A novel muscarinic M(4) receptor antagonist provides further evidence of an autoreceptor role for the muscarinic M(2) receptor sub-type.

Muscarinic M(2) (AF-DX 384, BIBN-161) and M(4) (PD102807) receptor antagonists were used to investigate the respective roles of these two receptor sub-types in the regulation of acetylcholine release in the rat hippocampus. In vivo dialysis studies revealed that only the muscarinic M(2) receptor antagonists significantly and concentration-dependently facilitate acetylcholine release. The newly developed muscarinic M(4) receptor antagonist was unable to regulate acetylcholine release except at the highest concentration tested. It would thus appear that the muscarinic receptor acting as negative autoreceptor in the rat hippocampus is of the muscarinic M(2) sub-type, the role of the muscarinic M(4) receptor being minimal in this regard.