Are there changes in sensitivity to 5-HT3 receptor ligands following chronic diazepam treatment?
Administration of 1-(3-chlorophenyl)-biguanide (mCPB), a 5-HT3 receptor agonist (1 and 10 mg/kg IP), was found to be significantly anxiogenic in vehicle treated rats tested in the plus-maze, while having no significant effect in rats withdrawn for 24 h from 21 days diazepam treatment (2 mg/kg/day), suggesting a decreased agonist action at 5-HT3 receptors following withdrawal from chronic diazepam treatment. In the social interaction test, diazepam withdrawn rats showed a significant decrease in social interaction when compared to the chronic vehicle treated group. This anxiogenic response was reversed by low doses of zacopride (0.0001-0.01 mg/kg IP); in the vehicle treated animals 0.1 mg/kg was significantly anxiogenic. The overall pattern of results with zacopride is explained by suggesting that the anxiogenic effects of high doses of zacopride are detectable at low levels of 5-HT function and are due to an agonist action of the S-isomer in the rat at 5-HT3 receptors. The anxiolytic action of low doses is attributed to the R-isomer acting at the R-zacopride binding site and is enhanced in conditions of high 5-HT function, e.g. in the diazepam withdrawn rats. If this hypothesis is correct, then we would predict the R-isomer alone would be more effective in reversing the anxiogenic effects of diazepam withdrawal than the racemate, used here.
Andrews
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Psychopharmacology Research Unit, Guy's Hospital, London, UK.
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D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003975:Diazepam / Q000494:pharmacology*; D007398:Interpersonal Relations; D008024:Ligands; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000523:psychology
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C055971:zacopride; D003975:Diazepam