Modulation of basal forebrain acetylcholine release: Implications for arousal state control

Cholinergic neurons of the basal forebrain supply the neocortex with acetylcholine (ACh) and play a major role in memory, attention, cortical activation and behavioral arousal. The basal forebrain contains a heterogenous population of cholinergic and GABAergic neurons, and these cells also produce nitric oxide (NO). Many studies have produced findings aiming to identify cellular mechanisms involved in ACh release in the cortex. Few studies have tried to identify the cellular mechanisms involved in the modulation of basal forebrain ACh release. This thesis describes research aiming to identify endogenous modulators of ACh release within the basal forebrain.; ACh release within the basal forebrain previously has not been quantified during sleep. This thesis research used in vivo microdialysis to test the hypothesis that basal forebrain ACh release varies as a function of sleep and wakefulness. Dialysis samples were collected from cat basal forebrain during states of wakefulness, NREM sleep, and REM sleep. The results showed that ACh release was highest during REM sleep, intermediate during wakefulness, and lowest during NREM sleep. The REM sleep-dependent increase in basal forebrain ACh suggests that the cholinergic basal forebrain may contribute to the regulation of REM sleep.; NO and NO synthase (NOS) inhibitors have been shown to modulate ACh release in brain stem and alter sleep-wake states. This thesis research tested the hypotheses that a NOS inhibitor delivered to the basal forebrain would alter basal forebrain ACh release and alter the sleep-wake cycle. NG-nitro-L-arginine (NLA) dialysis administration significantly enhanced ACh release in the substantia innominata (SI) region of the basal forebrain during wakefulness, NREM sleep and REM sleep. These studies suggest that NO modulates basal forebrain ACh release. Basal forebrain administration of the NOS inhibitor had no effect on the sleep-wake cycle. Since ACh release varied across the sleep-wake cycle, this study also tested the hypothesis that sleep-dependent changes in basal forebrain ACh release are site-specific. ACh release was measured in medial and lateral regions of the basal forebrain. The state-dependent changes in ACh release were specific to the lateral (SI) region of the basal forebrain. The functional significance of differences in ACh release profiles across basal forebrain areas remains to be addressed.; The research described in this thesis also tested the hypothesis that muscarinic and GABA_A receptors modulate ACh release in the SI region of the basal forebrain. Muscarinic autoreceptors modulate ACh release from cholinergic neurons in several brain regions. GABAergic neurons outnumber cholinergic neurons in the basal forebrain and these cholinergic neurons receive inhibitory GABAergic input. Cats were anesthetized with halothane. Control dialysis samples were collected followed by dialysis delivery of scopolamine, a muscarinic antagonist or bicuculline, a GABA_A antagonist and ACh was quantified. Dialysis delivery of bicuculline and scopolamine each caused a concentration-dependent increase in SI ACh release compared to control levels. This study suggests that muscarinic autoreceptors and GABA_A receptors modulate ACh release. The results from these studies encourage continuing efforts to elucidate the mechanisms by which the basal forebrain participates in the regulation of arousal states.