Muscarinic and GABA(A) receptors modulate acetylcholine release in feline basal forebrain

Acetylcholine (ACh) release within the basal forebrain changes significantly as a function of sleep and wakefulness, hence identifying the neurochemical modulators of basal forebrain ACh release will contribute to a mechanistic understanding of sleep cycle regulation. This study tested the hypothesis that muscarinic and gamma aminobutyric acid(A) (GABA(A)) receptors modulate basal forebrain ACh release. Cats were anaesthetized with halothane to hold arousal state constant and a microdialysis probe was aimed stereotaxically for the substantia innominata region of the basal forebrain. Four concentrations of the muscarinic antagonist scopolamine (0.1, 0.3, 1.0, and 10 nm) and five concentrations of the GABA(A) antagonist bicuculline (3, 10, 30, 100, and 300 mum) were delivered by reverse dialysis from the same probes used to collect ACh. These results are based on 27 experiments in nine animals. Scopolamine and bicuculline each caused a concentration dependent enhancement of ACh release. Scopolamine increased ACh by 118% above control levels whereas bicuculline was more effective, causing a 287% increase in ACh release. Scopolamine was more potent (EC50 = 0.16 nm) than bicuculline (EC50 greater than or equal to 90 mum) for increasing ACh release. The results support the hypothesis that substantia innominata ACh release is modulated by muscarinic autoreceptors and inhibited by GABA(A) receptors. These findings are consistent with the interpretation that inhibition of basal forebrain cholinergic neurotransmission by GABA contributes to the generation of sleep.