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Review
. 2011;11(8):1034-46.
doi: 10.2174/156802611795347564.

The role of extracellular adenosine in chemical neurotransmission in the hippocampus and Basal Ganglia: pharmacological and clinical aspects

Beáta Sperlágh  1 , E Sylvester Vizi
Affiliations
Free PMC article
Review

The role of extracellular adenosine in chemical neurotransmission in the hippocampus and Basal Ganglia: pharmacological and clinical aspects

Beáta Sperlágh et al. Curr Top Med Chem. 2011.
Free PMC article

Abstract

Now there is general agreement that the purine nucleoside adenosine is an important neuromodulator in the central nervous system, playing a crucial role in neuronal excitability and synaptic/non-synaptic transmission in the hippocampus and basal ganglia. Adenosine is derived from the breakdown of extra- or intracellular ATP and is released upon a variety of physiological and pathological stimuli from neuronal and non-neuronal sources, i.e. from glial cells and exerts effects diffusing far away from release sites. The resultant elevation of adenosine levels in the extracellular space reaches micromolar level, and leads to the activation A(1), A(2A), A(2B) and A(3) receptors, localized to pre- and postsynaptic as well as extrasynaptic sites. Activation of presynaptic A(1) receptors inhibits the release of the majority of transmitters including glutamate, acetylcholine, noradrenaline, 5-HT and dopamine, whilst the stimulation of A(2A) receptors facilitates the release of glutamate and acetylcholine and inhibits the release of GABA. These actions underlie modulation of neuronal excitability, synaptic plasticity and coordination of neural networks and provide intriguing target sites for pharmacological intervention in ischemia and Parkinson's disease. However, despite that adenosine is also released during ischemia, A(1) adenosine receptors do not participate in the modulation of excitotoxic glutamate release, which is nonsynaptic and is due to the reverse operation of transporters. Instead, extrasynaptic A(1) receptors might be responsible for the neuroprotection afforded by A(1) receptor activation.

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Figures

Fig. (1)
Fig. (1)
A schematic model of the interaction of P2X7, CB1 and A1 receptors located on glutamatergic terminals. Activation of P2X7 receptors facilitate and those of A1 receptors reduces the release of glutamate. Glutamate (Glu) released into synaptic gap activates AMPA and NMDA receptors on the postsynaptic site. ATP released from astrocytes [20] and microglia [172] acts on P2X7 receptors located on the terminal of glutamatergic neurons and facilitates the release of Glu ([173] for review see [174]). Adenosine decomposed from ATP acts on A1 receptors inhibiting the release of Glu [168, 175]. This inhibitory effect of A1 receptor activation may be mediated by inhibiting voltage-dependent Ca2+ channels, which reduces Ca transients measured in the bouton [176]. CB1 cannabinoid receptors together with A1 receptors are also expressed on glutamatergic terminals [80] and activation of both of these receptors results in a decrease of Glu release. Extremely high concentrations of adenosine act on A2A receptors to increase the release of Glu [77].
Fig. (2)
Fig. (2)
Inhibitory effect of adenosine on glutamate release evoked by axonal stimulation. Hippocampal slice preparation of the rat. For Methods see [147]. Electrical field stimulation was used. Note that A1 adenosine receptor antagonist DPCPX prevented the effect of adenosine to reduce Glu release. *, p<0.01 (compared to control); #, p<0.05 (comparison of the effect of adenosine and adenosine plus DPCPX).
Fig. (3)
Fig. (3)
The effect of low temperature (12 °C) and the selective A1 receptor antagonist DPCPX (50 nM) on combined oxygen glucose deprivation (OGD)-evoked [3H]glutamate efflux from rat hippocampal slices. Hippocampal slices were preloaded with [3H]glutamate and then superfused. After a 60-min preperfusion, perfusate samples were collected and the slices were exposed to OGD by the omission of the glucose and the replacement of 95% O2+5% CO2 with 95% N2 + 5 %CO2 from the perfusion solution according to the horizontal bar. Low temperature and DPCPX were applied from 30 min before the beginning of the sample collection period till the end of the sample collection period. The release of glutamate is expressed as a percentage of baseline. The curves show the mean±S.E.M of 16 (OGD), 7 (OGD + 12 °C) and 8 (OGD + DPCPX) experiments.
Fig. (4)
Fig. (4)
Scheme of exocytosis of glutamate in response to axonal firing and its release during ischemia. Note that adenosine inhibits the release of Glu under physiological condition. This type of release is [Ca2+]o-dependent. Glutamate is taken up by glutamatergic terminals through plasma membrane transporters. During ischemia the ion gradients that power Glu uptake run down and axonal firing fails to release Glu, but in response to reverse operation of Glu transporter Glu release occurs in [Ca2+]o–independent way. Glu released in this way diffuses far away and activates non-synaptic NR2B receptors inducing excitotoxicity [11]. Under this condition cooling inhibits the excessive release of Glu.
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