Serotonergic mechanisms on breathing modulation in the rat locus coeruleus


The locus coeruleus (LC) is a noradrenergic nucleus that plays an important role in the ventilatory response to hypercapnia. This nucleus is densely innervated by serotonergic fibers and contains high density of serotonin (5-HT) receptors, including 5-HT1A and 5-HT2. We assessed the possible modulation of respiratory response to hypercapnia by 5-HT, through 5-HT1A and 5-HT2 receptors, in the LC. To this end, we determined the concentrations of 5-HT and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in the LC after hypercapnic exposure. Pulmonary ventilation (V e, plethysmograph) was measured before and after unilateral microinjection (100 nL) of WAY-100635 (5-HT1A antagonist, 5.6 and 56 mM), 8-OHDPAT (5-HT1A/7 agonist, 7 and 15 mM), Ketanserin (5-HT2A antagonist, 3.7 and 37 mM), or (±)-2,5-dimethoxy-4-iodoamphetaminehydrochloride (DOI; 5-HT2A agonist, 6.7 and 67 mM) into the LC, followed by a 60-min period of 7% CO2 exposure. Hypercapnia increased 5-HTIAA levels and 5-HIAA/5-HT ratio within the LC. WAY-100635 and 8-OHDPAT intra-LC decreased the hypercapnic ventilatory response due to a lower tidal volume. Ketanserin increased CO2 drive to breathing and DOI caused the opposite response, both acting on tidal volume. The current results provide evidence of increased 5-HT release during hypercapnia in the LC and that 5-HT presents an inhibitory modulation of the stimulatory role of LC on hypercapnic ventilatory response, acting through postsynaptic 5-HT2A receptors in this nucleus. In addition, hypercapnic responses seem to be also regulated by presynaptic 5-HT1A receptors in the LC.

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This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Instituto Nacional de Ciência e Tecnologia (INCT) em Fisiologia Comparada. We thank Aretuza C. Carregari, Euclides Roberto Secato, and Ruither O.G. Carolino for excellent technical assistance and Dr. Patricia M. de Paula that kindly provided Idazoxan. Vanessa de Souza Moreno was the recipient of a FAPESP undergraduate scholarship (2005/56128-9).

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Correspondence to Luciane H. Gargaglioni.

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de Souza Moreno, V., Bícego, K.C., Szawka, R.E. et al. Serotonergic mechanisms on breathing modulation in the rat locus coeruleus. Pflugers Arch - Eur J Physiol 459, 357–368 (2010).

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  • Chemosensitivity
  • A6 region
  • Hypercapnia
  • Ventilation
  • Pons
  • Serotonin
  • 5-HT1A
  • 5HT2A