The effects of intracerebroventricular application of 8-Br-cGMP and LY-83,583, a guanylyl cyclase inhibitor, on sleep-wake activity in rats

Cyclic GMP is the second messenger that mediates most of the neuronal effects of nitric oxide (NO). Several lines of evidence suggest that NO-ergic mechanisms play an integral role in the regulation of vigilance. In the present study, we tested the effects of the activation of cGMP-receptive mechanisms and the inhibitor of guanylyl cyclase (GC), LY-83,583, on sleep in rats. Rats were injected intracerebroventricularly (icv) with 0.16, 4, 100, and 500 μg or 2.5 mg 8-Br-cGMP, a membrane-permeable analogue of cGMP, or 1 and 100 μg LY-83,583. Administration of 4 μg-2.5 mg 8-Br-cGMP increased wakefulness and suppressed rapid-eye-movement sleep (REMS) and non-REMS (NREMS) in rats when given before dark onset but not when given before the light period. The GC inhibitor LY-83,583 strongly promoted NREMS and suppressed REMS during the light period of the day. Furthermore, LY-83,583 induced striking increases in the delta-wave activity of the electroencephalogram (EEG) during NREMS, whereas EEG activity above the 4.5 Hz wave range was suppressed in all vigilance states. Our finding that cGMP has an arousal-promoting activity is in line with the hypothesis that NO/cGMP signaling pathway is involved in the regulation of vigilance.