RATIONALE: Several halogenated analogs of benztropine (BZT) have previously been characterized as potent dopamine (DA) uptake inhibitors with diminished reinforcing effects relative to cocaine. In addition to their effects on DA uptake, these compounds are potent muscarinic cholinergic antagonists. OBJECTIVES: The present experiments were designed to examine the hypothesis that the anticholinergic action of the BZT analogs contributes to their relatively low levels of self-administration. METHODS: Rhesus monkeys self-administered cocaine (0.03 mg/kg per injection, i.v.) under either a fixed-ratio 25 (FR 25; n=5) or progressive-ratio (PR; n=5) schedule until stable responding was established. Saline, cocaine (0.0003-0.1 mg/kg per injection), scopolamine (0.001-0.1 mg/kg per injection), or various combinations of cocaine and scopolamine were then made available for self-administration. RESULTS: Cocaine maintained dose-related self-administration under both schedules whereas scopolamine did not. In the majority of cases, combinations of cocaine and scopolamine maintained less self-administration than cocaine alone. CONCLUSIONS: This study supports the hypothesis that anticholinergic actions contribute to the diminished self-administration of BZT analogs relative to cocaine. The mechanism may involve antagonism of the reinforcing effect of cocaine and/or punishment of the self-administration response by the addition of an anticholinergic component of action.
RATIONALE: Several halogenated analogs of benztropine (BZT) have previously been characterized as potent dopamine (DA) uptake inhibitors with diminished reinforcing effects relative to cocaine. In addition to their effects on DA uptake, these compounds are potent muscarinic cholinergic antagonists. OBJECTIVES: The present experiments were designed to examine the hypothesis that the anticholinergic action of the BZT analogs contributes to their relatively low levels of self-administration. METHODS:Rhesus monkeys self-administered cocaine (0.03 mg/kg per injection, i.v.) under either a fixed-ratio 25 (FR 25; n=5) or progressive-ratio (PR; n=5) schedule until stable responding was established. Saline, cocaine (0.0003-0.1 mg/kg per injection), scopolamine (0.001-0.1 mg/kg per injection), or various combinations of cocaine and scopolamine were then made available for self-administration. RESULTS:Cocaine maintained dose-related self-administration under both schedules whereas scopolamine did not. In the majority of cases, combinations of cocaine and scopolamine maintained less self-administration than cocaine alone. CONCLUSIONS: This study supports the hypothesis that anticholinergic actions contribute to the diminished self-administration of BZT analogs relative to cocaine. The mechanism may involve antagonism of the reinforcing effect of cocaine and/or punishment of the self-administration response by the addition of an anticholinergic component of action.
Authors: Gregory P Mark; Anthony E Kinney; Michele C Grubb; Xiaoman Zhu; Deborah A Finn; Sarah L Mader; S Paul Berger; Anita J Bechtholt Journal: Brain Res Date: 2006-10-13 Impact factor: 3.252
Authors: Morgane Thomsen; P Jeffrey Conn; Craig Lindsley; Jürgen Wess; Joon Y Boon; Brian S Fulton; Anders Fink-Jensen; S Barak Caine Journal: J Pharmacol Exp Ther Date: 2009-12-08 Impact factor: 4.030