Effect of P₂‐purinoceptor antagonists on glutamatergic transmission in the rat hippocampus

Abstract

1 A study has been made of the effects of P2-purinoceptor antagonists on the evoked excitatory postsynaptic currents (e.p.s.cs) generated in CAl pyramidal cells on stimulation of Schaffer collaterals and in CA3 pyramidal cells on stimulation of mossy fibres. The effects of these antagonists on currents generated in the cells on application of glutamate has also been determined. 2 Suramin blocked the evoked e.p.s.cs with an 50% inhibition (ID50) of 62 ± 8 Mm (mean±s.e.mean, n = 17), spontaneous miniature e.p.s.cs and the currents induced by application of 100 gM glutamate with an ID" = 121 ± 36 gM (n = 15) in all the cells studied.3 Reactive Blue 2 (RB-2) in a concentration of 200 gM decreased the e.p.s.cs by 80 10% (n = 6) and the glutamate-activated currents by 83 ± 3% (n = 6). 4 Pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) in the concentration-range of 40-500 gM decreased the amplitude of the e.p.s.cs in 12 out of 13 cells studied. PPADS at 200 gM reduced the amplitude of the e.p.s.cs by 60± 10% (n = 3). PPADS did not affect the glutamate-induced currents in 4 cells and produced potentiation of the current amplitude by 60± 10% in 4 other cells. 5 These results suggest that both presynaptic and postsynaptic P2-purinoceptors in the hippocampus can modulate the release and action of endogenous glutamate.

Stimulation of P2Y1 Receptors Causes Anxiolytic-like Effects in the Rat Elevated Plus-maze: Implications for the Involvement of P2Y1 Receptor-Mediated Nitric Oxide Production

“…Furthermore, it should be emphasized that in contrast to the P2 receptor antagonists suramin and reactive blue 2 no direct glutamate antagonistic properties were found for PPADS (Fröhlich et al, 1996;Motin and Bennett 1995;Gu et al, 1998). The anxiolytic-like effects of ADPbS were also abolished after pretreatment with MRS 2179, which acts as a specific P2Y 1 receptor antagonist (Boyer et al, 1998).…”

Synaptic Control of Motoneuronal Excitability

“…P 2 receptor-mediated excitation has only been demonstrated for inspiratory-modulated hypoglossal motoneurons in neonatal mouse (in vitro), and adult rat (in vivo) (403) With the consideration that ATP acts as the principal fast excitatory transmitter at some central synapses (320,345), ATP may directly mediate specific behavioral inputs. Alternatively, ATP may modulate glutamatergic synaptic transmission (736,872) to motoneurons (403). P 2y receptors are present in the CNS (61); however, their role in motor control remains to be established.…”

Divergent Effects of the Purinoceptor Antagonists Suramin and Pyridoxal-5′-phosphate-6-(2′-naphthylazo-6′-nitro-4′,8′-disulfonate) (PPNDS) on α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

“…There are also reports that suramin inhibits glutamatergic synaptic transmission (Motin and Bennett, 1995;Gu et al, 1998) and whole-cell currents mediated by AMPA receptors (Nakazawa et al, 1995;Zona et al, 2000) and NMDA receptors (Ong et al, 1997;Peoples and Li, 1998). Suramin was observed to inhibit binding of radioligands to NMDA receptors (Balcar et al, 1995) but not kainate receptors (Ong et al, 1997), which suggested some selectivity among glutamate receptors.…”

“…A somewhat distinct structural family of purinoceptor antagonists was established some time ago with the development of PPADS (Lambrecht et al, 1992), which has since been widely used as a highly selective P2X receptor blocker. This compound does not have mirror symmetry, is much smaller than suramin, and was indeed found to have no or weak effects on glutamate receptor responses (Motin and Bennett, 1995;Gu et al, 1998;Zona et al, 2000). PPNDS, another member of this drug family, has recently been identified as having even greater affinity for P2X receptors and a marked selectivity toward the P2X1 receptor subtype with a nanomolar inhibition constant .…”