Adenosine is considered an important modulator of the nervous system acting at pre-, post-, and nonsynaptic levels. In models (e.g. the rat neuromuscular junction) where adenosine has only presynaptic (inhibitory, which are Al-receptor mediated; and excitatory, which are A2~-receptor mediated) effects, the action of adenosine on transmitter release depends on the intensity of stimulation. It is inhibitory with low frequencies of stimulation and excitatory with high frequencies of stimulation. This finding suggests that the presynaptic adenosine Al /AZA receptor activation balance depends on the pattern of stimulation. At the rat hippocampal slices, endogenous adenosine inhibits the neurophysiological basis of learning and memory: long-term potentiation (LTP), long-term depression (LTD), and depotentiation. Adenosine A ~A agonists facilitate LTP. Because the adenosine analogue 2-chloroadenosine in low concentrations (1 00 nM) inhibits N-methyl-D-aspartate (NMDA) currents in pyramidal cells, it i s likely that the inhibitory effects of adenosine on LTP and LTD/depotentiation are a consequence of its ability to inhibit NMDA currents. The modulatory actions of adenosine on synaptic plasticity support the role of this nucleoside in cognition, and therefore, A, antagonists and AZA agonists could be considered as potential cognitive enhancers. The adaptation of adenosine to activate presynaptic A1 or A 2 ~ receptors at low or high frequencies of stimulation anticipates the potential interest of A1 antagonists and A ~A agonists as enhancers of neuromuscular transmission. Drug Dev. Res. 39:353-360, 1996.