title: Development of tolerance after repeated administration of a selective muscarinic M1 antagonist biperiden in healthy human volunteers.
abstract: The muscarinic antagonist biperiden produces a dose-dependent inhibition of (REM) sleep on acute administration. The present study addressed the possibility of pharmacological tolerance after repeated biperiden administration. Six healthy volunteers were studied under sleep laboratory conditions in the following situations: one acclimatization, night, two baseline (that were averaged), 4 nights of biperiden administration, and 4 nights of placebo recovery administration. Six milligrams of biperiden and placebo were administered in identical capsules. Volunteers and technicians were blind to the order of the administration of the capsules. REM sleep time was reduced during the first and the second night, but was not significantly different in comparison with baseline by the third night. During placebo recovery nights, REM sleep time was not different from baseline. REM sleep latency was increased during the first and second nights of biperiden administration, but tolerance to this effect was observed by the third night. On placebo nights a dramatic shortening of REM latency was observed. The present findings support the hypothesis that anticholinergic drugs, even a selective M1 antagonist such as biperiden, induce tolerance soon after administration. A similar effect has been reported with scopolamine, a nonselective muscarinic antagonist, but the main difference is that biperiden withdrawal was not followed by an REM sleep rebound. The observed effect on REM sleep latency during placebo administration may be related to a supersensitivity to muscarinic M-1 receptors that trigger the first REM sleep period. Because short REM latency has been the main finding in the sleep of depressed patients, some implications of the present findings are discussed.
authors.affiliation: Departamento de Fisiologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Mexico.
authors.forename: R J
authors.initials: RJ
authors.lastname: Salin-Pascual
authors.forename: D
authors.initials: D
authors.lastname: Granados-Fuentes
authors.forename: L
authors.initials: L
authors.lastname: Galicia-Polo
authors.forename: E
authors.initials: E
authors.lastname: Nieves
authors.forename: J C
authors.initials: JC
authors.lastname: Gillin
mesh_terms: D000328:Adult; D001712:Biperiden / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D011930:Reaction Time / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012895:Sleep, REM / Q000187:drug effects*
chemical_list: D011976:Receptors, Muscarinic; D001712:Biperiden