P2Y receptor mediated inhibitory modulation of noradrenaline release in response to electrical field stimulation and ischemic conditions in superfused rat hippocampus slices

Abstract

In this study, the inhibitory regulation of the release of noradrenaline (NA) by P2 receptors was investigated in hippocampus slices pre-incubated with [(3)H]NA. Electrical field stimulation (EFS; 2 Hz, 240 shocks, and 1 ms) released NA in an outside [Ca(2+)]-dependent manner, and agonists of P2Y receptors inhibited the EFS-evoked [(3)H]NA release with pharmacological profile similar to that of the P2Y(1) and P2Y(13) receptor subtypes. This inhibitory modulation was counteracted by bicuculline and 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline + 2-amino-5-phosphonovalerate and 2-amino-4-phosphonobutyrate. In contrast, the excess release in response to 30 min combined oxygen and glucose deprivation was outside [Ca(2+)] independent, but still sensitive to the inhibition of both facilitatory P2X(1) and inhibitory P2Y(1) receptors. Whereas mRNA encoding P2Y(12) and P2Y(13) receptor subunits were expressed in the brainstem, P2Y(1) receptor immunoreactivity was localized to neuronal somata and dendrites innervated by the mossy fiber terminals in the CA3 region of the hippocampus, as well as somata of granule cells and interneurons in the dentate gyrus. In summary, in addition to the known facilitatory modulation via P2X receptors, EFS-evoked [(3)H]NA outflow in the hippocampus is subject to inhibitory modulation by P2Y(1)/P2Y(13) receptors. Furthermore, endogenous activation of both facilitatory and inhibitory P2 receptors may participate in the modulation of pathological NA release under ischemic-like conditions.