Interactions between LY354740, a group II metabotropic agonist and the GABA(A)-benzodiazepine receptor complex in the rat elevated plus-maze.
Flumazenil, a benzodiazepine (BZ) receptor antagonist, and naloxone, a non-selective mu-receptor antagonist, were used to investigate whether the anxiolytic action of LY354740 [1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate], a Group II metabotropic glutamate receptor agonist, was mediated through the benzodiazepine binding site on the GABA(A) receptor and opioid pathways. LY354740 (1.0-10.0 mg/kg i.p.) induced dose-dependent anxiolytic-like effects in the rat elevated plus-maze. The anxiolytic-like effects of LY354740 (10.0 mg/kg) and the benzodiazepine receptor agonist, chlordiazepoxide (CDP, 5.0 mg/kg i.p.) were blocked by flumazenil (15.0 mg/kg i.p.). By contrast, naloxone (10.0 mg/kg i.p.) failed to affect the anxiolytic-like effects of either LY354740 or CDP. The behaviour of animals treated with flumazenil or naloxone alone did not significantly differ from that of animals treated with vehicle alone. This study suggests that the anxiolytic-like effects of LY354740 on the elevated plus-maze may be directly or indirectly mediated by the benzodiazepine binding site on the GABA(A) receptor complex.
Ferris
P
P
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Seward
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E
Dawson
G R
GR
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000523:psychology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D002707:Chlordiazepoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists
D014151:Anti-Anxiety Agents; D001643:Bridged Bicyclo Compounds; D018757:GABA Modulators; D009292:Narcotic Antagonists; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D009270:Naloxone; D005442:Flumazenil; D002707:Chlordiazepoxide; C104753:eglumetad