Glial cell line-derived neurotrophic factor promotes sleep in rats and rabbits

Various growth factors (e.g., growth hormone-releasing hormone, acidic fibroblast growth factor, nerve growth factor, brain-derived neurotrophic factor, and interleukin-1) are implicated in sleep regulation. It is hypothesized that neuronal activity enhances the production of such growth factors, and they in turn form part of the sleep regulatory mechanism. Glial cell line-derived neurotrophic factor (GDNF) promotes development, differentiation, maintenance, and regeneration of neurons, and its production is induced by well-characterized sleep regulatory substances such as interleukin-1 and tumor necrosis factor. Therefore, we investigated whether GDNF would promote sleep. Twenty-six male Sprague-Dawley rats and 30 male New Zealand White rabbits were surgically implanted with electroencephalogram (EEG) and electromyogram (EMG; rats only) electrodes, a brain thermistor, and a lateral intracerebroventricular cannula. The animals were injected intracerebroventricularly with pyrogen-free saline and on a separate day with one of the following doses of GDNF: 5, 50, and 500 ng in rabbits and 50 and 500 ng in rats. The EEG, brain temperature, EMG (in rats), and motor activity (in rabbits) were recorded for 23 h after the intracerebroventricular injection. GDNF (500-ng dose) increased the time spent in nonrapid eye movement sleep in both rats and rabbits. Rapid eye movement sleep was not affected by the lower doses of GDNF but was inhibited in rabbits after the high dose. EEG slow-wave activity was not affected by GDNF. The current results provide further evidence that various growth factors are involved in sleep regulation.