Abstract
Nitric oxide (NO) and serotonin play an important role in the functioning of the medial prefrontal cortex, but their interaction has been poorly explored. The aim of this work was to study the effects of local nitrergic signals on the activity of the serotonin system in this cortical area. In male Sprague–Dawley rats, using in vivo microdialysis, we showed that the infusion of diethylamine nonoate (0.1 mM, 0.5 mM, 1 mM), an NO donor, into the medial prefrontal cortex led to an increase in extracellular serotonin levels, which correlated with the drug concentration during the first 15 min of infusion. Diethylamine nonoate, at a concentration of 2.5 mM, reduced extracellular seritonin levels. Infusion of N-nitro-L-arginine (0.5 mM), an NO synthase inhibitor, into the medial prefrontal cortex decreased the basal extracellular serotonin level in this area, as well as delayed and attenuated a rise in the serotonin level caused by the local administration of fluoxetine (10 µM), a selective serotonin reuptake inhibitor. These findings indicate that in the medial prefrontal cortex, in a quiet waking state, tonic endogenous nitrergic signals, as well as their moderate pharmacological enhancement by NO donor administration, activates the serotonin system in this area by increasing the extracellular serotonin pool, while a stronger nitrergic stimulation acts in the opposite way.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1134%2FS0022093022020181/MediaObjects/10893_2022_8218_Fig1_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1134%2FS0022093022020181/MediaObjects/10893_2022_8218_Fig2_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1134%2FS0022093022020181/MediaObjects/10893_2022_8218_Fig3_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1134%2FS0022093022020181/MediaObjects/10893_2022_8218_Fig4_HTML.gif)
Similar content being viewed by others
REFERENCES
Porrini C, Ramarao N, Tran SL (2020) Dr. NO and Mr. Toxic – the versatile role of nitric oxide. Biol Chem 401:547–572. https://doi.org/10.1515/hsz-2019-0368
Garthwaite J (2019) NO as a multimodal transmitter in the brain: discovery and current status. Br J Pharmacol 176:197–211. https://doi.org/10.1111/bph.14532
Chong PS, Poon CH, Fung ML, Guan L, Steinbusch HWM, Chan YS, Lim WL, Lim LW (2019) Distribution of neuronal nitric oxide synthase immunoreactivity in adult male Sprague–Dawley rat brain. Acta Histochem 121:151437. https://doi.org/10.1016/j.acthis.2019.08.004
Ghasemi M, Claunch J, Niu K. (2019) Pathologic role of nitrergic neurotransmission in mood disorders. Prog Neurobiol 173:54–87. https://doi.org/10.1016/j.pneurobio.2018.06.002
Zhou QG, Zhu XH, Nemes AD, Zhu DY (2018) Neuronal nitric oxide synthase and affective disorders. IBRO Rep 5:116–132. https://doi.org/10.1016/j.ibror.2018.11.004
Saulskaya NB., Burmakina MA, Trofimova NA (2021) Nitric oxide inhibits the functional activation of the medial prefrontal cortex serotonin system during fear formation and decreases fear generalization. Neurochem J 15:266–272. https://doi.org/10.1134/s1819712421030107
Jacobs DS, Moghaddam B (2021) Medial prefrontal cortex encoding of stress and anxiety. Int Rev Neurobiol. 158:29–55. https://doi.org/10.1016/bs.irn.2020.11.014
Pastor V, Medina JH (2021) Medial prefrontal cortical control of reward- and aversion-based behavioral output: Bottom-up modulation Eur J Neurosci 53:3039–3062. https://doi.org/10.1111/ejn.15168
Liang HY, Chen ZJ, **ao H, Lin YH, Hu YY, Chang L, Wu HY, Wang P, Lu W, Zhu DY, Luo CX (2020) nNOS-expressing neurons in the vmPFC transform pPVT-derived chronic pain signals into anxiety behaviors. Nat Commun 11:2501. https://doi.org/10.1038/s41467-020-16198-5
Kühn ER, Bellon K, Huybrechts L, Heyns W (1983) Endocrine differences between the Wistar and Sprague–Dawley laboratory rat: influence of cold adaptation. Horm Metab Res 15:491–498. https://doi.org/10.1055/s-2007-1018767
Saulskaya NB, Sudorgina PV (2016) Activity of the nitrergic system of the medial prefrontal cortex in rats with high and low levels of generalization of a conditioned reflex fear reaction. Neurosci Behav Physiol 46:964–970. https://doi.org/10.1007/s11055-016-0338-2
Saulskaya NB, Marchuk OE (2020) Inhibition of serotonin reuptake in the medial prefrontal cortex during acquisition of a conditioned reflex fear reaction promotes formation of generalized fear. Neurosci Behav Physiol 50:432–438. https://doi.org/10.1007/s11055-020-00918-x
Riga D, Motos MR, Glas A, Smit AB, Spijker S, Van den Oever MC (2014) Optogenetic dissection of medial prefrontal cortex circuitry. Front Systemic Neurosci 8:230. https://doi.org/10.3389/fnsys.2014.00230
Woo E, Sansing LH, Arnsten AFT, Datta D (2021) Chronic stress weakens connectivity in the prefrontal cortex: architectural and molecular changes. Chronic Stress 5:1–22. https://doi.org/10.1177/24705470211029254
Hardingham N, Dachtler J, Fox K (2013) The role of nitric oxide in pre-synaptic plasticity and homeostasis. Front Cell Neurosci 7:190. https://doi.org/10.3389/fncel.2013.00190
Lu Y, Simpson KL, Weaver KJ, Lin RC (2010) Coexpression of serotonin and nitric oxide in the raphе complex: cortical versus subcortical circuit. Anat Rec Hoboken 293:1954–1965 https://doi.org/10.1002/ar.21222
Robinson SW, Bourgognon JM, Spiers JG, Breda C, Campesan S, Butcher A, Mallucci GR, Dinsdale D, Morone N, Mistry R., Smith TM, Guerra-Martin M, Challiss RAJ, Giorgini F, Steinert JR (2018) Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clam** ability. PLoS Biol 16:e2003611. https://doi.org/10.1371/journal.pbio.2003611
Garthwaite J (2007) Neuronal nitric oxide synthase and the serotonin transporter get harmonious. PNAS 104:7739-7740. https://doi.org/10.1073/pnas.0702508104
Roenker NL, Gudelsky GA, Ahlbrant R, Horn PS, Richtand NM (2012) Evidence for involvement of nitric oxide and GABAb receptors in MK-801—stimulated release of glutamate in rat prefrontal cortex. Neuropharmacology 63:575–581. https://doi.org/10.1016/j.neuropharm.2012.04.032
Asano S, Matsuda T, Nakasu Y, Maeda S, Nogi H, Baba A (1997) Inhibition by nitric oxide of the uptake of [3H]serotonin into rat brain synaptosomes. Jpn J Pharmacol 75:123–128. https://doi.org/10.1016/S0021-5198(19)31323-X
Chanrion B, Mannoury la Cour C, Bertaso F, Lerner-Natoli M, Freissmuth M, Millan MJ, Bockaert J, Marin P (2007) Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity. Proc Natl Acad Sci USA 104:8119–8124. https://doi.org/10.1073/pnas.0610964104
Guevara-Guzman R, Emson PC, Kendrick KM (1994) Modulation of in vivo striatal transmitter release by nitric oxide and cyclic GMP. J Neurochem 62:807–810. https://doi.org/10.1046/j.1471-4159.1994.62020807.x
Wegener G, Volke V, Rosenberg R (2000) Endogenous nitric oxide decreases hippocampal levels of serotonin and dopamine in vivo. Br J Pharmacol 130:575–580. https://doi.org/10.1038/sj.bjp.0703349
Sayed N, Baskaran P, Ma X, van den Akker F, Beuve A (2007) Desensitization of soluble guanylyl cyclase, the NO receptor, by S-nitrosylation. Proc Natl Acad Sci U S A 104:12312–12317. https://doi.org/10.1073/pnas.0703944104
Funding
This work was carried out within the State Program “Basic Scientific Research for Long-Term Development and Competitiveness of the Society and State”.
Author information
Authors and Affiliations
Contributions
Conceptualization and experimental design (N.B.S.); data collection (M.A.B., N.A.T., N.B.S.); data processing (N.B.S., M.A.B.); writing the manuscript (N.B.S., M.A.B., N.A.T.).
Corresponding author
Ethics declarations
CONFLICT OF INTEREST
The authors declare that they have neither evident nor potential conflict of interest associated with the publication of this article.
Additional information
Translated by A. Polyanovsky
Russian Text © The Author(s), 2022, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2022, Vol. 108, No. 3, pp. 369–378https://doi.org/10.31857/S0869813922030086.
Rights and permissions
About this article
Cite this article
Saulskaya, N.B., Burmakina, M.A. & Trofimova, N.A. Effect of Activation and Blockade of Nitrergic Neurotransmission on Serotonin System Activity of the Rat Medial Prefrontal Cortex. J Evol Biochem Phys 58, 500–507 (2022). https://doi.org/10.1134/S0022093022020181
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0022093022020181