Effect of diazepam on cortical 5-HT release and behaviour in the guinea-pig on exposure to the elevated plus maze.
Previous studies have used the elevated plus maze to test for "anxiolytic" drugs in rats. The present study demonstrates that guinea-pigs handled daily from birth exhibit similar behaviour to rats on the plus maze. Pretreatment with diazepam (1.0 mg/kg) significantly increased the time the animals spent in the open arms and amount of entries into the open arms. Using intra-cortical microdialysis on exposure of the guinea-pig to the elevated plus maze resulted in increased extracellular 5-HT in the frontal cortex. Diazepam reduced, but not significantly, the increase in extracellular 5-HT and produced an "anxiolytic" profile of behaviour. Pretreatment with the benzodiazepine antagonist flumazenil (10.0 mg/kg) fully antagonised the behavioural effects of diazepam. Flumazenil also reduced the effect of diazepam on the increase in extracellular 5-HT observed on exposure of the guinea-pig to the elevated plus maze. Flumazenil alone decreased basal extracellular cortical 5-HT but had no effect on behaviour in the elevated plus maze. The results show that an increase in extracellular 5-HT occurs in the guinea-pig exposed to aversive conditions. While it remains to be determined whether the "anxiolytic" effects of diazepam in the guinea-pig are causally associated with decreased extracellular 5-HT, it is of interest that the selective benzodiazepine antagonist also prevented the increase in basal extracellular 5-HT produced by the exposure to the elevated plus maze but had no effect on behaviour. Results indicate that there is no simple relationship between inhibition of 5-HT release and the "anxiolytic" action of benzodiazepines.
Rex
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Department of Physiology and Pharmacology, University of Nottingham Medical School, Queen's Medical Centre, UK.
Marsden
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CA
Fink
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H
D000818:Animals; D001007:Anxiety / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects*; D003975:Diazepam / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D006168:Guinea Pigs; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*
D012701:Serotonin; D005442:Flumazenil; D006897:Hydroxyindoleacetic Acid; D003975:Diazepam