Activation of 5-HT_1A receptors attenuates tachycardia induced by restraint stress in rats

Abstract

To better understand the central mechanisms that mediate increases in heart rate (HR) during psychological stress, we examined the effects of systemic and intramedullary (raphe region) administration of the serotonin-1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) on cardiac changes elicited by restraint in hooded Wistar rats with preimplanted ECG telemetric transmitters. 8-OH-DPAT reduced basal HR from 356 Ϯ 12 to 284 Ϯ 12 beats/min, predominantly via a nonadrenergic, noncholinergic mechanism. Restraint stress caused tachycardia (an initial transient increase from 318 Ϯ 3 to 492 Ϯ 21 beats/min with a sustained component of 379 Ϯ 12 beats/min). ␤-Adrenoreceptor blockade with atenolol suppressed the sustained component, whereas muscarinic blockade with methylscopolamine (50 g/kg) abolished the initial transient increase, indicating that sympathetic activation and vagal withdrawal were responsible for the tachycardia. Systemic administration of 8-OH-DPAT (10, 30, and 100 g/kg) attenuated stress-induced tachycardia in a dose-dependent manner, and this effect was suppressed by the 5-HT1A antagonist WAY-100635 (100 g/kg). Given alone, the antagonist had no effect. Systemically injected 8-OH-DPAT (100 g/kg) attenuated the sympathetically mediated sustained component (from ϩ85 Ϯ 19 to ϩ32 Ϯ 9 beats/min) and the vagally mediated transient (from ϩ62 Ϯ 5 to ϩ25 Ϯ 3 beats/min). Activation of 5-HT1A receptors in the medullary raphe by microinjection of 8-OH-DPAT mimicked the antitachycardic effect of the systemically administered drug but did not affect basal HR. We conclude that tachycardia induced by restraint stress is due to a sustained increase in cardiac sympathetic activity associated with a transient vagal withdrawal. Activation of central 5-HT1A receptors attenuates this tachycardia by suppressing autonomic effects. At least some of the relevant receptors are located in the medullary rapheparapyramidal area.serotonin; psychological stress; heart rate; sympathetic; medullary raphe THAT PSYCHOLOGICAL STRESS consistently elicits sympathetically mediated tachycardic responses is firmly established, but the central mechanisms generating increases in cardiac sympathetic activity remain poorly understood (6). In addition to a theoretical interest, this issue is of major clinical importance, inasmuch as the ability to suppress potentially deleterious increases in cardiac sympathetic activity at its origin, in the brain, would be a valuable alternative to widely used ␤-blockers. Few attempts have been made to reach this goal, mainly because of a lack of knowledge of the localization and pharmacological sensitivity of presympathetic cardiomotor neurons. Recent evidence indicates that the final medullary relay for the descending pathways that activate the heart during stress is located in the raphe-parapyramidal area and that relevant cardiomotor neurons are sensitive to, and could be inhibited by, serotonin-1A (5-HT 1A ) receptor agonists (13,23).Involvement of 5-HT 1A receptors in cardiovasc...

Central 5-HT receptors in cardiovascular control during stress

“…In this study and in the cited above work from Nalivaiko's laboratory (Nalivaiko et al, 2005;Ngampramuan et al, 2008), effects of the drug were clearly receptorspecific as they were suppressed by a selective 5-HT1A receptor antagonist WAY-100,635.…”

“…Systemic administration of 8-OH-DPAT also reduced stressactivated vagal withdrawal observed at the beginning of the restraint (Ngampramuan et al, 2008); see Fig. 1D.…”

“…They found that systemic administration of 8-OH-DPAT (a selective 5-HT1A receptor antagonist) suppressed, in a dose-dependent manner, tachycardic and pressor responses to psychological stressors-airjet stress in rabbits and restraint stress in rats (Nalivaiko et al, 2005;Ngampramuan et al, 2008) (Fig. 1A).…”

Inhibition of the cardiovascular response to stress by systemic 5-HT1A activation: sympathoinhibition or anxiolysis?

“…An action on autoreceptors located in medullary raphé neurons is usually assumed (25,27). The medullary raphé has been recognized as a critical relay for the cardiac, thermogenic, and cutaneous vasoconstrictor responses to both psychological, cold, and inflammatory stressors (for a review, see Ref.…”

“…flammatory (26), air jet (26), open field (34), restraint (27), and social stress (25), it has been widely assumed that systemically administered 5-HT 1A agonists reduce all those sympathetic responses by acting on the medullary raphé (25,27).…”