Stimulation of 5-HT1A receptors in the dorsal raphe ameliorates the impairment of spatial learning caused by intrahippocampal 7-chloro-kynurenic acidin naive and pretrained rats

Objective: The present study investigated the effect of stimulating 5-HT1A receptors in the dorsal raphe on the impairment of spatial learning caused by intrahippocampal 7-chloro-kynurenic acid (7-Cl-Kyn) in naive rats and in rats familiar with the general requirements of the task. Methods: A week a fter implantation of cannulae to give access to the dorsal raphe (DR) and t he CAI region of the dorsal hippocampus, rats started their 5 days acquisit ion training on a two-platform spatial discrimination task in a water maze. On each acquisition day, WAY 100635 and 8-OH-DPAT alone or in combination were injected into the dorsal raphe (DR) 5 min before intrahippocampal inje ctions of 7-Cl-Kyn which was given 10 min before the training session. Simi lar experiments were conducted in rats that had been familiarized with the general requirements of the task by pretraining them in the water maze in t he absence of distal cues. Results: 7-Cl-Kyn (3 mug/mul), injected bilatera lly in the CA1 region of the dorsal hippocampus, impaired choice accuracy w ith no significant effect on choice latency. Rats treated with 7-Cl-Kyn ten ded to spend more time swimming close to the pool walls and made more error s of omission than controls in the first two sessions. Administered into th e DR, the 5-HT1A receptor agonist 8-OH-DPAT (1 mug/0.5 mul) had no effect o n any parameter of rats' performance but antagonized the impairment of choi ce accuracy caused by intrahippocampal 7-Cl-Kyn. Injected into the DR, 1 mu g/0.5 mul WAY 100635, a 5-HT1A receptor antagonist, had no effect on rats' performance or on the impairment caused by intrahippocampal 7-ClKyn, but an tagonized the effect of 8-OH-DPAT on the 7-Cl-Kyn- induced deficit. The non -mnemonic behavioral disturbances shown by naive rats treated with 7-Cl- Ky n were greatly reduced in pretrained rats which, nevertheless, showed a mar ked impairment of choice accuracy similar to that of naive rats. As in prev ious experiments, administration of 1 mu g10.5 mul 8-OH-DPAT in the dorsal raphe antagonized the impairment of choice accuracy caused by intrahippocam pal 7-Cl-Kyn without any effect on other parameters of rats' performance. C onclusions: The results show that stimulation of presynaptic 5-HT1A recepto rs in the dorsal raphe counteracts the deficit in spatial learning caused b y a reduced NMDA-mediated excitatory input on pyramidal cells in the hippoc ampus. The possible mechanisms and the importance of these findings for the symptomatic treatment of memory disorders in man are discussed.