Neuropeptide Y increases in vivo hippocampal extracellular glutamate levels through Y1 receptor activation

Neuropeptide Y's (NPY) anticonvulsant effect is generally attributed to its inhibitory effect on glutamate release from presynaptic nerve terminals, which is nicely demonstrated in in vitro settings. To date no study has attempted to investigate the effect of NPY in vivo on extracellular (EC) glutamate levels thus, via intracerebral microdialysis, we determined NPY's effect on hippocampal glutamate concentrations in vivo, and consequently the involvement of Y1 receptors to this effect. NPY or the Y1 agonist D-His26-NPY was intrahippocampally administered in rats for 2 h, during which the hippocampal glutamate dialysate levels were monitored. Pilocarpine was subsequently co-administered with NPY or D-His26-NPY to determine their effect on pilocarpine-induced limbic seizures. Unexpectedly we noted that intrahippocampal administration of NPY or D-His26-NPY increased glutamate dialysate levels in a reproducible manner. NPY attenuated pilocarpine induced seizures, whereas D-His26-NPY did not. To clarify the role of Y1 receptors in NPY's glutamatergic effect, NPY was co-administered with the selective Y1 antagonist BVD10. Hippocampal Y1 receptor blockade prevented the NPY-induced increase in hippocampal glutamate, proving that this induced glutamate increase is clearly Y1 receptor mediated. This is the first evidence that NPY enhances hippocampal EC glutamate overflow in vivo via hippocampal Y1 receptors without interfering with or contributing to NPY's anticonvulsant effect. Whilst this finding contrasts with the supposed glutamatergic hypothesis for NPY in the hippocampus, it is of significance to further assist in deciphering NPY's mechanisms of action in in vivo settings.

► NPY's effect on hippocampal glutamate levels in vivo.
► NPY and Y1 receptor agonist enhance hippocampal glutamate levels in vivo.
► Y1 receptor antagonist BVD10 prevents NPY-induced glutamate increase.
► NPY-induced glutamate increase does not interfere/contribute to NPY's anticonvulsant effect.