Effects of 5-HT1A receptor ligands in a modified Geller-Seifter conflict model in the rat

In a modified Geller-Seifter conflict procedure, rats were trained to lever-press for food under a multiple variable interval-fixed ratio (VI30: food; FR10: food + shock) schedule of reinforcement. The ability to antagonize response suppression in the punished period is considered a good predictor for anxiolytic activity. Chlordiazepoxide and alprazolam increased punished responding. The 5-HT1A receptor agonists flesinoxan (R(+)-N-[2[4-(2,3-dihydro-2-2-hydroxymethyl-1,4-benzodioxin-5-yl)- 1-piperazinyl]ethyl]-4-fluorobenzoamide; 0.1-10.0 mg/kg) and 8-OH-DPAT (8-hydroxy-2-(di-n-propyl-amino)tetralin; 0.03-0.5 mg/kg) significantly increased punished responding, supporting a role of the 5-HT1A receptor in anxiety. 8-OH-DPAT and flesinoxan also reduced unpunished responding. The anxiolytic effects of 8-OH-DPAT and flesinoxan could only be antagonized with a high dose (1.0 and 3.0 mg/kg respectively) of the 5-HT1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). All doses of WAY-100635 antagonized the 5-HT1A-induced effects on unpunished responding. The dissimilarity in dose-response curve of WAY-100635 on punished and unpunished behaviour poses questions about the mediation of these effects.