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Previously, we have described the modulatory effect of diadenosine polyphosphates Ap 4 A and Ap 5 A on synaptic transmission in the rat hippocampal slices mediated by presynaptic receptors (Klishin et al., 1994). In contrast, we now describe how nonhydrolyzable Ap 4 A analog diadenosine-5Ј,5ٞ-P 1 ,P 4 -[␤,␤Ј-methylene]tetraphosphate (AppCH 2 ppA) at low micromolar concentrations exerts strong nondesensitizing inhibition of orthodromically evoked field potentials (OFPs) without affecting the amplitude of excitatory postsynaptic currents and antidromically evoked field potentials, as recorded in hippocampal CA1 zone. The effects of AppCH 2 ppA on OFPs are eliminated by a P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2Ј,4Ј-disulfonic acid (PPADS) but not mimicked by purinoceptor agonists ␣,␤-methylene-ATP and adenosine 5Ј-O-(3-thio)-triphosphate, indicating that a P2-like receptor is involved but not one belonging to the conventional P2X/P2Y receptor classes. Diadenosine polyphosphate receptor (P4) antagonist Ip 4 I (diinosine tetraphosphate) was unable to modulate AppCH 2 ppA effects. Thus, the PPADS-sensitive P2-like receptor for AppCH 2 ppA seems to control selectively dendritic excitation of the CA1 neurons. The specific nitric oxide (NO)-scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide is shown to significantly attenuate AppCH 2 ppA-mediated inhibitory effects, indicating that NO is involved in the cascade of events initiated by AppCH 2 ppA. Further downstream mediation by adenosine A1 receptors is also demonstrated. Hence, AppCH 2 ppA-mediated effects involve PPADS-sensitive P2-like receptor activation leading to the production of NO that stimulates intracellular synthesis of adenosine, causing in turn postsynaptic A1 receptor activation and subsequent postsynaptic CA1 dendritic inhibition. Such spatially selective postsynaptic dendritic inhibition may influence dendritic electrogenesis in pyramidal neurons and consequently mediate control of neuronal network activity.

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