Neuromodulatory Actions Of Adenosine Research Articles

Adenosine A2A receptors in neuronal outgrowth: a target for nerve regeneration?

Adenosine A2A receptors in neuronal outgrowth: a target for nerve regeneration?

G protein‐independent neuromodulatory action of adenosine on metabotropic glutamate signalling in mouse cerebellar Purkinje cells

Adenosine receptors (ARs) are G protein-coupled receptors (GPCRs) mediating the neuromodulatory actions of adenosine that influence emotional, cognitive, motor, and other functions in the central nervous system (CNS). Previous studies show complex formation between ARs and metabotropic glutamate receptors (mGluRs) in heterologous systems and close colocalization of ARs and mGluRs in several central neurons. Here we explored the possibility of intimate functional interplay between G(i/o) protein-coupled A(1)-subtype AR (A1R) and type-1 mGluR (mGluR1) naturally occurring in cerebellar Purkinje cells. Using a perforated-patch voltage-clamp technique, we found that both synthetic and endogenous agonists for A1R induced continuous depression of a mGluR1-coupled inward current. A1R agonists also depressed mGluR1-coupled intracellular Ca(2+) mobilization monitored by fluorometry. A1R indeed mediated this depression because genetic depletion of A1R abolished it. Surprisingly, A1R agonist-induced depression persisted after blockade of G(i/o) protein. The depression appeared to involve neither the cAMP-protein kinase A cascade downstream of the alpha subunits of G(i/o) and G(s) proteins, nor cytoplasmic Ca(2+) that is suggested to be regulated by the beta-gamma subunit complex of G(i/o) protein. Moreover, A1R did not appear to affect G(q) protein which mediates the mGluR1-coupled responses. These findings suggest that A1R modulates mGluR1 signalling without the aid of the major G proteins. In this respect, the A1R-mediated depression of mGluR1 signalling shown here is clearly distinguished from the A1R-mediated neuronal responses described so far. These findings demonstrate a novel neuromodulatory action of adenosine in central neurons.

Persistence of the neuromodulatory effects of adenosine on synaptic transmission after long-term potentiation and long-term depression

Adenosine modulates long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus. We tested whether induction of LTP or LTD might reciprocally modify the role of adenosine as an inhibitory modulator of synaptic transmission in the hippocampus. The experiments were performed on hippocampal slices of the rat. Two separate sets of the Schaffer pathway were alternately stimulated. Evoked field excitatory postsynaptic potentials (fEPSPs) were recorded extracellularly from CA1 stratum radiatum. Long-term potentiation (LTP) was induced by high-frequency stimulation and long-term depression (LTD) by low-frequency stimulation. The inhibitory effects of the adenosine analogue, 2-chloroadenosine (CADO, 0.1–5 μM), on the fEPSP slope were similar in both pathways (EC 50=0.72 (95% confidence intervals: 0.50–1.1) μM and EC 50=0.84 (0.55–1.3) μM, n=6). After induction of LTP in the test pathway, a second concentration–response curve was obtained. CADO was significantly less potent as compared to the first concentration–response curve, however the inhibitory effects of CADO were still similar in the potentiated pathway (EC 50=2.2 (1.6–3.1) μM) and in the control pathway (EC 50=2.1 (1.5–3.0) μM, n=6). The inhibitory effects of CADO (0.1–5 μM) were also not significantly different in the pathway where LTD was previously induced (EC 50=1.7 (1.5–2.0) μM), compared to the control non-depressed pathway (EC 50=1.7 (1.4–2.0) μM, n=6). In conclusion, the neuromodulatory action of adenosine seems to be maintained in the presence of substantial variations in long-term synaptic efficiency during LTP or LTD.

Effect of adenosine receptor blockade on pial arteriolar dilation during sciatic nerve stimulation.

In the present study, we report the effects of adenosine receptor antagonists on pial vasodilatation during contralateral sciatic nerve stimulation (SNS). The pial circulation was observed through a closed cranial window in alpha-chloralose-anesthetized rats. In artificial cerebrospinal fluid (CSF), SNS resulted in a 30.5 +/- 13.2% increase in pial arteriolar diameter in the hindlimb somatosensory cortex. Systemic administration of the selective adenosine A2A receptor antagonist, 4-(2-[7-amino-2-[2-furyl][3,2,4]triazolol[2,3-a][1,3,5]triazin-5-yl-amino] ethyl)phenol (ZM-241385), significantly (P < 0.05, n = 6) attenuated the SNS-induced vasodilatation. Systemic administration of 8-(p-sulfophenyl)theophylline (8SPT), a nonselective antagonist that is blood-brain barrier (BBB) impermeable, had no effect on vasodilatation to SNS. In contrast, systemic theophylline, which readily penetrates the BBB, nearly abolished the SNS-induced vasodilatation (P < 0.01; n = 7). Topical superfusion of 8SPT significantly (P < 0.01; n = 6) attenuated vasodilatation during SNS. Topical superfusion of 8- cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist, significantly potentiated SNS-induced vasodilatation (P < 0.01; n > or = 5). Hypercarbic vasodilatation and somatosensory-evoked potentials were not affected by any of the compounds tested. Our findings suggest that luminal endothelial adenosine receptors are not involved in the arteriolar response to SNS, as demonstrated by a lack of effect with systemic 8SPT. Furthermore, the adenosine A2A receptor subtype appears to be involved in the dilator response to SNS. Finally, the neuromodulatory action of adenosine, via the A1 receptor subtype, significantly influences SNS-induced vasodilatation. Thus the present study provides further evidence for a role of adenosine in the regulation of CBF during somatosensory stimulation.

Inhibition of adenosine kinase and adenosine uptake in guinea-pig CNS tissue by halogenated tubercidin analogues

Two halogenated analogues of tubercidin (7-deazaadenosine) viz. 5-iodotubercidin and 5′-deoxy-5-iodotubercidin, previously were shown to be potent inhibitors of guinea-pig brain adenosine kinase activity and adenosine uptake in guinea-pig cerebral cortex slices. A further series of halogenated tubercidin analogues have been investigated; of the 9 compounds tested, 5′-deoxy-5-iodotubericidin was the most potent adenosine kinase inhibitor while 5-iodotubercidin was the most potent in inhibiting the facilitated uptake of adenosine. These compounds may be useful for elucidating the involvement of adenosine kinase in adenosine uptake, the maintenance of intracellular adenosine levels and in the neuromodulatory actions of adenosine in the CNS.

Adenosine selectively inhibits noncholinergic transmission in guinea pig bronchi.

The neuromodulatory action of adenosine and ATP was investigated in isolated guinea pig bronchial strip chain preparations contracted with electrical field stimulation. The tissues were placed in organ baths containing physiological salt solution and stimulated at 8-Hz frequency, 0.5-ms pulse duration, and 30 V (approximately 100 mA) for 5 s. Electrical field stimulation evoked a biphasic contraction of bronchial muscle, consisting of an initial contraction followed by a sustained contraction, which was mediated by intramural cholinergic and noncholinergic nerve stimulations, respectively. Adenosine, at concentrations greater than M, caused a concentration-dependent inhibition in the height of the noncholinergically mediated contraction, accompanied by a very weak inhibition on the cholinergically mediated response. ATP (10(-5) to 3 x 10(-3) M) also produced a similar inhibitory effect on the noncholinergically mediated contraction, but the inhibitory potency was less than that of adenosine. The inhibitory response to adenosine was enhanced by the pretreatment with dipyridamole (2 x 10(-6) M) but antagonized with aminophylline (10(-5) M). Contractions of bronchial muscle evoked by exogenous acetylcholine (2 x 10(-6) M) or substance P (2 x 10(-7) M) were significantly inhibited by the adenosine (3 x 10(-4) M) pretreatment. These data suggest that in isolated guinea pig bronchi adenosine selectively inhibits noncholinergic neurotransmission through prejunctional P1-purinoceptors.