title: Muscarinic receptor agonists decrease cocaine self-administration rates in drug-naive mice.
abstract: (5R,6R)-6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[ 3.2.1]octane (PTAC) is a selective muscarinic receptor ligand. The compound exhibits high affinity for central muscarinic receptors with partial agonist mode of action at muscarinic M(2) and M(4) and antagonist mode of action at muscarinic M(1), M(3) and M(5) receptor subtypes. The compound was earlier reported to exhibit functional dopamine receptor antagonism in rodents despite its lack of affinity for dopamine receptors. In the present study, we report that PTAC, as well as the muscarinic receptor agonists pilocarpine and oxotremorine, dose-dependently decreased rates of intravenous self-administration (fixed ratio 1) of the indirect dopamine receptor agonist cocaine in drug naive mice. Similar decreases in cocaine self-administration rates were obtained with the dopamine receptor antagonists olanzapine, clozapine, risperidone, fluphenazine and haloperidol. These findings suggest that compounds with partial muscarinic receptor agonist mode of action may be used in the medical treatment of cocaine abuse.
authors.affiliation: Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Rasmussen
authors.forename: P
authors.initials: P
authors.lastname: Sauerberg
authors.forename: E B
authors.initials: EB
authors.lastname: Nielsen
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
authors.forename: C
authors.initials: C
authors.lastname: Thomsen
authors.forename: M J
authors.initials: MJ
authors.lastname: Sheardown
authors.forename: L
authors.initials: L
authors.lastname: Jeppesen
authors.forename: D O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: N W
authors.initials: NW
authors.lastname: DeLapp
authors.forename: C
authors.initials: C
authors.lastname: Whitesitt
authors.forename: J S
authors.initials: JS
authors.lastname: Ward
authors.forename: H E
authors.initials: HE
authors.lastname: Shannon
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: A
authors.initials: A
authors.lastname: Fink-Jensen
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D018721:Muscarinic Agonists / Q000494:pharmacology*; D010095:Oxotremorine / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D012646:Self Administration; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: C115974:6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo(3.2.1)octane; D014150:Antipsychotic Agents; D001643:Bridged Bicyclo Compounds; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D018721:Muscarinic Agonists; D013830:Thiadiazoles; D010862:Pilocarpine; D010095:Oxotremorine; D003042:Cocaine