Abstract
Within the last 10 years, attention has been increasingly focused on the role in neuronal function of nucleotides other than cyclic AMP. In this overview it is intended t o summarize some of the factors indicating a role for purine derivatives in neuronal adaptation a t the cellular level, and t o present a hypothesis that these compounds may also modulate neuronal function by altering the pharmacological characteristics of neurotransmitter receptors.
Interest in adenine derivatives blossomed when Sattin & Rall (1970) described the elevation of cyclic A M P concentration in slices of guinea-pig cerebral cortex which resulted from the application of adenosine. It was also noted that adenosine would
1978
Possible Roles for Purine Compounds in Neuronal Adaptation
TREVOR W. STONE Department of Physiology, S t . George's Hospital Medical School, University of London, London SW17 ORE, U.K.
Within the last 10 years, attention has been increasingly focused on the role in neuronal function of nucleotides other than cyclic AMP. In this overview it is intended t o summarize some of the factors indicating a role for purine derivatives in neuronal adaptation a t the cellular level, and t o present a hypothesis that these compounds may also modulate neuronal function by altering the pharmacological characteristics of neurotransmitter receptors.
Adenine derivatives
Interest in adenine derivatives blossomed when Sattin & Rall (1970) described the elevation of cyclic A M P concentration in slices of guinea-pig cerebral cortex which resulted from the application of adenosine. It was also noted that adenosine would 576th MEETING, LONDON potentiate the cyclic AMP increase produced by noradrenaline and histamine. It was concluded that the interaction with noradrenaline occurred at a-receptors (Sattin et al., 1979 , though this conclusion may require reassessing in the light of electrophysiological experiments indicating the presence in guinea-pig cortex of a /%receptor which is prone to rapid desensitization (Stone & Taylor, 1977~) .
When adenosine, AMP or ATP are applied to single neurons in vivo by microiontophoresis, a powerful depression of firing frequency results (Stone & Taylor, 19776, 1978a,b; Kostopoulos & Phillis, 1977) . This inhibition can be prevented by theophylline (Stone & Taylor, 19776, 1978a) , which also blocks the adenosine-induced elevation of cyclic AMP in vitro (Sattin et al., 1975) .
Encouraged by this pharmacological similarity of the biochemical and electrophysiological effects of adenosine, we have also demonstrated a mutual potentiation between adenosine and noradrenaline in producing depression of neuronal firing in the central nervous system (Stone, 1978; Stone &Taylor, 19786) . There are also examples of a potentiation between adenosine and noradrenaline in the peripheral nervous system (Hedqvist & Fredholm, 1976) .
Most of the current interest in adenine nucleotides concerns a possible presynaptic inhibitory action. Several groups have shown a marked reduction of acetylcholine release from somatic (Ribeiro & Walker, 1975; Ginsborg & Hirst, 1972 ) and autonomic (Vizi & Knoll, 1976 ) nerve terminals and inhibition of noradrenaline release from sympathetic axons (Clanachan et al., 1977; Enero & Saidrnan, 1977 ; Hedqvist 8c Fredholm, 1976) . The inhibition of acetylcholine release produced by morphine hasalso been found to be susceptible to blockade by theophylline, so that an intermediate step involving the release of adenosine derivatives by morphine seems possible (Sawynok & Jhamandas, 1976) .
A report that CoA inhibits acetylcholine release does not appear to have considered the possibility of metabolism to adenosine which occurs with other adenine nucleotides (Cook et al., 1978) . As would be expected in this case, theophylline blocked the action of CoA.
Of course, for any of these nucleotide effects to have functional significance, the compounds involved would presumably need to be released from tissues. Several studies have demonstrated a release of adenosine or its nucleotides (including cyclic derivatives) fromcentral-nervous tissue in vitro (Sun et Adenine nucleotides are released at the neuromuscular junction, apparently from presynaptic motor nerve terminals (Silinsky, 1975) . Israel et al. (1976), however, have concluded that ATP release from the nerve electroplaque junction of Torpedo is of postsynaptic origin.
Adenine derivatives are known to be released on stimulation of autonomic nerves (Burnstock, 1972) , although the nucleotide originates postsynaptically in some cases at least (Fredholm, 1976) .
The evidence from peripheral tissues would be consistent with a role in synaptic adaptation to changes of activity. An increase in activity in presynaptic axons and terminals would cause the release of more adenines, which would act as negativefeedback modulation of synaptic transmitter release. An increased release of transmitter as an adaptational response to diminished input would also occur.
In the central nervous system a feedback modulation of neurotransmitter release occurs, which is dependent on the activation of postsynaptic (Andtn et al., 1970) . This phenomenon has been explained by postulating interneurons or postsynaptic axon collaterals feeding back on to the presynaptic neuron, but it is interesting that the phenomenon can be most clearly demonstrated for transmitters, such as dopamine (3,4-dihydroxyphenethylamine) and noradrenaline, which activate adenylate cyclase. It may be that activation of the cyclase postsynaptically increases the concentration of adenines in the synaptic region sufficiently to depress transmitter release. Blockade of the postsynaptic receptors would lower the purine efflux and lead to a compensatory increase in transmitter release.
Vol. 6 In a more obviously functional sense, adenine derivatives may serve as mediators of a general neural adaptation to excessive depolarizing activity. Any depolarizing stimulus, such as electrical, Kf or dicarboxylic amino acids causes the release of adenines from brain tissue (Pull & McIlwain, 1972; Shimizu & Daly, 1972) . As the released purines inhibit firing directly and potentiate responses to inhibitory transmitters, such as noradrenaline and dopamine (Stone, 1978; Stone & Taylor, 1978a ,b,c), they would seem to be suitable candidates for mediators of such a homoeostatic mechanism.
More intriguing, however, is the possibility that adenine derivatives might mediate an adaptational communication between transmitter specific pathways, even though these may impinge on any given neuron at anatomically distant sites. Consider the synaptic cluster represented in Fig. 1 . The neurotransmitter released by neuron B entrains the cycle of events leading to the formation of adenines, which can leave the postsynaptic neuron and could potentially interact with neurons A, C, D and E, presynaptically or postsynaptically. It may be that only neuron E or its transmitter can be affected by adenosine. Such a pharmacological interaction would obviously allow considerable specificity of neuronal interaction. According to classical concepts of integration by synaptic potentials, each postsynaptic event influences all other synaptic inputs to a greater to lesser extent, a major determinant of that extent being proximity on the postsynaptic membrane.
All the adenine derivatives under discussion here can be transported along axons into synaptic terminals, released from those terminals, and then taken up into postsynaptic neurons (Kuroda & McIlwain, 1974; Schubert & Kreutzberg, 1974; Schubert et al., 1977) . The possibilities for specific neurochemical interaction therefore potentially extend throughout the whole length of neural pathways (McIlwain, 1976 (McIlwain, , 1977 . 
Guanine derivatives
Relatively little work has been done on the role of guanine derivatives in neuronal function. It is now well known that guanine nucleotides are necessary for the activation of adenylate cyclase by many hormones, including catecholamines (Birnbaumer, 1976) . Guanine derivatives potentiate the activation of adenylate cyclase by noradrenaline in the cerebral cortex (Ahn et al., 1976; Sulakhe et al., 1977) , and we have observed an interaction electrophysiologically on the firing rate of single cortical neurons in uiuo (Stone, 1978; Stone & Taylor, 1978b,c) . As guanosine can be transported along axons and dendrites (Schubert & Kreutzberg, 1974; Schubert et al., 1977) and cyclic GMP is released by axon terminals , it might be worth investigating further a possible extracellular role of guanines in neuronal function.
Possible mediation by nucleotides of receptor adaptation
Since many of the effects of neuronal nucleotides discussed above involve actions on membrane receptors, and since some receptors appear to have requirements for specific nucleotides for activation to occur, it is perhaps worth speculating about the possible significance of the receptor site for neuromodulator action.
Consider, for example, the action of noradrenaline in circumstances where there is relatively little available adenosine. Since a large fraction of central a-receptors require the co-presence of adenosine (Sattin et al., 1975) , the noradrenaline would act preferentially on 8-receptors. The resultant activation of adenylate cyclase and efflux of adenine compounds might then facilitate activation of a-receptors (Fig. 2) . A balance would thus be struck between the two types of receptor. In many tissues where a-and 8-receptors have different functions, such a feedback would serve an obvious adaptational purpose. Even in tissues such as gut where a-and 8-receptors bothmediateasimilar overall decrease of activity, there are well defined differences in a and 8 responses (Bulbring & Tomita, 1969) .
Interactions of this type could even involve different neurotransmitters. Acetylcholine, for example, appears to cause an activation of guanylate cyclase (Goldberg et al.,  1973) , possibly via the mediation of Ca2+. Subsequently released GMP might then be available to promote the activation of /%receptors by noradrenaline.
BIOCHEMICAL SOClETY TRANSACTIONS
Modulation of transmitter action by such mechanisms might be particularly important in the heart where excesses of activity are undesirable. It is therefore of great interest that several Russian groups have obtained direct evidence for such a system in molluscan and frog hearts (see Turpaev & Sakharov, 1973) . In the former, acetylcholine causes the release of ATP, which lowers the affinity of the receptor for acetylcholine.
In frog, acetylcholine induces the release of UTP or UDP, which also decreases the cholinergic sensitivity of the heart. It will be interesting to discover whether there is any functional relationship between these phenomena and the reported action of adenosine of preventing the apparent desensitization to noradrenaline and histamine of cyclic AMP-generating systems in rabbit and guinea-pig brain (Daly, 1976) .
A transition between HI and H2 receptors for histamine may also be mediated by nucleotides. 4-Methylhistamine normally activates selectively H2 receptors, but it appears to act on HI receptors in the presence of adenosine (Daly, 1976) .

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