Potential role of muscarinic receptors in schizophrenia

The role of muscarinic receptors in schizophrenia was investigated using th e muscarinic agonist PTAC. PTAC was highly selective for muscarinic recepto rs, was a partial agonist at muscarinic M-2/M-4 receptors and an antagonist at M-1, M-3 and Ms receptors. PTAC was highly active in animal models pred ictive of antipsychotic behavior including inhibition of conditioned avoida nce responding in rats and blockade of apomorphine-induced climbing behavio r in mice. Amphetamine-induced Fos expression in rat nucleus accumbens was inhibited by PTAC, thus directly demonstrating the ability of PTAC to modul ate DA activity. In electrophysiological studies in rats, PTAC acutely inhi bited the firing of A10 DA cells and after chronic administration decreased the number of spontaneously firing DA cells in the A10 brain area. However , PTAC did not appreciably alter the firing of A9 DA cells. Thus, PTAC appe ars to have novel antipsychotic-like activity and these data suggest that m uscarinic compounds such as PTAC may represent a new class of antipsychotic agents.