S 15535, a benzodioxopiperazine acting as presynaptic agonist and postsynaptic 5‐HT 1A receptor antagonist, prevents the impairment of spatial learning caused by intrahippocampal scopolamine

The effect of S 15535 (4‐benzodioxan‐5‐yl)1‐(indan‐2‐yl)piperazine), an agonist at presynaptic and antagonist at postsynaptic 5‐HT 1A receptors, on the impairment of spatial learning caused by intrahippocampal scopolamine in a two‐platform spatial discrimination task was studied. Scopolamine (4.0 μg μl −1 ), injected bilaterally into the CA1 region of the dorsal hippocampus 10 min before each training session, impaired choice accuracy with no effect on choice latency and errors of omission. Administered subcutaneously 30 min before each training session, S 15535 1.0 (but not 0.3) mg kg −1 did not modify choice accuracy but prevented its impairment by intrahippocampal scopolamine. WAY 100635, a 5‐HT 1A receptor antagonist, injected into the dorsal raphe at 1.0 μg 0.5 μl −1 5 min before scopolamine, had no effect on choice accuracy and latency or errors of omission and did not modify the effect of scopolamine but completely antagonized the effect of S 15535 (1.0 mg kg −1 ) on scopolamine‐induced impairment of choice accuracy. The results confirm a previous report (Carli et al ., 1998) that stimulation of presynaptic 5‐HT 1A receptors in the dorsal raphe counteracts the deficit caused by intrahippocampal scopolamine, probably by facilitating the transfer of facilitatory information from the entorhinal cortex to the hippocampus. Drugs that stimulate action on presynaptic 5‐HT 1A receptors, such as S 15535 and other partial 5‐HT 1A receptors agonists, may be useful in the symptomatic treatment of human memory disturbances associated with loss of cholinergic innervation to the hippocampus.British Journal of Pharmacology (1999) 128 , 1207–1214; doi: 10.1038/sj.bjp.0702915