Adenosine A1 receptors inhibit adenylate cyclase activity and neurotransmitter release and hyperpolarize pyramidal neurons in rat hippocampus.

Abstract

Adenosine is a neuromodulator with multiple actions upon the physiology and biochemistry of the brain. Although the receptors that inhibit synaptic transmission and regulate cyclic AMP formation have been well characterized in terms of their pharmacological properties, the receptor(s) that mediate the postsynaptic actions of adenosine have not. We have used the adenosine-mediated inhibition of low calcium bursting in the rat hippocampal slice preparation as a measure of a postsynaptic effect of adenosine. Low calcium bursting consists of repetitive spiking evoked by antidromic stimulation of the CA1 pyramidal neurons and can be suppressed by adenosine. In the present study, we compared the effects of a selective adenosine A1 receptor antagonist, 8-cyclopentyltheophylline, on functional responses to adenosine in hippocampal slices. Its apparent affinities for the receptors mediating the following effects were increases in cyclic AMP formation (1700 nM), decreases in cyclic AMP formation after forskolin pretreatment (57 nM), inhibition of excitatory synaptic responses (42 nM), inhibition of repetitive spiking (45 nM), and it was a competitive antagonist for all responses tested. These data demonstrate that inhibition of transmitter release, adenylate cyclase and low calcium bursting in the hippocampus are all mediated via adenosine receptors that have pharmacological properties similar to the A1 receptor and that 8-cyclopentyltheophylline has a high degree of selectivity for this receptor as opposed to the A2 receptor that mediates increases in cyclic AMP formation.