Comparison of acute and chronic treatment of various serotonergic agents with those of diazepam and idazoxan in the rat elevated X-maze.
The aim of this study was to use the elevated X-maze to compare acute and chronic treatments of a 5-HT1A partial agonist, ipsapirone, a 5-HT2 antagonist, ritanserin, and a 5-HT3 antagonist, ondansetron, with those of established anxiolytic (diazepam) and anxiogenic (idazoxan) compounds. Acute diazepam (5 mg/kg IP) produced a significant increase in the percentage open:total entries and time and time spent in the end of the open arms (anxiolytic profile) on the elevated X-maze. Chronic treatment with diazepam (5 mg/kg IP twice daily for 14 days) still produced an anxiolytic profile which was not apparent 24 h after cessation of chronic treatment (withdrawal). In contrast, idazoxan given both acutely (0.25 mg/kg IP) and chronically (0.8 mg/kg/h at a flow rate of 5.5 microliters/h for 14 days, via osmotic minipumps) resulted in a significant decrease in the percentage open:total entries and time and time spent in the end of the open arms (anxiogenic profile). Acute administration of ipsapirone had no effect on any of the behavioural parameters at doses of 0.01 and 1 mg/kg IP, while 0.1 mg/kg IP produced a significant anxiogenic profile. Chronic treatment with ipsapirone (0.01, 0.1 and 1 mg/kg IP twice daily for 14 days) had no significant effect on rat behaviour on the X-maze but 24 h after ending treatment, ipsapirone at the highest dose used (1 mg/kg) produced a significant anxiogenic profile which was absent when the animals were tested 7 days after cessation of treatment. Ritanserin (0.05 and 0.25 mg/kg IP) had no effect acutely on any of the parameters measured but chronic treatment (0.25 mg/kg IP, twice daily for 14 days) produced a significant anxiolytic effect which was still present 24 h but not 7 days after cessation of treatment. Acute ondansetron (0.01, 0.1 and 1 mg/kg IP) had no effect while chronic ondansetron (0.01 mg/kg IP, twice daily for 14 days) produced a significant anxiolytic profile which was not a result of handling during the chronic dosing schedule, an effect was not measureable 24 h after treatment ended. The results demonstrate that the X-maze can detect anxiolytic activity in non-benzodiazepine drugs, as ritanserin and ondansetron showed anxiolytic profiles but only after chronic treatment. In contrast, the X-maze failed to detect any anxiolytic activity with the 5-HT1A partial agonist ipsapirone after either acute or chronic treatment.
Department of Physiology and Pharmacology, Medical School, Queen's Medical Centre, Nottingham, UK.
I K
IK
Wright
M
M
Heaton
N
N
Upton
C A
CA
Marsden
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004146:Dioxanes / Q000494:pharmacology*; D019329:Idazoxan; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D017294:Ondansetron; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D016713:Ritanserin / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
D000317:Adrenergic alpha-Antagonists; D014151:Anti-Anxiety Agents; D004146:Dioxanes; D007093:Imidazoles; D011743:Pyrimidines; D012702:Serotonin Antagonists; D016713:Ritanserin; D012701:Serotonin; D017294:Ondansetron; C043077:ipsapirone; D003975:Diazepam; D019329:Idazoxan