Adenosine mediates sedative action of various centrally active drugs

Adenosine and its analogs depress the firing of neurons in various brain regions. The primary mode of action of adenosine in exerting this action appears to be the depression of calcium entry, thus decreasing presynaptic neurotransmitter release. Adenosine uptake inhibitors and adenosine deaminase inhibitors potentiate the depressant actions of adenosine. Caffeine and theophylline, methylxanthines, antagonize these actions. Adenosine is therefore likely to be released and to exert an ongoing modulation of the neuron excitability in the intact brain. Adenosine uptake by nerve terminals appears to be important in regulating the extracellular concentration of adenosine and thus of adenosine's action. A number of groups of centrally active sedative, anxiolytic and anticonvulsant drugs inhibit adenosine uptake by brain synaptosomal preparations. It is proposed that these agents exert their sedative effects by inhibiting adenosine uptake and thus potentiating depressant actions by locally released adenosine on neuronal activity.