The Nitric Oxide Synthase InhibitorNG-Nitro-l-Arginine Increases Basal Forebrain Acetylcholine Release during Sleep and Wakefulness

Abstract

Cholinergic neurotransmission in the basal forebrain changes across the sleep/wake cycle, and considerable data show cortical activation by ACh originating from basal forebrain neurons. These findings have stimulated efforts to elucidate molecular modulators of ACh release within the basal forebrain. Basal forebrain cholinergic neurons contain nitric oxide synthase (NOS), the enzyme that produces the gaseous neuromodulator nitric oxide. This study tested the hypothesis that administration of an NOS inhibitor to the basal forebrain would alter basal forebrain ACh release, sleep, and respiratory rate. Seven cats were instrumented for recording sleep and wakefulness and for <i>in vivo</i> microdialysis and microinjection. Compared with Ringer9s solution (control), microdialysis delivery of the NOS inhibitor<i>N</i>^G-nitro-l-arginine (NLA; 10 mm) increased ACh release during wakefulness (33%), non-rapid eye movement (NREM) sleep (70%), and rapid eye movement (REM) sleep (16%). Mean ± SEM ACh levels (pmol/10 min) during control and NLA dialysis, respectively, were 0.58 ± 0.03 and 0.77 ± 0.06 in wakefulness, 0.36 ± 0.01 and 0.61 ± 0.06 in NREM sleep, and 0.68 ± 0.06 and 0.79 ± 0.09 in REM sleep. Increases in ACh release were not evoked by dialysis delivery of the less active enantiomer<i>N</i>^G-nitro-d-arginine. Dialysis administration of NLA did not alter respiratory rate. Sleep-dependent changes in basal forebrain ACh release were localized specifically to lateral basal forebrain regions and did not occur in medial basal forebrain sites. Microinjection of NLA into the lateral basal forebrain did not significantly alter the sleep/wake cycle. In contrast to NLA-induced depression of REM sleep and ACh release in the cat pons, the present results demonstrate that NLA increased ACh release in the cat basal forebrain and had no effect on sleep. The different effects of NLA on ACh release in the cat pons and cat basal forebrain may prove relevant for developing compounds that differentially alter cholinergic neurotransmission in specific brain regions.