Antipsychotic-like effect of the muscarinic acetylcholine receptor agonist BuTAC in non-human primates

TY - JOUR

T1 - Antipsychotic-like effect of the muscarinic acetylcholine receptor agonist BuTAC in non-human primates

AU - Andersen, Maibritt B

AU - Croy, Carrie Hughes

AU - Dencker, Ditte

AU - Werge, Thomas

AU - Bymaster, Frank P

AU - Felder, Christian C

AU - Fink-Jensen, Anders

PY - 2015/4/16

Y1 - 2015/4/16

N2 - 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.

AB - 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.

KW - Animals

KW - Antipsychotic Agents

KW - Behavior, Animal

KW - Cebus

KW - Male

KW - Muscarinic Agonists

KW - Primates

KW - Receptors, Muscarinic

U2 - 10.1371/journal.pone.0122722

DO - 10.1371/journal.pone.0122722

M3 - Journal article

C2 - 25880220

SN - 1932-6203

VL - 10

SP - 1

EP - 13

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 4

M1 - e0122722

ER -