5‐HT1A, but not 5‐HT2 and 5‐HT7, receptors in the nucleus raphe magnus modulate hypoxia‐induced hyperpnoea

Nucci, Tatiane B.; Branco, Luiz G.S.; Gargaglioni, Luciane H.

doi:10.1111/j.1748-1716.2008.01853.x

Cited by 26 publications

(22 citation statements)

References 68 publications

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“…We also observed that LC noradrenergic neurons play no role in basal ventilation [7]. Additionally, previous studies from our laboratory demonstrated that microinjections of WAY-100635 and Ketanserin in the preoptic area [22] and nucleus raphe magnus [42] did not affect ventilation during normocapnia. Recently, we observed that a reduction of approximately 80% of LC noradrenergic neurons was associated with a large decrease (∼64%) in the ventilatory response to CO 2 , indicating that LC exerts an important excitatory influence on CO 2 drive to breathing [7].…”

Section: Discussionsupporting

confidence: 50%

Serotonergic mechanisms on breathing modulation in the rat locus coeruleus

Moreno

Bícego

Szawka

et al. 2009

Pflugers Arch - Eur J Physiol

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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-HT(1A) and 5-HT(2). We assessed the possible modulation of respiratory response to hypercapnia by 5-HT, through 5-HT(1A) and 5-HT(2) 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 (VE: , plethysmograph) was measured before and after unilateral microinjection (100 nL) of WAY-100635 (5-HT(1A) antagonist, 5.6 and 56 mM), 8-OHDPAT (5-HT(1A/7) agonist, 7 and 15 mM), Ketanserin (5-HT(2A) antagonist, 3.7 and 37 mM), or (+/-)-2,5-dimethoxy-4-iodoamphetaminehydrochloride (DOI; 5-HT(2A) agonist, 6.7 and 67 mM) into the LC, followed by a 60-min period of 7% CO(2) 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 CO(2) 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-HT(2A) receptors in this nucleus. In addition, hypercapnic responses seem to be also regulated by presynaptic 5-HT(1A) receptors in the LC.

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Section: Discussionsupporting

confidence: 50%

Serotonergic mechanisms on breathing modulation in the rat locus coeruleus

Moreno

Bícego

Szawka

et al. 2009

Pflugers Arch - Eur J Physiol

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“…The 5-HT 1A autoreceptors in dorsal raphé nuclei and other brain regions are involved in regulating the firing of serotonergic neurons (Zifa and Fillion, 1992). Activation of 5-HT 1A R increases phrenic nerve activity (Wilken et al, 1997; Teng et al, 2003; Wang et al 2007; Nucci et al, 2008; Valic et al, 2008) and induces an increase in phasic and tonic genioglossus muscle activity important for tongue protrusion and the prevention of airway obstruction (Besnard et al, 2007). 5-HT 1A R also exerts excitatory modulation on respiratory rhythm generation (Hilaire et al, 1997), and, when co-activated with 5-HT 2A R, it is reportedly involved in the depolarization of PBC neurons (Schwarzacher et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Postnatal changes in the expressions of serotonin 1A, 1B, and 2A receptors in ten brain stem nuclei of the rat: implication for a sensitive period

Liu

Wong‐Riley

2010

Neuroscience

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A critical period in respiratory network development occurs in the rat around postnatal days (P)12–13, when abrupt neurochemical, metabolic, and physiological changes were evident. As serotonin (5-HT) and its receptors are involved in respiratory modulation, and serotonergic abnormality is implicated in Sudden Infant Death Syndrome, we hypothesized that 5-HT receptors are significantly down-regulated during the critical period. This was documented recently for 5-HT2AR in several respiratory nuclei. The present study represents a comprehensive analysis of postnatal development of 5-HT1AR and 5-HT1BR in ten brain stem nuclei and 5-HT2AR in six nuclei not previously examined. Optical densitometric analysis of immunohistochemically-reacted neurons from P2 to P21 indicated four developmental patterns of expression: 1) Pattern I: a high level of expression at P2–P11, an abrupt and significant reduction at P12, followed by a plateau until P21 (5-HT1AR and 5-HT1BR in raphé magnus [RM], raphé obscurus [ROb], raphé pallidus [RP], pre-Bötzinger complex [PBC], nucleus ambiguus [Amb], and hypoglossal nucleus [XII; 5-HT1AR only]). 2) Pattern II: a high level at P2–P9, a gradual decline from P9 to P12, followed by a plateau until P21 (5-HT1AR and 5-HT1BR in the retrotrapezoid nucleus [RTN]/parafacial respiratory group [pFRG]). 3) Pattern III: a high level at P2–P11, followed by a gradual decline until P21 (5-HT1AR in the ventrolateral subnucleus of solitary tract nucleus [NTSVL] and the non-respiratory cuneate nucleus [CN]). 4) Pattern IV: a relatively constant level maintained from P2 to P21 (5-HT1AR in the commissural subnucleus of solitary tract nucleus [NTSCOM]; 5-HT1BR in XII, NTSVL, NTSCOM, and CN; and 5-HT2AR in RM, ROb, RP, RTN/pFRG, NTSVL, and NTSCOM). Thus, a significant reduction in the expression of 5-HT1AR, 5-HT1BR, and 5-HT2AR in multiple respiratory-related nuclei at P12 is consistent with reduced serotonergic transmission during the critical period, thereby rendering the animals less able to respond adequately to ventilatory distress.

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“…Other studies demonstrate an important recruitment of 5-HT pathways in response to hypoxia. 5-HT acting on 5-HT1A receptors in the nucleus raphe magnus plays no role under normal conditions but modulates breathing during hypoxia (38). In the anteroventral preoptic region, both 5-HT1A and 5-HT7 receptors are involved in the inhibitory modulation of the hypoxic ventilatory response (39).…”

Section: Discussionmentioning

confidence: 99%

The Role of 5-HT3 and Other Excitatory Receptors in Central Cardiorespiratory Responses to Hypoxia: Implications for Sudden Infant Death Syndrome

et al. 2009

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Although brainstem serotonergic (5-HT) systems are involved in the protective responses to hypoxia, abnormalities of 5-HT function are strongly implicated in SIDS, and the neurochemical mechanisms by which 5-HT receptors influence brainstem cardiorespiratory responses to hypoxia remains unclear. This study focuses on the role of excitatory neurotransmission, including 5-HT3 signaling, to cardiac vagal neurons (CVNs) that dominate the control of heart rate. Excitatory synaptic inputs to CVNs, located in the nucleus ambiguus (NA), were recorded simultaneously with respiratory activity in in vitro brainstem slices. During control conditions excitatory inputs to CVNs were blocked by application of NMDA and AMPA/kainate glutamatergic receptor antagonists, whereas the 5-HT3 and purinergic receptor antagonists ondansetron and pyridoxalphosphate-6-azophenyl-2Ј,4Ј-disulfonic acid (PPADS), respectively, had no effect. However, during hypoxia ondansetron inhibited excitatory neurotransmission to CVNs. In recovery from hypoxia, spontaneous and respiratory-related excitatory events were blocked by glutamatergic and purinergic receptor blockers, respectively, whereas ondancetron had no effect. These results demonstrate that hypoxia recruits a 5-HT pathway to CVNs that activates 5-HT3 receptors on CVNs to maintain parasympathetic cardiac activity during hypoxia. Exaggeration of this 5-HT neurotransmission could increase the incidence of bradycardia and risk of sudden infant death during hypoxia. (Pediatr Res 65: 625-630, 2009) E pisodes of apnea and bradycardia are common in infants who succumb to SIDS (1,2). Although a specific cause in a majority of SIDS death is unknown, developmental abnormalities of serotonin (5-HT) function in the ventral medulla have recently been closely correlated with SIDS (3). These abnormalities involve multiple elements of 5-HT function including increased number of 5-HT neurons, reduction of 5-HT1A receptor binding, and relative reduction of 5-HT transporter function (4). In agreement with these findings, the study of cerebrospinal fluids of SIDS victims showed a significant increase of the metabolites of 5-HT (5,6). Medullary 5-HT abnormalities and enhanced 5-HT activity may result in exaggeration of responses to hypoxia including deleterious bradyarrhythmias.Respiratory responses to hypoxia include initial an increase, followed by a decrease, in the respiratory frequency in most mammals (7,8). Similarly, hypoxia evokes an initial increase in heart rate followed by a parasympathetically mediated bradycardia and ultimately, cessation of cardiac contractions (9 -11). This biphasic response to hypoxia is likely partly because of the biphasic increase followed by decrease in inhibitory GABAergic and glycinergic inputs to cardiac vagal neurons (CVNs) located within the nucleus ambiguus (NA) (12). However, the role of excitatory neurotransmission to CVNs in cardiorespiratory responses to hypoxia remains unclear.Hypoxia evokes neurotransmitter release in the brainstem including 5-HT (13), ATP...

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5‐HT_1A, but not 5‐HT₂ and 5‐HT₇, receptors in the nucleus raphe magnus modulate hypoxia‐induced hyperpnoea

Abstract: These data suggest that 5-HT acting on 5-HT(1A) receptors in the NRM increases the hypoxic ventilatory response.

Cited by 26 publications

References 68 publications

Serotonergic mechanisms on breathing modulation in the rat locus coeruleus

Serotonergic mechanisms on breathing modulation in the rat locus coeruleus

Postnatal changes in the expressions of serotonin 1A, 1B, and 2A receptors in ten brain stem nuclei of the rat: implication for a sensitive period

The Role of 5-HT3 and Other Excitatory Receptors in Central Cardiorespiratory Responses to Hypoxia: Implications for Sudden Infant Death Syndrome

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