The effect of medetomidine on GABA and benzodiazepine receptors in vivo: lack of anxiolytic but some evidence of possible stress-protective activity.
Medetomidine, a new selective alpha 2-adrenoceptor agonist, potentiated bicuculline seizures in mice. In vivo pretreatment with medetomidine in mouse cerebral cortex reduced dose-dependently (2.5-100 micrograms/kg) GABA-potentiated 3H-flunitrazepam binding. The affinity of 3H-muscimol was also reduced by medetomidine. This effect of medetomidine on GABA-potentiated benzodiazepine binding was reversed by pretreatment with atipamezole (1 mg/kg), a specific alpha 2-antagonist. In an elevated plus-maze model of anxiety medetomidine (0.5-10 micrograms/kg) was inactive both in rats and mice and did not antagonize the behavioural effects of an anxiogenic beta-carboline, DMCM. However, at lower doses medetomidine (10 but not 50 micrograms/kg) antagonized the swimming stress caused increase of central benzodiazepine binding sites (labeled with 3H-Ro 15-1788) in mouse cerebral cortex. The increase of peripheral benzodiazepine binding sites on brain and heart cryostat cut slices caused by stress was also antagonized by pretreatment with medetomidine. The behavioural and biochemical data obtained in this study are evidence that medetomidine does not have anxiolytic effect but may have, in lower doses, stress-protective activity.
Rägo
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Department of Pharmacology and Toxicology, University of Kuopio, Finland.
MacDonald
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Saano
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Airaksinen
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MM
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001640:Bicuculline; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D005442:Flumazenil / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D008297:Male; D020926:Medetomidine; D009118:Muscimol / Q000378:metabolism / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013268:Stimulation, Chemical; D013312:Stress, Physiological / Q000517:prevention & control*; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D011963:Receptors, GABA-A; D014316:Tritium; D009118:Muscimol; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; D020926:Medetomidine; D001640:Bicuculline