Nitric oxide from the laterodorsal tegmental neurons: Its possible retrograde modulation on norepinephrine release from the axon terminal of the locus coeruleus neurons

Abstract

Nitric oxide released from the cholinergic neurons in the pons may play important roles in sleep–wake regulation. However, there are few reports demonstrating the mechanisms of nitric oxide release in the cholinergic neurons in the pons. The present study investigated the effects of drug delivery of N-methyl- d-aspartic acid on nitric oxide and the neurotransmitters released in the laterodorsal tegmental nucleus (LDT), one of the major cholinergic cell groups in the pons, in rats by in vivo microdialysis with a view to clarifying nitric oxide functions in the cholinergic system. The application of N-methyl- d-aspartic acid (1mM) into the LDT induced a significant increase in NO 2and NO 3 for 40 min ( P<0.001). Furthermore the same dose of N-methyl- d-aspartic acid induced a significant increase in cyclic GMP for 30 min ( P<0.05), as well as in acetylcholine ( P<0.001) and norepinephrine for 15 min ( P<0.001). 3-(4-Morpholinyl)-sydonone imine hydrochloride (a nitric oxide donor, 5mM) also induced significant increase in norepinephrine ( P<0.05). Pretreatment with 1mM 2-amino-5-phosphonopentanoic acid (an antagonist of N-methyl- d-aspartic acid receptor) prevented the N-methyl- d-aspartic acid-induced increase in cyclic GMP ( P<0.01), acetylcholine and norepinephrine ( P<0.01), while that with 1mM N G-nitro- l-arginine (an inhibitor of nitric oxide synthase) prevented the increase in cyclic GMP ( P<0.01) and norepinephrine ( P<0.01) but not in acetylcholine. These results suggested that nitric oxide release in the LDT induced by activation of the N-methyl- d-aspartic acid receptor on the cholinergic neurons of the LDT, then through the cyclic GMP system, facilitates norepinephrine release from the terminals of noradrenergic neurons in the locus coeruleus. Based on these findings, we propose a possible role of nitric oxide in the LDT is as a retrograde regulator of norepinephrine release from the locus coeruleus.