Unexpected antipsychotic-like activity with the muscarinic receptor ligand (5 R,6 R)6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane

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(5 R,6 R) 6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane (PTAC) is a potent muscarinic receptor ligand with high affinity for central muscarinic receptors and no or substantially less affinity for a large number of other receptors or binding sites including dopamine receptors. The ligand exhibits partial agonist effects at muscarinic M 2 and M 4 receptors and antagonist effects at muscarinic M 1, M 3 and M 5 receptors. PTAC inhibited conditioned avoidance responding, dopamine receptor agonist-induced behavior and d-amphetamine-induced FOS protein M 5 expression in the nucleus accumbens without inducing catalepsy, tremor or salivation at pharmacologically relevant doses. The effect of PTAC on conditioned avoidance responding and dopamine receptor agonist-induced behavior was antagonized by the acetylcholine receptor antagonist scopolamine. The compound selectively inhibited dopamine cell firing (acute administration) as well as the number of spontaneously active dopamine cells (chronic administration) in the limbic ventral tegmental area (A10) relative to the non-limbic substantia nigra, pars compacta (A9). The results demonstrate that PTAC exhibits functional dopamine receptor antagonism despite its lack of affinity for the dopamine receptors and indicate that muscarinic receptor partial agonists may be an important new approach in the medical treatment of schizophrenia.