The influence of 5-HT₂ and 5-HT₄ receptor antagonists to modify drug induced disinhibitory effects in the mouse light/dark test

Abstract

1. The ability of 5-HT₂ and 5-HT₄ receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box.

2. The 5-HT_2A/2B/2C receptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose-related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box.

3. Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5-HT_1A receptor ligands, 8-OH-DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT₃ receptor antagonists, ondansetron (100 fold) R(+)-zacopride (100 fold) and S(−)-zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)_A receptor antagonist, devazepide (100 fold). It also reduced the onset of action of disinhibition following treatment with the 5-HT synthesis inhibitor parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects of the CCK_B receptor antagonist CI-988, the angiotensin AT₁ receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril.

4. The 5-HT₄ receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls. The antagonists failed to modify mouse behaviour when administered alone.

5. GR113808 was also shown to cause a dose-related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8-OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-zacopride, sulpiride, tiapride, devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine.

6. It was concluded that in BKW mice (a) the failure of 5-HT₂ and 5-HT₄ receptor antagonists when administered alone to modify behaviour in the light/dark test indicates an absence of an endogenous 5-HT tone at the 5-HT₂ and 5-HT₄ receptors and (b) the enhancement by the 5-HT₂ receptor antagonists and attenuation by the 5-HT₄ receptor antagonists of drug-induced disinhibition indicates a plurality of 5-HT receptor involvement in the mediation of drug-induced disinhibitory profiles in the mouse.

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