Functional mapping of the cardiorespiratory effects of dorsal and median raphe nuclei in the rat

Abstract

The dorsal (DRN) and median (MRN) raphe nuclei are important sources of serotonergic innervation to the forebrain, projecting to sites involved in cardiovascular regulation. These nuclei have been mapped using electrical stimulation, which has the limitation of stimulating fibers of passage. The present study maps these areas with chemical stimulation, investigating their influence on cardiorespiratory parameters. Urethane-anesthetized (1.2 g/kg, iv) male Wistar rats (280-300 g) were instrumented for pulsatile and mean blood pressure (MBP), heart rate, renal nerve activity, and respiratory frequency recordings. Microinjections of L-glutamate (0.18 M, 50-100 nl with 1% Pontamine Sky Blue) were performed within the DRN or the MRN with glass micropipettes. At the end of the experiments the sites of microinjection were identified. The majority of sites within the MRN (86.1%) and DRN (85.4%) evoked pressor responses when stimulated (DRN: ∆MBP = +14.7 ± 1.2; MRN: ∆MBP = +13.6 ± 1.3 mmHg). The changes in renal nerve activity and respiratory rate caused by Lglutamate were +45 ± 11 and +42 ± 9% (DRN; P < 0.05%), +40 ± 10 and +29 ± 7% (MRN, P < 0.05), respectively. No significant changes were observed in saline-microinjected animals. This study shows that: a) the blood pressure increases previously observed by electrical stimulation within the raphe are due to activation of local neurons, b) this pressor effect is due to sympathoexcitation because the stimulation increased renal sympathetic activity but did not produce tachycardia, and c) the stimulation of cell bodies in these nuclei also increases the respiratory rate.

Brainstem network disruption: A pathway to sudden unexplained death in epilepsy?

“…The two-hit pathomechanism assumes that mechanisms causing structural abnormalities beyond the focus, for example, excitotoxic effects of spreading seizure activity, are responsible for the mesencephalic abnormalities that represent the "first hit." Dorso-mesencephalic structures, for example, periaqueductal gray, colliculi, raphe, and cuneiform nucleus, not only play an important role in cardio-respiratory control but also in seizure control and arousal (Alvarenga, Pires, & Futuro Neto, 2005;Dampney, 2015;Furman et al, 2015;Müller-Ribeiro, Goodchild, McMullan, Fontes, & Dampney, 2016;N'Gouemo & Faingold, 2000;Soper, Wicker, Kulick, N'Gouemo, & Forcelli, 2016;Trindade-Filho et al, 2008;Zhang et al, 2018). Structural abnormalities in these regions could, therefore, render the patient prone to longer and more severe seizures that are not only more likely to be generalized but also more often associated with prolonged phases of impaired consciousness Zhan et al, 2016;Kundishora et al, 2017) that prevent the patient from perceiving and reacting to a post-ictal respiratory depression.…”

Localization of serotoninergic neurons that participate in regulating diaphragm activity in the cat

“…Since each raphe nucleus receives different inputs, this widespread network of cells is likely capable of altering phrenic motoneuron activity during a variety of different behaviors. Many non-serotoninergic neurons within the medullary raphe nuclei also provide inputs to phrenic motoneurons, indicating that multiple neurotransmitters mediate the effects of stimulation of midline brainstem areas on breathing (Alvarenga et al, 2005; Bernard, 1998; Dias et al, 2007; 2008; Holtman et al, 1986; Lalley, 1986b, a; 1986b; Lalley et al, 1997; Li et al, 2006b; Millhorn, 1986; Nattie and Li, 2001; Verner et al, 2004). …”

“…Attempts have been made to pinpoint the cells by examining respiratory responses to electrical or chemical stimulation of midline areas that contain serotoninergic neurons, sometimes in combination with the blockade of serotonin receptors to differentiate the serotonin-dependent and independent components of the responses that were elicited (Alvarenga et al, 2005; Bernard, 1998; Dias et al, 2007; 2008; Holtman et al, 1986; Lalley, 1986b, a; 1986b; Lalley et al, 1997; Li et al, 2006b; Millhorn, 1986; Nattie and Li, 2001; Verner et al, 2004). Other studies have generated focal lesions near the medullary midline to determine which regions participate in regulating respiratory activity (Dias et al, 2007; Hodges et al, 2004; Jakus et al, 1998; Messier et al, 2002; Taylor et al, 2006).…”

Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity

“…However, this was not observed with fluoxetine or sertraline, in which the respiratory effects were mild and did not differ from the effect of the vehicle. These results do not exclude a role for central 5-HT in the brainstem respiration circuitry because the 5-HT effects in this regard are complex and have excitatory as well as inhibitory effects (4,5,14). …”

“…Peripheral administration of several 5-HT receptor antagonists, particularly 5-HT 2 blockers, is associated with hypotension and/or sympathoinhibition (1). It should also be noted that some raphe nuclei, which are mainly serotonergic, play a role in the central control of respiration in mammals (4,5). However, little is known about the short-term respiratory effects of intravenously injected serotonergic drugs, especially the SSRIs.…”