and HVA concentrations. The M2 receptor agonist, carbachol (i.c.v.), and physostigmine (i.p.) produced dose-dependent changes, with lower doses inducing an increase in levels of DA, DOPAC and HVA and higher doses tending to increase the amine concentrations while reducing brain levels of its metabolites. The results indicate that the muscarinic M1 and M2 receptors modulate rat brain DA activity by functioning as heteroreceptors on dopaminergic neurones. The M1 receptors appear to decrease dopaminergic activity whereas the M2 receptors function to augment DA release. However, the specificity of the M2 receptor agonist, carbachol, and physostigmine, appear to be lost on dose increment. The biochemical data garnered from this study corroborates the pharmacological data, from an earlier study from this laboratory, which indicated that M1 receptor agonists and M2 receptor antagonists attenuate DA-mediated behavioural paradigms, which are augmented by M1 receptor antagonists and M2 receptor agonists.