Selective antagonism of the ataxic effects of zolpidem and triazolam by the GABAA/alpha1-preferring antagonist beta-CCt in squirrel monkeys.
BACKGROUND
Delineation of the receptor mechanisms underlying the behavioral effects of benzodiazepines should allow for the development of drugs with improved clinical utility and reduced side effects. OBJECTIVES. The purpose of the present study was to investigate the role of GABAA/alpha1 receptors in the sedative and motor-impairing effects of benzodiazepines.


METHODS
Squirrel monkeys were tested with the GABAA/alpha1-preferring agonist zolpidem and the nonselective benzodiazepine agonist triazolam alone and in combination with the GABAA/alpha1-preferring antagonist beta-CCt and the nonselective benzodiazepine antagonist flumazenil. During 30-min experimental sessions, all occurrences of normal behaviors like locomotion, environment- and self-directed behaviors, as well as side effects such as ataxia, rest and procumbent postures were scored.


RESULTS
Zolpidem and triazolam produced dose-dependent reductions in locomotion and environment-directed behavior and increased ataxia and procumbent posture. Triazolam, but not zolpidem, also engendered species-typical rest posture at some doses. Flumazenil antagonized all of the behavioral effects of zolpidem and triazolam, whereas beta-CCt antagonized only zolpidem- and triazolam-induced ataxia.


CONCLUSIONS
GABAA/alpha1 receptor mechanisms appear to play a key role in the ataxic effects of benzodiazepine agonists in squirrel monkeys, similar to recent results with transgenic mice. In contrast to the findings of these recent studies, GABAA mechanisms other than or in addition to those mediated at the alpha1 subunit may play a more important role in the sedative/hypnotic effects of benzodiazepines in squirrel monkeys.
Platt
Donna M
DM
Harvard Medical School, New England Regional Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough, MA 01772-9102, USA. donna_platt@hms.harvard.edu
Rowlett
James K
JK
Spealman
Roger D
RD
Cook
James
J
Ma
Chunrong
C
D000818:Animals; D001259:Ataxia / Q000139:chemically induced* / Q000188:drug therapy; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005442:Flumazenil / Q000494:pharmacology; D018755:GABA Agonists / Q000009:adverse effects* / Q000494:pharmacology; D018757:GABA Modulators / Q000009:adverse effects* / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000009:adverse effects* / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D012453:Saimiri; D012919:Social Behavior; D014229:Triazolam / Q000009:adverse effects* / Q000494:pharmacology; D000077334:Zolpidem
D002243:Carbolines; D018755:GABA Agonists; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D014229:Triazolam; D005442:Flumazenil; D000077334:Zolpidem; C043232:tert-butyl beta-carboline-3-carboxylate