ADENOSINE-ANALOGS AND SLEEP IN RATS

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Abstract
The effects of N6-L-(phenylisopropyl)adenosine, cyclohexyladenosine and adenosine-5''-N-ethylcarboxamide on sleep were examined in rats. These effects consist of increased slow wave sleep2 from 6.6 to 45.7%, in all doses used for cyclohexyladenosine and adenosine-5''-N-ethylcarboxamide and for 0.1 and 0.3 .mu.mol/kg of N6-L-(phenylisopropyl)adenosine and increased values for rapid eye movement[REM]-sleep, amounting to 56.2 and 51.6% for 0.1 .mu.mol/kg of cyclohexyl-adenosine and 0.3 .mu.mol/kg of N6-L-(phenylisopropyl)adenosine, respectively. Slow wave sleep1 decreased but values for wakefulness and total sleep were unchanged for 0.03, 0.1 and 0.3-.mu.mol/kg doses of the drugs. Only 0.9-.mu.mol/kg dose of cyclohexyladenosine and N6-L-(phenylisopropyl)adenosine increased wakefulness and decreased total sleep, whereas the same dose of adenosine-5''-N-ethylcarboxamide increased total sleep during the 0- to 3-h time interval. All 3 agents reduced REM sleep at the 0.9-.mu.mol/kg dose. The effect on sleep of all 3 adenosine analogs was obtained with nanomolar doses of the drugs and it diminished or disappeared when the drug dose reached micromolar range (0.9 .mu.mol/kg). It appears that activation of A1 rather than A2 receptors contributed to the sleep effects of the drugs because adenosine and adenosine analogs activate A1 receptors in nanomolar quantities whereas activation of A2 receptors requires micromolar concentration of these compounds. The effects on sleep of adenosine analogs in rats differ from the effects on sleep of barbiturates and benzodiazepines, because the latter do not increase REM sleep and because increases in slow-wave sleep2 and rapid-eye-movement sleep by adenosine analogs were obtained only at certain dosages and could not be further augmented by a dose increase.

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