ISCHEMIA-INDUCED EXTRACELLULAR RELEASE OF SEROTONIN PLAYS A ROLE IN CA1 NEURONAL CELL-DEATH IN RATS

Background and Purpose: Serotonin, via 5-HT2 receptors, exerts an excitatory effect on CA1 neurons and may play a role in ischemia-induced excitotoxic damage. To evaluate the role of serotonin in ischemia, both neurochemical and histopathological studies were performed. Methods: Neurochemical studies included rats that were subjected to 12.5 or 20 minutes of normothermic ischemia by two-vessel occlusion plus hypotension, and extracellular serotonin levels were measured in the hippocampus (12.5 minutes' ischemia, n=5) or striatum (20 minutes' ischemia, n=13) by microdialysis. In the histopathological study the effect of 8 mg/kg ritanserin, a 5-HT2 antagonist, administered continuously from 30 minutes prior to ischemia until 1 hour of recirculation was evaluated in five rats subjected to 10 minutes of ischemia. After 3 days, the numbers of normal-appearing neurons in the CA1 subregions were counted. Results: Ischemia of 12.5 minutes' duration induced a fourfold increase in serotonin in the hippocampus (mean+/-SEM baseline, 1.86+/-0.25 pmol/ml perfusate; during ischemia, 8.14+/-0.89 pmol/ml; p<0.05 by analysis of variance). Twenty minutes of ischemia induced a 25-fold increase in serotonin in the dorsolateral striatum (baseline, 0.98+/-0.15 pmol/ml; ischemia, 24.4+/-5.93 pmol/ml; p<0.001). The histopathological study demonstrated severe ischemic damage in all CA1 subregions of nontreated animals (medial, 34+/-16 normal-appearing neurons, middle, 52.2+/-22.9 neurons; lateral, 56.6+/-21.8 neurons). Treatment with ritanserin significantly attenuated ischemic damage (medial, 117.6+/-6.5 neurons; middle, 131.4+/-4.9 neurons; lateral, 130+/-7.5 neurons; p<0.01 different from nontreated). Conclusions: Taken together, these results suggest that serotonin plays a detrimental role, mediated by 5-HT2 receptors, in the development of ischemic damage.