Additive effect of 5-HT2C and CB1 receptor blockade on the regulation of sleep-wake cycle

Previous data show that serotonin 2C (5-HT ) and cannabinoid 1 (CB ) receptors have a role in the modulation of sleep-wake cycle. Namely, antagonists on these receptors promoted wakefulness and inhibited rapid eye movement sleep (REMS) in rodents. The interaction of these receptors are also present in other physiological functions, such as the regulation of appetite. Blockade of 5-HT receptors modulat the effect of CB receptor antagonist, presumably in consecutive or interdependent steps. Here we investigate, whether previous blockade of 5-HT receptors can affect CB receptor functions in the sleep-wake regulation. Wistar rats were equipped with electroencephalography (EEG) and electromyography (EMG) electrodes. Following the recovery and habituation after surgery, animals were injected intraperitoneally (ip.) with SB-242084, a 5-HT receptor antagonist (1.0 mg/kg) at light onset (beginning of passive phase) followed by an injection with AM-251, a CB receptor antagonist (5.0 or 10.0 mg/kg, ip.) 10 min later. EEG, EMG and motor activity were analyzed for the subsequent 2 h. Both SB-242084 and AM-251 increased the time spent in active wakefulness, while decreased the time spent in non-REMS and REMS stages in the first 2 h of passive phase. In combination, the effect of the agents were additive, furthermore, statistical analysis did not show any interaction between the effects of these drugs in the modulation of vigilance stages. Our results suggest that 5-HT receptor blockade followed by blockade of CB receptors evoked additive effect on the regulation of sleep-wake pattern.