ABSTRACT Xanomeline[3 (3-hexyloxy-1, 2, 5-thiadiazol-4-yI)-1, 2, 5, 6-tetrahydro-1-methylpyhdlne)] was evaluated In vWo in rat brain for effects on neurotransmitter turnover and inhibftion of ex vivo binding of muscarinic radigands. Xanomeline produced dose-related Increases In the metaboifte of dopamine, dihydroxyphen-ylacetic acid (DOPAC), in stnatum. The increases in stnatal DOPAC levels produced by xanomeline were antagonized by the relatively selective M1 antagonist trihexyphenidyl, suggesting that xanomellne interacts with M1 heteroreceptors on dopamine nerve terminals. Xanomeiine produced small increases in stilatal acetylchoiine levels and did not antagonize the large increases in acetyicholine produced by the nonselective muscannic agonist oxotremodne, indicating that xanomeline did not tock M2 autoreceptors. Xanomeline inhibited ex vivo binding of muscarinic radloligands to homogenates of brain and the inhibition of ex vivo binding occurred in the same dose range as increases in DOPAC levels. Xanomeline did not appreciably induce salivation or antagonize oxotremorine-induced salivation indicating that xanomeline does not interact with M3 receptors. The effects of xanomeline on ex vivo binding and DOPAC levels lasted for about 3 hr and were evident after oral administration. An analog of xanomeline with similar in vivo effects did not inhibit acetyl-cholinesterase or choline acetyltransferase and inhibited choline uptake only at concentrations much higher than those required to inhibit binding. These data indicate xanomeline is selective agonist for M1 over M2 and M3 receptors in vivo in rat. It is not known whether xanomeline interacts with m4 or m5 receptors in vivo.