Acute zolpidem administration produces pharmacodynamic and receptor occupancy changes at similar doses.
Zolpidem is chemically unrelated to classical benzodiazepines but has demonstrated relatively high affinity binding to the alpha(1) GABA(A) receptor. To assess pharmacodynamic and neurochemical effects of zolpidem, open-field behavior, pentylenetetrazole-induced seizure threshold and benzodiazepine receptor binding in vitro were evaluated in the same animal following a single dose of zolpidem. Zolpidem (2, 5 and 10 mg/kg), lorazepam (2 mg/kg) or vehicle was administered intraperitoneally in male CD-1 mice. Behavioral activity, assessed by three open-field parameters, was decreased following the two highest doses of zolpidem (5 and 10 mg/kg), and reached significance at the 10 mg/kg dose. Locomotor activity was also decreased significantly by lorazepam as expected. Pentylenetetrazole-induced seizure threshold was increased with the administration of 2 and 10 mg/kg zolpidem as well as with lorazepam. Apparent affinity (K(D)) of [3H]flunitrazepam, a non-selective ligand, for the benzodiazepine receptor in cortical membrane preparations was not significantly changed, while receptor number (Bmax) was decreased at all doses of zolpidem, reaching significance at the 10 mg/kg dose. These results confirm that the behavioral effects of zolpidem are similar to those of classical benzodiazepines. In addition, zolpidem had no significant effect on the affinity of the benzodiazepine receptor for [3H]flunitrazepam, but did decrease the density of receptor binding sites.
Fahey
Jeanne M
JM
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and the Division of Clinical Pharmacology, Tufts-New England Medical Center, 136 Harrison Avenue, Boston, MA 02111, USA. jeanne.fahey@tufts.edu
Grassi
Jeffrey M
JM
Reddi
Jyoti M
JM
Greenblatt
David J
DJ
D000818:Animals; D000927:Anticonvulsants; D001667:Binding, Competitive / Q000187:drug effects; D003292:Convulsants / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005445:Flunitrazepam / Q000493:pharmacokinetics; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D008140:Lorazepam / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000494:pharmacology; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011955:Receptors, Drug / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D000077334:Zolpidem
D000927:Anticonvulsants; D003292:Convulsants; D006993:Hypnotics and Sedatives; D011725:Pyridines; D011955:Receptors, Drug; D011963:Receptors, GABA-A; D005445:Flunitrazepam; D000077334:Zolpidem; D008140:Lorazepam; D010433:Pentylenetetrazole