Abstract
Cholinergic, muscarinic receptor agonists exhibit functional dopamine antagonism and muscarinic receptors have been suggested as possible future targets for the treatment of schizophrenia and drug abuse. The muscarinic ligand (5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane (BuTAC) exhibits high affinity for muscarinic receptors with no or substantially less affinity for a large number of other receptors and binding sites, including the dopamine receptors and the dopamine transporter. In the present study, we wanted to examine the possible antipsychotic-like effects of BuTAC in primates. To this end, we investigated the effects of BuTAC on d-amphetamine-induced behaviour in antipsychotic-naive Cebus paella monkeys. Possible adverse events of BuTAC, were evaluated in the same monkeys as well as in monkeys sensitized to antipsychotic-induced extrapyramidal side effects. The present data suggests that, the muscarinic receptor ligand BuTAC exhibits antipsychotic-like behaviour in primates. The behavioural data of BuTAC as well as the new biochemical data further substantiate the rationale for the use of muscarinic M1/M2/M4-preferring receptor agonists as novel pharmacological tools in the treatment of schizophrenia.
Highlights
Cholinergic agents exhibit antipsychotic effects in schizophrenic patients
Since the historical muscarinic receptor profile of BuTAC has been slightly revised when tested in novel functional in vitro assays using the antibody capture method for G-protein activation [10], we found it relevant to test the muscarinic reference compounds xanomeline and PTAC in the same functional in vitro assays
We have earlier reported that PTAC exhibits partial agonist mode of action at M2 and M4 receptors and antagonist mode of action at M1, M3 and M5 receptors [15]
Summary
Cholinergic agents exhibit antipsychotic effects in schizophrenic patients. Pfeiffer and Jenney administered the partial muscarinic receptor agonist arecoline by subcutaneous injection to twenty-three schizophrenic patients and clinical improvement described as “lucid intervals” were reported in more than 80% of the patients [1]. Preclinical data indicate antipsychotic potential of cholinergic compounds [1,2] even though parasympathomimetic side effects have hampered firm conclusions. Antipsychotic-Like Effect of BuTAC in Non-Human Primates
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