ABSTRACT
Various studies indicate that exogenous melatonin has hypnotic properties in humans, which may be mediated by its influence on the circadian timing system or direct sleep-promoting actions, e.g. through a modulation of GABAergic transmission. The aim of the present placebo-controlled study was to examine the effects of melatonin on sleep in rats and the contribution of gamma-aminobutyric acid (GABA)A receptors. Sleep-wake behaviour was assessed in nine rats after intraperitoneal (i.p.) administration of pharmacological doses of melatonin (5 and 10 mg kg(-1)) and after combined administration of the GABAA receptor antagonist picrotoxin (1.5 mg kg(-1)) and melatonin (10 mg kg(-1)). To prevent chronobiotic effects, melatonin was delivered in the middle of the light period. Neither doses of melatonin exerted significant effects on brain temperature, sleep architecture or sleep electroencephalogram (EEG). Moreover, melatonin failed to attenuate the picrotoxin-induced promotion of wakefulness. These observations indicate that melatonin hardly influences sleep-wake behaviour in rats.
Subject(s)
Antioxidants/pharmacology , GABA Antagonists/pharmacology , Melatonin/pharmacology , Picrotoxin/pharmacology , Sleep, REM/drug effects , Wakefulness/drug effects , Animals , Antioxidants/administration & dosage , Behavior, Animal/drug effects , Body Temperature/drug effects , Electrodes, Implanted , Electroencephalography , Electromyography , Frontal Lobe/physiology , GABA Antagonists/administration & dosage , Melatonin/administration & dosage , Occipital Lobe/physiology , Picrotoxin/administration & dosage , Random Allocation , Rats , Receptors, GABA/drug effectsABSTRACT
Many hypnotics, such as benzodiazepines, are agonistic modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors. Such compounds increase the ability to fall and stay asleep, but inhibit rapid-eye movement (REM) sleep and deep non-REM sleep. However, tolerance to their hypnotic action may develop rapidly. Previous findings in rats and humans demonstrate that the gamma-aminobutyric acid(A) agonist 4, 5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THIP) promotes deep non-REM sleep and increases non-REM sleep continuity. To investigate the effects of repeated administration, we assessed sleep in rats before, during, and after chronic dosing of THIP (3 mg/kg, once daily for 5 days; n = 9) or of placebo (n = 8). The substances were administered i.p. at the onset of darkness. The electroencephalogram (EEG) and electromyogram were recorded during the first 6 h after injection. During baseline recording, the placebo and the THIP group exhibited similar sleep patterns. After the first THIP injection, rats displayed more non-REM sleep, longer non-REM episodes, and higher levels of slow wave activity in the EEG within non-REM sleep than the placebo group rats. The effects were sustained during all treatment days. REM sleep was not affected. After drug withdrawal, the sleep patterns of the THIP and the placebo group were practically identical again. These observations suggest that THIP does not rapidly produce tolerance toward its sleep effects and abrupt drug withdrawal may not be associated with sleep disturbances. These findings confirm and extend the existing information suggesting that THIP may be promising for treatment of insomnia.