Activation of 5-Hydroxytryptamine 1A Receptors Suppresses the Cardiovascular Response Evoked From the Dorsomedial Hypothalamic Nucleus

Abstract

Abstract-The dorsomedial hypothalamic nucleus is a key component of the central pathways subserving the cardiovascular response to psychological stress, which is believed to be an important risk factor for hypertension. Previous studies indicate that 5-hydroxytryptamine 1A receptors can modulate the cardiovascular responses associated with stress. In this study, we determined in anesthetized rats the effects of systemic or intracisternal administration of 8-hydroxy-2-(di-npropylamino)tetralin, a selective agonist of 5-hydroxytryptamine 1A receptors, and then subsequent administration of the selective antagonist WAY-100635 on the cardiovascular response evoked by activation of the dorsomedial hypothalamic nucleus (by microinjection of bicuculline). The increase in mean arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA) evoked by bicuculline injection into the dorsomedial hypothalamic nucleus was greatly reduced (by 80% to 90%) by administration of 8-hydroxy-2-(di-n-propylamino)tetralin and then completely restored by subsequent administration of WAY-100635, whether administered systemically or intracisternally. In contrast, systemic administration of 8-hydroxy-2-(di-n-propylamino)tetralin had no significant effect on the baseline level or reflex changes in RSNA evoked by chemoreceptor or baroreceptor stimulation and resulted in only a modest reduction ( Key Words: Ⅲ hypothalamus Ⅲ stress Ⅲ baroreflex Ⅲ chemoreceptors P sychological stress is believed to be an important risk factor for hypertension and other cardiovascular disorders. 1 Studies in conscious and anesthetized rats have demonstrated that the dorsomedial hypothalamic nucleus (DMH) plays a critical role in mediating the autonomic, neuroendocrine, and behavioral response to psychological stress, such as air jet stress. 2 Activation of neurons in the DMH evokes anxiety-like behavior associated with a wide range of autonomic and hormonal responses, including increases in heart rate (HR; mediated via an increase in cardiac sympathetic nerve activity 3,4 ), renal sympathetic nerve activity (RSNA), gastrointestinal motility, and in the secretion of adrenomedullary hormones and adrenocorticotropic hormone (corticotropin [ACTH]). 2-8 Conversely, bilateral microinjections into the DMH of muscimol (a ␥-aminobutyric acid type A [GABA A ] receptor agonist) or of kynunerate (an antagonist of ionotropic glutamate receptors) greatly reduces the increases in arterial pressure, HR, ACTH secretion, and anxiety-like behavior normally evoked by air jet stress. 8 -10 It has been shown recently that the DMH also plays an important role in generating thermoregulatory responses.Activation of neurons in the DMH evokes an increase in the activity of sympathetic nerves innervating brown adipose tissue (BAT), accompanied by increases in BAT temperature and end-tidal CO 2 , 3 as well as cutaneous vasoconstriction. 11 These thermoregulatory effects may also be part of a stress response because an increase in body temperature can be induced by stress (so-cal...

Central 5-HT receptors in cardiovascular control during stress

“…In contrast, recent work from Dampney's laboratory demonstrated that systemic or intra-cisternally administered 8-OH-DPAT reduces not only tachycardia but also rises in AP and in renal sympathetic activity elicited in anesthetized rats from the dorsomedial hypothalamus (a principal ''defence area'' that mediates stress-induced cardiovascular alterations) (Horiuchi et al, 2005). Once again, the discrepancy is likely to be due to a different location in the brainstem of cardiomotor and vasomotor presympathetic neurons expressing 5-HT1A receptors.…”

3,4-Methylenedioxymethamphetamine- and 8-Hydroxy-2-di-n-propylamino-tetralin-Induced Hypothermia: Role and Location of 5-Hydroxytryptamine 1A Receptors

“…Microinjection of DPAT into the region of the rRP blocks leptin-induced thermogenesis in rats (Morrison, 2004) and cold-induced cutaneous vasoconstriction in rabbits (Ootsuka and Blessing, 2006). The location of neurons containing 5-HT 1A receptors involved in the cardiovascular responses to leptin and chemical disinhibition of the dorsomedial hypothalamus has likewise been reported to be in the region of the rRP and medullary brainstem (Morrison, 2004;Horiuchi et al, 2005).…”

“…Neurons in the rRP are known to express 5-HT 1A receptors (Helke et al, 1997), and studies to date have demonstrated that microinjections of DPAT into the rRP block thermogenesis induced by leptin and cutaneous vasoconstriction induced by cold (Morrison, 2004;Ootsuka and Blessing, 2006a). Likewise microinjections of DPAT into various regions of the brainstem and rRP inhibit the cardioexcitatory responses to leptin and to hypothalamic stimulation (Morrison, 2004;Horiuchi et al, 2005).…”

Induction of Fos-immunoreactivity in the rat brain following disinhibition of the dorsomedial hypothalamus

“…Microinjection of BMI into the DMH has been employed in numerous studies in order to disinhibit neurons in the region (Horiuchi et al, 2004(Horiuchi et al, , 2005Da Silva et al, 2006;McDowall et al, 2006;Nakamura and Morrison, 2007), but this study represents the first in which direct evidence for neuronal activation resulting from this disinhibition has been presented. In contrast to a previous report that employed electrical stimulation and relatively high doses of kainate for study (Silveira et al, 1995), we found that the extent of the area of uniformly increased Fos expression emanating from the site of microinjection in the DMH could be delineated with reasonable clarity.…”

“…Given that projections of neurons in the DMH are predominantly ipsilateral (Thompson and Swanson, 1998), we anticipated that, as was reported previously (Silveira et al, 1995), significant lateralization of BMI-induced increases in Fos expression would be evident in areas where neuronal activation was directly dependent on neural circuitry, rather than secondary to the state of profound behavioral and "emotional" arousal so evoked. Although this dose of BMI has been employed extensively in microinjection studies targeting the DMH (Bailey and DiMicco, 2001;Samuels et al, 2002;Zaretskaia et al, 2002;Horiuchi et al, 2005;da Silva et al, 2006;de Menezes et al, 2006), the area of neuronal excitation evoked by such injections has never been delineated. Therefore, we also assessed the extent of the area of Fos expression in the vicinity of the injection site in the DMH.…”