Purinergic Neurotransmission Focus On Adenosine

It has been known for quite some time that ATP is capable of exerting profound effects on the nervous system (Drury and Szent-Gysrgyi 1929). However, adenosine and adenosine nucleotides have gained acceptance as neuroactive substances in the CNS only relatively recently (Cooper et al. 2001). Adenosine is released from neurons and glia, but many of the neurotransmitter criteria outlined in the beginning of this chapter are not met. Nonetheless, adenosine is able to activate many cellular functions that are able to produce changes in neuronal and behavioral states. For example, adenosine is able to stimulate cAMP in vitro in brain slices, and caffeine (which in addition to being a phosphodiesterase inhibitor is a well-known adenosine receptor antagonist) is able to block this response.

Four adenosine receptors have been cloned (A1, A2A, A2B, and A3), each of which exhibits unique tissue distribution, ligand binding affinity (nanomolar range), and signal transduction mechanisms (Cooper et al. 2001). Currently available data suggest that the high-affinity adenosine receptors (A1 and A2A) may be activated under normal physiological conditions, whereas in pathological states such as hypoxia and inflammation (in which high adenosine concentrations [micromolar range] are present), low-affinity A2B and A3 receptors are also activated. A2B receptors are expressed in low levels in the brain but are ubiquitous in the rest of the body, whereas A2A receptors are found in high concentrations in areas of the brain that receive dopaminergic projections (i.e., striatum, nucleus accumbens, and olfactory tubercle) (Nestler et al. 2001). Given this receptor's distribution and the inverse relationship between DA and adenosine, it has been postulated that A2A antagonists may have some utility in the treatment of Parkinson's disease (Nestler et al. 2001).

The mood stabilizer and antiepileptic drug carbamazepine acts as an antagonist of the A1 subtype and also decreases protein levels of the receptor (for a review, see Gould et al. 2002).

Adenosine is widely regarded as important in the homeostasis of blood flow and metabolic demands in peripheral tissue physiology. Adenosine is also able to alter the function (both pre- and postsynaptically) of numerous neurotransmitters and their receptors, including NMDA, metabotropic glutamate receptors, ionotropic nicotinic receptors, NE, 5-HT, DA, GABA, and various peptidergic receptors. Recent evidence implicates adenosine as a fatigue factor in the decrease of cholinergic activity-arousal via presynaptic inhibition of glutamate release (Brambilla et al. 2005). In addition, P2X (ligand-gated ion channels) and P2Y (G protein-coupled receptors) are purine receptors that can be activated by ATP. It has been demonstrated that ATP is released from astrocytes (through an unknown mechanism) and that the release is accompanied by glutamate release (Ca2+-dependent) (Innocenti et al. 2000). However, more data suggest that it may be adenosine (that is derived from ATP) that serves as the true ligand for these purinergic receptors (Fields and Stevens-Graham 2002). The ATP/adenosine is then able to activate purine receptors (P2Y receptors) on neighboring astrocytes, and this stimulates Ca2+ influx and subsequent release of glutamate and ATP to then impact other astrocytes and neurons. This may be a critical component in the communication process between glial cells, as well as representing a signaling molecule from glia to neurons (Fields and Stevens-Graham 2002).

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