Purinergic modulation of norepinephrine release and uptake in rat brain cortex: contribution of glial cells

The pathogenesis of psychiatric and neurodegenerative diseases is often associated with a deregulation of noradrenergic transmission. Considering the potential involvement of purinergic signaling in the modulation of noradrenergic transmission in the brain cortex, this study aimed to identify the P2Y receptor subtypes involved in the modulation of neuronal release and neuronal/glial uptake of norepinephrine. Electrical stimulation (100 pulses at 5 Hz) of rat cortical slices induced norepinephrine release that was inhibited by ATP and ADP (0.01–1 mM), adenosine 5′- O-(2-thiodiphosphate) (ADPβS, 0.03–0.3 mM), and UDP (0.1–1 mM). The effect of ADPβS was mediated by P2Y1receptors and possibly by A1/P2Y1heterodimers since it was attenuated by the A1receptor antagonist DPCPX and by the P2Y1receptor antagonist MRS 2500 but was resistant to the effect of adenosine deaminase (ADA). UDP inhibited norepinephrine release through activation of P2Y6receptors, an effect that was abolished by the P2Y6receptor antagonist MRS 2578 and by DPCPX, indicating that it depends on the formation and/or release of adenosine and activation of A1receptors. Supporting this hypothesis, the inhibitory effect of UDP was also prevented by inhibition of ectonucleotidases, by ADA and was attenuated by the inhibitor of nucleoside transporter 6-[(4-nitrobenzyl)thio]-9-β-d-ribofuranosylpurine (NBTI). Additionally, the inhibitory effect of UDP was attenuated when norepinephrine uptake 1 or 2 was inhibited. In astroglial cultures, ADPβS and UDP increased norepinephrine uptake mainly by activation of P2Y1and P2Y6receptors, respectively. The results indicate that neuronal and glial P2Y1and P2Y6receptors may represent new targets of intervention to regulate noradrenergic transmission in CNS diseases.