The effect of diazepam on adenosine uptake and adenosine-stimuiated adenylate cyclase in guinea-pig brain

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Abstract
The adenosine-stimulated adenylate cyclase of guinea pig brain was used to examine the potency of diazepam as an adenosine uptake inhibitor. Diazepam at concentrations in the range 10-500 .mu.M stimulated the production of cAMP in incubated slices of guinea pig cerebral cortex, with maximal 5-fold stimulations over basal levels by 200 .mu.M diazepam. The increases can be largely (but not completely) blocked by the adenosine antagonist theophylline or by addition of excess adenosine deaminase to the system. The stimulation of cAMP production was apparently due to a blockade of adenosine uptake which resulted in an increase in extracellular adenosine and concomitant activation of the adenosine receptor coupled to adenylate cyclase. Since the cAMP response to standard adenosine uptake blockers (dipyridamole, dilazep) can be completely blocked by theophylline or adenosine deaminase, a small component of the diazepam response cannot be explained by an adenosine effect. The concentration of diazepam at which the 1st significant cAMP increase occurs was 10 .mu.M or slightly lower. This is significantly higher than the concentration of diazepam needed to saturate the pharmacologically characterized CNS receptors for benzodiazepines.