Actions and some interactions of 5-HT1A ligands in the elevated X-maze and effects of dorsal raphe lesions

Effects of 5-HT_1A agonists and partial agonists on open/total arm entry ratio (OTR) have been examined in the elevated X-maze anxiety model. 8-OH-DPAT (0.05–0.2 mg/kg), RU 24969 (0.5–2.0 mg/kg) and BAY R 1521 (0.1–1.2 mg/kg) produced dose-dependent reductions in OTR, signifying anxiogenic effects. Buspirone reduced OTR only at doses (0.25–5.0 mg/kg) decreasing total entries; gepirone (0.1–5.0 mg/kg) was inactive. Ipsapirone (0.25–5.0 mg/kg) increased OTR and at 1.0 mg/kg antagonised the anxiogenic action of 8-OH-D-PAT, RU 24969 and BAY R 1531. Gepirone (2.5 mg/kg) failed to antagonise 8-OH-DPAT, but the dose was limited by its effect on total entries. The anxiogenic effect of a low dose of 8-OH-DPAT was also prevented byp-chlorophenylalanine (p-CPA) pretreatment and reversed to anxiolytic by 5,7-dihydroxytryptamine lesions of dorsal raphe, which spared median raphe. These lesions also abolished the anxiolytic effect of ipsapirone without affecting the anxiogenic response to yohimbine. This study provides preliminary evidence that 8-OH-DPAT may be capable of acting as an agonist and ipsapirone as an antagonist at a presynaptic site related to dorsal raphe which is separate from the site of action of yohimbine. 5-HT_1A agonists and partial agonists may have multiple sites and/or mechanisms of action in the elevated X-maze.