A role for nitric oxide in serotonin neurons of the midbrain raphe nuclei

• Published in: The European journal of neuroscience Vol. 51; no. 9; pp. 1881 - 1899
• Main Authors: Gartside, Sarah E., Yurttaser, Abdurrahman Ercan, Burns, Amy L., Jovanović, Nebojša, Smith, Katie J., Amegashiti, Nana Shika, Olthof, Bas M. J.
• Format: Journal Article
• Language: English
• Published: France Wiley Subscription Services, Inc 01.05.2020
• Subjects: Autocrine signalling; Brain; Dorsal raphe nucleus; Electrophysiology; Firing pattern; Guanylate cyclase; Immunohistochemistry; Labeling; Mesencephalon; neuronal nitric oxide synthase; Neurons; Nitric oxide; Nitric-oxide synthase; Raphe nuclei; rat; serotonergic; Serotonin; soluble guanylyl cyclase; dorsal raphe nucleus; neuronal nitric oxide synthase; rat; soluble guanylyl cyclase; serotonergic
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.14713

Neuronal nitric oxide synthase (nNOS) catalyses the production of the neurotransmitter nitric oxide. nNOS is expressed in the dorsal raphe nucleus (DRN), a source of ascending serotonergic projections. In this study, we examined the distribution nNOS and the function of nitric oxide in the DRN and adjacent median raphe nucleus (MRN) of the rat. We hypothesized that nNOS is differentially expressed across the raphe nuclei and that nitric oxide influences the firing activity of a subgroup of 5‐HT neurons. Immunohistochemistry revealed that, nNOS is present in around 40% of 5‐HT neurons, throughout the DRN and MRN, as well as in some non‐5‐HT neurons immediately adjacent to the DRN and MRN. The nitric oxide receptor, soluble guanylyl cyclase, was present in all 5‐HT neurons examined in the DRN and MRN. In vitro extracellular electrophysiology revealed that application of the nitric oxide donor, diethylamine NONOate (30–300 µM) inhibited 60%–70% of putative 5‐HT neurons, excited approximately 10% of putative 5‐HT neurons and had no effect on the rest. The inhibitory response to nitric oxide was blocked by [1H‐[1,2,4]oxadiazolo‐[4, 3‐a]quinoxalin‐1‐one (ODQ, 30 or 100 µM), indicating mediation by soluble guanylyl cyclase. Juxtacellular labelling revealed that nitric oxide inhibits firing in both putative 5‐HT neurons which express nNOS and those which do not express nNOS. Our data are consistent with the notion that nitric oxide acts as both a trans‐synaptic and autocrine signaller in 5‐HT neurons in the DRN and MRN and that its effects are widespread and primarily inhibitory. Around half of the 5‐HT neurons in the dorsal/median raphe nuclei express neuronal nitric oxide synthase—the synthetic enzyme for nitric oxide (NO)—while all 5‐HT neurons in this region express soluble guanylyl cyclase—the receptor for NO. Exogenously applied NO inhibits firing in the majority of 5‐HT neurons via activation of soluble guanylyl cyclase. NO inhibits some 5‐HT neurons which can themselves synthesis NO as well as some 5‐HT neurons which cannot.