Attenuation of ischemic efflux of endogenous amino acids by the novel 5-HT 1A/5-HT 2 receptor ligand adatanserin

Abstract

Using sodium azide (NaN 3)-induced anoxia plus aglycaemia as a model of chemically-induced ischemia in the hippocampal slice, we have evaluated the effects of the novel 5-HT 1A partial agonist/5-HT 2 receptor antagonist adatanserin and the 5-HT 1A receptor agonist BAYx3702 on the efflux of endogenous glutamate, aspartate and GABA. BAYx3702 (10–1000 nM) produced a significant ( P<0.05) dose-related attenuation of ischemic efflux of both glutamate and GABA with maximum decrease being observed at 100 nM (73 and 69%, respectively). This attenuation was completely reversed by the addition of the 5-HT 1A antagonist, WAY-100635 (100 nM). Similarly, adatanserin (10–1000 nM) produced a significant ( P<0.05) dose-related attenuation in glutamate and GABA efflux with a maximum of 72 and 81% at 100 nM, respectively. This effect was completely reversed by the 5-HT 2A/C receptor agonist, DOI but unaffected by WAY-100635. The 5-HT 2A receptor antagonist MDL-100907 produced a comparable attenuation of glutamate when compared to adatanserin, while the 5-HT 2C receptor antagonist, SB-206553, had no effect on ischemic efflux. None of these compounds significantly altered aspartate efflux from this preparation. In conclusion, the 5-HT 1A receptor partial agonist 5-HT 2 receptor antagonist, adatanserin is able to attenuate ischemic amino acid efflux in a comparable manner to the full 5-HT 1A agonist BAYx3702. However, in contrast to BAYx3702, adatanserin appears to produce it effects via blockade of the 5-HT 2A receptor. This suggests that adatanserin may be an effective neuroprotectant, as has been previously demonstrated for full 5-HT 1A receptor agonists such as BAYx3702.