Rashid Giniatullin

ATP contributes to the generation of network‐driven giant depolarizing potentials in the neonatal rat hippocampus

In the immature hippocampus, the so‐called ‘giant depolarizing potentials’ (GDPs) are network‐driven synaptic events generated by the synergistic action of glutamate and GABA. Here we tested the hypothesis that ATP, a widely distributed neurotransmitter, directly contributes to the network activity during the first postnatal week. We found that in CA3 pyramidal cells, in the presence of the adenosine antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX), ATP produced a transient facilitation of GDPs followed by a depressant effect. A similar biphasic effect was produced by blockade of the ectoATPase activity with 6‐N,N‐diethyl‐d‐β,γ‐dibromomethylene ATP (ARL‐67156). The effects of exogenous and endogenous ATP on GDPs were prevented by the P2X receptor antagonist pyridoxal phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS). On pyramidal cells, ATP upregulated spontaneous action‐potential‐dependent GABAA‐mediated synaptic events (GABA‐SPSPs), suggesting a network‐driven effect. Recordings from interneurones allowed comparison of ATP effects on GABAergic and glutamatergic synaptic activity. While ATP depressed GABA‐SPSPs via metabotropic P2Y1 receptors, it up‐ and downregulated glutamatergic SPSPs via PPADS‐sensitive receptors. Thus, ATP exerts an excitatory action on CA3 pyramidal cells via facilitation of GDPs and SPSPs. This excitatory drive is propagated to pyramidal cells by interneurons that represent the ‘common pathway’ for generation of GDPs and SPSPs. Our results show that ATP operating via distinct P2X and P2Y receptors directly contributes to modulate network activity at the early stages of postnatal development.

Trapping blockage of muscle nicotinic cholinoreceptors by mecamilamine

Nicotinic cholinergic receptors can be blocked by both competitive and noncompetitive blocking agents of cholinoreceptors interacting with different regions of ionic channels [1]. Noncompetitive blocking agents may be divided into two subgroups: simple blocking agents of open channels and trapping blocking agents, which were originally described for glutamate receptors [2–5]. Earlier, we showed in the study on chromaffin rat cells that mecamilamine, a well-known neuronal blocking agent of channels, blocked neuronal cholinoreceptors by the trapping mechanism [6]. This blockade is characterized by unblocking during membrane depolarization and activation of receptors by an agonist [4, 6]. The neuromuscular junction is a common model for studying the action of ionic-channel blocking agents [7, 8]. Earlier [9], it was hypothesized that mecamilamine can block channels in a neuromuscular synapse as a simple blocking agent; however, the trapping mechanism has not been studied yet. Hence, we assessed the mechanism of the mecamilamine effect on the receptor-channel complex of muscle cholinoreceptors. Experiments were carried out using an isolated neuromuscular preparation (sciatic nerve–sartorius muscle) of Rana ridibunda frogs using the standard technique of two-electrode potential fixation described earlier [10]. After infrequent nerve stimulations ( f = 0.05 Hz), mecamilamine at concentrations of 5–20 μ M induced dose-dependent decrease in the amplitude and the decay time constant of evoked endplate currents (EECs). These effects were washed out slowly. A typical experiment with 20 μ M mecamilamine is shown on Fig. 1. It was estimated after approximating averaged dose–effect relationships with Hill’s equation that, at – 70 mV, I C 50 = 7.8 μ M and n H = 1.2 ( n = 9) . Hill’s constant was practically the same as for neuronal cholinoreceptors ( n H = 1.1 [6]), which indicated that the channel was blocked by a single molecule of the blocking agent, whereas the concentration at which the blocking-agent effect was half the maximum ( I C 50 ) for muscle cholinoreceptors was considerably higher than that for neuronal receptors (0.34 μ M [6]). The latter suggests that mecamilamine has a smaller blocking effect on muscle cholinoreceptors.

The mechanisms underlying modulation of the receptor-channel complex functioning by chlorhexidine.

A wide spectrum of antiseptic drugs with various effects is used for local treatment of purulent inflammations. Chlorhexidine biogluconate is one of these drugs, however, in addition to the antiseptic effect, it seems to influence the neuromuscular junction activity, which may be important for disease development and should be at least taken into account. It has been previously suggested that chlorhexidine has a channel-blocking effect on a neuromuscular junction [1], although the type and mechanisms of this blockage remain unclear. Therefore, in this study, we analyzed the mechanism underlying the chlorhexidine effect on the receptor–channel complex of the muscle cholinoreceptor.

ATP induces generation of slow depolarizing waves in the CA3 region of the newborn rat hippocampus

* Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, ul. Butlerova 5a, Moscow, 117485 Russia ** Kazan State Medical University, ul. Butlerova 49, Kazan, Russia One of important fields of modern neurophysiology is investigations on the mediator role of adenosine triphosphate (ATP) in the central nervous system (CNS). Purinergic receptors sensitive to both ATP and

ATP effect on spontaneous GABAergic activity in the hippocampus of neonatal rats.

In adult animals, extracellular ATP and its derivatives, such as ADP and adenosine, are efficient modulators of synaptic transmission [1, 2, 7]. As shown in the hippocampus of adult animals, ATP and adenosine modulate synaptic activity via specific P2X receptors, which are sensitive to the nonselective antagonist PPADS, as well as via inhibitory A1 purine receptors [5, 6]. However, the question remains open with regard to neonatal animals, because of the specific glutamateand GABA-ergic synaptic transmission in their hippocampi [4]. Since P2X2, P2X4, and P2X6 purine receptors have been detected by immunohistochemical methods in the neonatal hippocampus [8], we studied the ATP effect on the synaptic activity of pyramidal cells in the CA3 region of the neonatal hippocampus. ATP Effect on Spontaneous GABAergic Activity in the Hippocampus of Neonatal Rats