5HT2 receptor activation facilitates P2X receptor mediated excitatory neurotransmission to cardiac vagal neurons in the nucleus ambiguus

Abstract

SummaryParasympathetic preganglionic cardiac vagal neurons (CVNs) which dominate the control of heart rate are located within the nucleus ambiguus (NA). Serotonin (5HT), and in particular 5HT2 receptors, play an important role in cardiovascular function in the brainstem. However, there is a lack of information on the mechanisms of action of 5HT2 receptors in modulating parasympathetic cardiac activity. This study tests whether activation of 5HT2 receptors alters excitatory glutamatergic and purinergic neurotransmission to CVNs. Application of α-methyl-5-hydroxytryptamine (α-Me-5HT), a 5HT2 agonist, reversibly increased both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in CVNs. Similar responses were obtained with alphamethyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine hydrochloride (BW723C86), and mchlorophenylpiperazine (m-CPP), 5HT2B and 5HT2B/C receptor agonists, respectively. The facilitation evoked by α-Me-5HT was prevented by the 5HT2B/C receptor antagonist SB206553 hydrochloride (SB206553). Interestingly, the blockage of both NMDA and non-NMDA glutamatergic receptors did not prevent α-Me-5HT-evoked facilitation of mEPSCs, however, the responses were blocked by the P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). The responses evoked by α-Me-5HT were mimicked by application of α,β-methylene ATP (α,β-Me-ATP), a P2X receptor agonist, which were also blocked by PPADS. In summary, these results indicate activation of 5HT2 receptors facilitates excitatory purinergic, but not glutamatergic, neurotransmission to CVNs.

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

“…In agreement with previous studies (35), during control conditions neither the 5-HT3 antagonist ondansetron (100μM) nor the P2 receptor blocker PPADS (100μM) significantly altered the frequency of spontaneous EPSCs in CVNs (2.0 ± 0.1 Hz versus 1.7 ± 0.2 Hz, n = 7; P > 0.05, Fig. 2, A, and 1.9 ± 0.1 Hz versus 2.1 ± 0.2 Hz, n = 6; P > 0.05, Fig.…”

Severe spontaneous bradycardia associated with respiratory disruptions in rat pups with fewer brain stem 5-HT neurons

“…Although progress has been made toward characterizing inhibitory neurotransmitters responsible for this cardiorespiratory instability [e.g., GABA, adenosine (1)], there is little information regarding the role of serotonin . This is of interest because 5-HT not only projects to multiple brain stem loci participating in cardiorespiratory control, but also interacts extensively with GABA and adenosine signaling within these loci (1,10,11). Apnea, bradycardia, and the resulting desaturation are highly associated with an increase in morbidity and mortality (12,22).…”

5HT1A receptors inhibit glutamate inputs to cardiac vagal neurons post-hypoxia/hypercapnia

“…Although other neurotransmitter containing pathways and receptors have been identified within the nucleus ambiguous, and particularly on CVNs, their physiological role remains unclear. For example, multiple serotonergic terminals and receptor subtypes have been characterized in the nucleus ambiguus region (Izzo et al, 1993; Dergacheva et al, 2007; Audero et al, 2008; Dergacheva et al, 2008; Dergacheva et al, 2009a; Dergacheva et al, 2009b; Duncan et al, 2009; Hodges et al, 2009; Kinney, 2009; Pavone et al, 2009). In particular, 5HT1A receptors are expressed within the nucleus ambiguus and ventrolateral medulla respectively (Chitravanshi and Calaresu, 1992; Thor et al, 1992; Futuro-Neto et al, 1993; Dando et al, 1998; Paterson et al, 2006a; Paterson et al, 2006b).…”