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VOL. 71 (2), 283-319, 2005 PURINERGIC SIGNALLING: THERAPEUTIC POTENTIAL

notion that A2A receptor antagonists may be useful for the treatment
of Parkinson’s disease and levodopa-induced dyskinesias.

ATP inhibits the release of the excitatory transmitter, glutamate,
and stimulates the release of the inhibitory transmitter, GABA, from
hippocampal nerves. In addition, ATP coreleased with glutamate
induces long-term potentiation (LTP) in CA1 neurons associated with
learning and memory (24). Nanomolar concentrations of ATP induce
long-lasting enhancement of LTP in hippocampal neurons; the P2
antagonist, suramin, inhibits activity of the ectoenzyme, apyrase,
which has been shown to participate in the mechanisms of memory
acquisition. It has been suggested that ATP coreleased with glutamate,
activates CA1 pyramidal hippocampal neurones, allowing calcium to
enter postsynaptic cells and thereby inhibiting the effectiveness of
NMDA receptors in inducing LTP. Since P2X receptors contribute to
synaptic transmission, mainly at low frequencies of stimulation, they
may act as a dynamic low-frequency filter, preventing weak stimuli
from inducing long-lasting changes in synaptic efficacy. Large rises in
[Ca2+]i in CA1 neurons induce LTP, but small rises induce long-term
depression (LTD). ATP and activation of glutamate NMDA receptors
leads to potentiation of LTP-CA1 neurons (24) in keeping with the
synergism that often occurs between cotransmitters (23). There is
expression of functional P2X receptor channels in the axons of CA3
neurons branching to their postsynaptic targets and predominantly in
nerve terminals forming synapses with interneurons. ATP released
from astrocytes acts as an activity-dependent signalling molecule in
neurone-glia communication, resulting in astrocyte Ca2+ waves and
synaptic modulation; neuron-glia crosstalk may represent an integral
part of activity-dependent plasticity of neural networks. Clearly there
are multiple roles for P2 and P1 receptors in relation to learning and
memory, but the way that therapeutic manipulation of purinergic
mechanisms can be utilized to improve these functions is still
unresolved. Higher order cognitive functions, including hearing and
memory in the prefrontal cortex, also involve purinergic signalling.
Adenosine-related compounds might prove helpful in the treatment of
memory disorders and impaired intellectual performance related to
caffeine intake.

ATP injected into the supraoptic nucleus of the hypothalamus
has antidiuretic effects, perhaps through release of arginine

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