title: Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats.
abstract: Acetylcholine (ACh) esterase inhibitors like galantamine and donepezil have been tested as adjunct treatment in schizophrenia. Although ACh esterase inhibition might confer some antipsychotic activity, the role of allosteric potentiation of nicotinic ACh receptors (nAChRs), which is an additional mechanism of galantamine, remains elusive. Therefore, the potential antipsychotic-like effects of galantamine and donepezil, respectively, alone, and in combination with the dopamine D2/3 receptor antagonist, raclopride, were tested in the conditioned avoidance response (CAR) test and extrapyramidal side-effect liability was assessed with the catalepsy test. Neither galantamine nor donepezil alone suppressed CAR selectively. Galantamine, but not donepezil, enhanced the raclopride-induced suppression of CAR, predicting augmentation of antipsychotic activity. In contrast to donepezil, galantamine did not increase catalepsy, alone or combined with raclopride. These data suggest that allosteric potentiation of nAChRs may mediate the antipsychotic-like effect of adjunctive galantamine and provide support for the development of alpha7 nAChR-selective allosteric potentiators for schizophrenia.
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Wiker
authors.forename: Björn
authors.initials: B
authors.lastname: Schilström
authors.forename: Carina
authors.initials: C
authors.lastname: Sandbäck
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Wadenberg
authors.forename: Torgny H
authors.initials: TH
authors.lastname: Svensson
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D005702:Galantamine / Q000494:pharmacology*; D007189:Indans / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D020891:Raclopride / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D014150:Antipsychotic Agents; D002800:Cholinesterase Inhibitors; D004338:Drug Combinations; D007189:Indans; D010880:Piperidines; D005702:Galantamine; D020891:Raclopride; D000077265:Donepezil