Abstract
The role of GABAB receptors in sleep is still poorly understood. GHB (γ-hydroxybutyric acid) targets these receptors and is the only drug approved to treat the sleep disorder narcolepsy. GABAB receptors are obligate dimers comprised of the GABAB2 subunit and either one of the two GABAB1 subunit isoforms, GABAB1a and GABAB1b. To better understand the role of GABAB receptors in sleep regulation, we performed electroencephalogram (EEG) recordings in mice devoid of functional GABAB receptors (1−/− and 2−/−) or lacking one of the subunit 1 isoforms (1a−/− and 1b−/−). The distribution of sleep over the day was profoundly altered in 1−/− and 2−/− mice, suggesting a role for GABAB receptors in the circadian organization of sleep. Several other sleep and EEG phenotypes pointed to a more prominent role for GABAB1a compared with the GABAB1b isoform. Moreover, we found that GABAB1a protects against the spontaneous seizure activity observed in 1−/− and 2−/− mice. We also evaluated the effects of the GHB-prodrug GBL (γ-butyrolactone) and of baclofen (BAC), a high-affinity GABAB receptor agonist. Both drugs induced a state distinct from physiological sleep that was not observed in 1−/− and 2−/− mice. Subsequent sleep was not affected by GBL whereas BAC was followed by a delayed hypersomnia even in 1−/− and 2−/− mice. The differential effects of GBL and BAC might be attributed to differences in GABAB-receptor affinity. These results also indicate that all GBL effects are mediated through GABAB receptors, although these receptors do not seem to be involved in mediating the BAC-induced hypersomnia.