Published online before print June 6, 2005, doi: 10.1161/01.HYP.0000169970.68151.17
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(Hypertension. 2005;46:173.)
© 2005 American Heart Association, Inc.
Original Articles |
Activation of 5-Hydroxytryptamine 1A Receptors Suppresses the Cardiovascular Response Evoked From the Dorsomedial Hypothalamic Nucleus
From the Department of Physiology and Institute for Biomedical Research, The University of Sydney, Australia.
Correspondence to Dr R.A.L. Dampney, Department of Physiology, F13, The University of Sydney, NSW 2006, Australia. E-mail rogerd{at}physiol.usyd.edu.au
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Abstract |
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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-n-propylamino)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 (12 mm Hg) in baseline mean arterial pressure. The results indicate that activation of 5-hydroxytryptamine 1A receptors in the brain stem causes a potent and selective suppression of the hypertensive and sympathoexcitatory response evoked by stimulation of the dorsomedial hypothalamic nucleus but has little effect on the tonic level or baroreceptor or chemoreceptor reflex control of RSNA.
Key Words: hypothalamus • stress • baroreflex • chemoreceptors
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Introduction |
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Psychological 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 activity3,4), 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 [GABAA] 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 CO2,3 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-called "stress hyperthermia").12 In addition, bilateral injections of muscimol or kynurenate into the DMH greatly reduces the thermogenic and cardiovascular components of the febrile response generated by injection of prostaglandin E2 (PGE2) into the preoptic area of the hypothalamus.13,14 Thus, the DMH appears to be a component of the central pathways mediating the sympathetic changes accompanying fever, as well as those evoked by psychological stress.
The descending pathways that mediate the different components of the sympathetic response evoked by activation of the DMH have been shown to include synapses in the rostral ventrolateral medulla (RVLM) and in the region of the raphe pallidus (RPa) in the rostral midline medulla. In particular, the increase in RSNA evoked from the DMH is largely dependent on a synapse in the RVLM, whereas the increase in HR, BAT sympathetic activity, and cutaneous vasoconstrictor activity is largely dependent on a synapse in the RPa.3,4,7,11,15,16 Consistent with the hypothesis that these descending pathways mediate the sympathetic changes accompanying psychological stress or fever, inhibition of neurons in RPa suppresses the tachycardia normally evoked by air jet stress in conscious rats17 as well as the tachycardia and thermogenic response evoked by injection of PGE2 into the preoptic area of anesthetized rats.15,18
Several lines of evidence suggest the possibility that 5-hydroxytryptamine 1A (5-HT1A) receptors in the brain may play a role in modulating autonomic responses evoked from the DMH. First, the RPa and RVLM contain 5-HT1A receptors,19 and these are also present in the DMH itself.20 Second, systemic administration of the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into conscious rabbits abolishes the cutaneous vasoconstriction and greatly reduces the thermogenic response associated with fever,21 which, as mentioned above, depends on activation of neurons in the DMH. These effects of 8-OH-DPAT are likely attributable to a central action of the drug because it is known that systemically administered 8-OH-DPAT affects sympathetic activity by an action on the central nervous system.22 Third, Morrison23 reported recently that microinjection of 8-OH-DPAT into the RPa reduced the BAT thermogenic response and tachycardia evoked by systemic injection of leptin, which acts, at least in part, on neurons in the DMH.24,25
In light of the above recent findings, the aim of this study was to test the hypothesis that central 5-HT1A receptors modulate the cardiovascular response evoked by activation of DMH neurons. For this purpose, we first determined the effect of activation of 5-HT1A receptors (by systemic or intracisternal administration of 8-OH-DPAT) on the changes in arterial pressure, HR, and RSNA evoked by disinhibition of the DMH. We then tested the effect of subsequent administration of WAY-100635, a highly potent and selective competitive antagonist of 5-HT1A receptors,26 on the DMH-evoked response. In addition, as a control, we also determined the effects of administration of these drugs on the baroreceptor and chemoreceptor reflex control of RSNA.
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Experiments were performed on male Sprague–Dawley rats (body weight 410 to 480 g). All experimental procedures were approved by the animal ethics committee of the University of Sydney. Anesthesia was induced by isoflurane (2% in oxygen). The trachea was cannulated and catheters were placed in a femoral artery and a femoral vein for the recording of pulsatile arterial pressure and drug injection, respectively. The isoflurane anesthesia was gradually withdrawn while being replaced by urethane (1.3 to 1.4 g/kg IV infused over 20 minutes). The body temperature was monitored using a rectal probe and maintained in the range of 37°C to 38°C with a heating pad.
The rat was then mounted in a stereotaxic apparatus and the renal nerve exposed and prepared for recording as described previously.7 A small portion of the dorsal surface of the cortex was exposed to allow insertion of a micropipette into the DMH. After completion of all surgical procedures, neuromuscular blockade was induced with tubocurarine chloride hydrate (Sigma; 0.6 mg IV bolus and 0.2 mg per hour continuous infusion), and all animals were artificially ventilated with a respiratory pump at a level that maintained end-tidal CO2 close to 4%. The adequacy of anesthesia without neuromuscular blockade was verified by the absence of a withdrawal response to nociceptive stimulation of a hindpaw and during neuromuscular blockade by a stable baseline arterial pressure, HR, and RSNA. Additional doses of urethane (0.1 g/kg IV) were injected if required. The mean arterial pressure (MAP) and HR signals were derived from the pulsatile pressure signal via a low-pass filter and ratemeter, respectively. All signals were recorded on a computer using a PowerLab system (AD Instruments) and, in some experiments, a DAT data recorder (TEAC), for later analysis.
Microinjections were made into the DMH as described previously.7 The compound injected was bicuculline methochloride (Tocris; 10 pmol in 20 nL). The vehicle solution was artificial cerebrospinal fluid adjusted to pH 7.4, and the injectate contained 0.5% fluorescent microspheres to allow later histological determination of the injection sites. An initial microinjection of bicuculline was made into the DMH. After 55 to 80 minutes, the selective 5-HT1A receptor agonist 8-OH-DPAT (Tocris) was administered (100 µg/kg IV). After an additional 5 to 10 minutes, a second microinjection of bicuculline was made into the same DMH site, and there was then a further waiting period of 45 to 50 minutes. The selective 5-HT1A receptor antagonist WAY-100635 (Sigma) was then administered (100 µg/kg IV), after which there was an additional waiting time of 5 to 10 minutes, followed by a third and final microinjection of bicuculline into the same site in the DMH. It has been demonstrated previously that microinjection of 10 pmol bicuculline into the DMH evokes a significant but submaximal increase in MAP, HR, and RSNA.7
To test the effects of intravenous 8-OH-DPAT and WAY-100635 administration on the chemoreceptor reflex, in 4 of the above experiments a bolus injection of sodium cyanide (NaCN) solution (Sigma; 100 µg/kg in 400 µL IV) was injected 10 minutes before and then 5 minutes after administration of 8-OH-DPAT (100 µg/kg IV) and then again 5 minutes after administration of WAY-100635 (100 µg/kg IV). All compounds injected intravenously were dissolved in physiological saline solution.
In 5 other experiments, the procedures were the same as the experiments in which 8-OH-DPAT and WAY-100635 were injected intravenously, except that in this case, the drugs were injected intracisternally in a dose that was 10x smaller (10 µg/kg in a volume of 3 to 5 µL). In these experiments, the drugs were applied bilaterally (5 µg/kg each side) to the exposed dorsolateral surface of the medulla, inside the dura mater. In 2 experiments, a similar volume of Evans’ Blue dye was injected in the same fashion. Subsequent examination of the brain stem demonstrated that the dye diffused to cover the dorsal and ventral medullary surface and the ventral surface of the caudal pons but did not spread to the midbrain or higher levels.
At the end of each experiment, the rat was euthanized with an overdose of pentobarbital sodium, the brain was removed, and after fixation in paraformaldehyde solution, coronal sections (50 µm) were cut on a freezing microtome and mounted onto glass slides. Injection sites were determined using a fluorescence microscope and mapped onto standard sections of the atlas by Paxinos and Watson.27
To determine the effects of administration of 8-OH-DPAT and WAY-100635 on the cardiac-related component of RSNA, the pulse-triggered average of the full-wave–rectified RSNA signal was determined as described previously.28 It is known that the cardiac-related component of RSNA arises from entrainment of the medullary, sympathetic burst-generating circuits by inhibitory inputs from baroreceptors.29 The magnitude of the cardiac-related component of RSNA after administration of 8-OH-DPAT and subsequent administration of WAY-100635 was measured with respect to the baseline RSNA just before administration of each of these drugs. Comparisons of the magnitudes of the changes in MAP (in mm Hg), HR (in bpm), and RSNA (measured as the percentage of the prestimulus baseline) evoked by microinjections of bicuculline into the DMH, or by chemoreceptor stimulation, were made using 1-way ANOVA. Pair-wise comparisons between the control responses and after administration of 8-OH-DPAT and after subsequent administration of WAY-100635 were made using the paired t test, with application of the Bonferroni procedure for multiple comparisons. A similar procedure was also used to compare the magnitudes of the cardiac-related component of the RSNA before and after administration of 8-OH-DPAT and after subsequent administration of WAY-100635. A P value <0.05 was regarded as statistically significant. All values are presented as means±SEM.
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Effects of Systemic Administration of 8-OH-DPAT and WAY-100635
Baseline Variables
After intravenous administration of the 5-HT1A selective agonist 8-OH-DPAT (100 µg/kg), the MAP and HR decreased by 12±1 mm Hg and 32±7 bpm, respectively (Table 1), reaching new stable levels by 5 to 10 minutes after the injection. In contrast, administration of 8-OH-DPAT had no significant effect on RSNA at this time (Table 1). After administration of WAY-100635 (100 µg/kg), the MAP, HR, and RSNA increased by 21±3 mm Hg, 22±5 bpm, and 15±4%, respectively, compared with the levels just before WAY-100635 administration (Table 1).
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Responses Evoked From DMH
In 7 experiments, bicuculline (10 pmol in 20 nL) was injected into the DMH before and after intravenous administration of 8-OH-DPAT. The centers of the injection sites were confirmed to be located within the DMH (Figure 1). As described previously,4,7 the MAP, HR, and RSNA began to increase within 10 to 20 seconds after injection of bicuculline in the DMH, reached a peak after 5 to 10 minutes, and then declined gradually, returning to baseline levels after 
30 minutes (Figure 2). After 8-OH-DPAT administration, the increases in MAP, HR, and RSNA evoked by microinjection of the same dose (10 pmol) of bicuculline into the same site in the DMH were greatly reduced (by 80% to 90%; Figure 2). After subsequent administration of WAY-100635, the cardiovascular response evoked by an additional microinjection of bicuculline (10 pmol) into the same site in the DMH was completely restored (ie, the evoked increases in MAP, HR, and RSNA were not significantly different [P>0.5 in all cases] from those evoked by bicuculline microinjection into the DMH before administration of 8-OH-DPAT [Figure 2]).
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Chemoreceptor and Baroreceptor Reflex Changes in RSNA
In 4 of these 7 experiments, the chemoreceptor-sympathetic reflex was also tested by measuring the increase in RSNA evoked by a bolus injection of NaCN (100 µg/kg IV). In all experiments, a bolus injection of NaCN evoked short-lasting increases in MAP and RSNA, accompanied by a brief bradycardia (Figure 3). No such effects were observed when the same volume of the vehicle saline solution was injected intravenously. The magnitudes of the chemoreceptor reflex increase in RSNA after administration of 8-OH-DPAT or after subsequent administration of WAY-100635 were not significantly different from the control response (Figure 3; P>0.5 in both cases). Similarly, in 3 experiments (Figure 4), the amplitude of the cardiac-related component of RSNA after administration of 8-OH-DPAT was virtually unchanged (104±4% of the control amplitude before 8-OH-DPAT administration). However, after subsequent administration of WAY-100635 in these experiments, the cardiac-related component was significantly increased (P<0.05) to 130±5% of the control amplitude.
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Effects of Intracisternal 8-OH-DPAT and WAY-100635
Intracisternal administration of 8-OH-DPAT (10 µg/kg) and WAY-100635 (10 µg /kg) had very similar effects on baseline levels of MAP, HR, and RSNA (Table 2) to those observed after intravenous administration of these drugs (Table 1). Similarly, the increases in MAP, HR, and RSNA evoked by bicuculline injections into the DMH in these experiments were greatly reduced by intracisternal 8-OH-DPAT and then subsequently restored by intracisternal WAY-100635 (Figure 5). Histological examination confirmed that the injection sites for these experiments were within the DMH.
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Discussion |
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The results of the present study demonstrate that systemic injection of the selective 5-HT1A receptor agonist 8-OH-DPAT causes a profound suppression of the pressor, renal sympathoexcitatory and tachycardia response to disinhibition of the DMH, but had no effect on either the baseline tonic level of RSNA or on the phasic changes in RSNA reflexly evoked by chemoreceptor or baroreceptor stimulation. Furthermore, the inhibitory effect of 8-OH-DPAT on the DMH-evoked response was completely reversed by subsequent administration of the highly selective 5-HT1A receptor antagonist WAY-100635,26 which further indicates that the observed effects were mediated specifically by 5-HT1A receptors. Furthermore, intracisternal injections of 10-fold lower doses of 8-OH-DPAT and then WAY-100635 also caused almost complete suppression and then complete reversal of the DMH-evoked responses, indicating that activation of 5-HT1A receptors in the lower brain stem alone is sufficient to produce this suppression.
The dose of 8-OH-DPAT injected intravenously (100 µg/kg) was within the range (5 to 150 µg/kg) that has been shown previously to produce dose-dependent effects on arterial pressure and HR in rats,30 and was the same as the dose that, in conscious rabbits, causes inhibition of the cardiovascular and thermogenic responses associated with fever or cold stress.21,31 In agreement with previous studies,30,32 8-OH-DPAT administration resulted in modest but significant falls in MAP and HR (12 mm Hg and 32 bpm, respectively). Although we found that the baseline level of RSNA was not altered by systemic administration of 8-OH-DPAT, the fact that the MAP and HR decreased suggests that there was inhibition of sympathetic nerves innervating other vascular beds and the heart. In fact, Nosjean and Guyenet32 found that in anesthetized rats, 8-OH-DPAT administration resulted in a decrease in lumbar sympathetic nerve activity of 18%. Consistent with this, Lovick33 found that microinjection of 8-OH-DPAT into the RVLM resulted in a small decrease in MAP and HR, accompanied by an increase in hindlimb vascular conductance and no change in renal vascular conductance. Thus, 8-OH-DPAT may have nonuniform effects on the sympathetic outflow, with greater effects on lumbar and cardiac sympathetic activity than on RSNA. However, the fact that the RSNA remained constant despite the decrease in MAP suggests that there was some inhibitory effect on the renal sympathetic outflow because otherwise, the RSNA would have increased reflexly as a consequence of baroreceptor unloading.
As mentioned above, systemic injection of 8-OH-DPAT abolishes or greatly reduces the cutaneous vasoconstrictor and thermogenic components of the febrile response,21 as well as the sympathetically mediated cutaneous vasoconstriction induced by cold,31 the former being dependent on activation of neurons within the DMH.13,14 The central pathway mediating cold-induced cutaneous vasoconstriction may also include a synapse in the DMH.11 Thus, together, the present and previous observations suggest the possibility that all sympathetically mediated cardiovascular and noncardiovascular responses that are mediated by neurons within the DMH can be powerfully suppressed by activation of central 5-HT1A receptors. However, further studies are needed to test this hypothesis.
Intracisternal administration of 8-OH-DPAT was sufficient to suppress the DMH-evoked response. In 2 experiments, intracisternal administration of a similar volume of dye indicated that the injectate did not spread more rostrally than the pons. Thus, although diffusion of the drug to higher brain regions cannot be ruled out, this suggests that the intracisternally administered 8-OH-DPAT acts mainly on neurons within the lower brain stem. Consistent with this, intracisternal administration of angiotensin II, in contrast to intracereboventricular administration, acts mainly on neurons in the brain stem.34
In the medulla, neurons in the RPa and RVLM are likely sites of action of 8-OH-DPAT. RPa neurons mediate the tachycardia, increased BAT sympathetic activity, and increased cutaneous sympathetic activity that can be evoked by activation of the DMH.3,7,11,15,16 The RPa also contains a high density of 5-HT1A receptors,19 and microinjection of 8-OH-DPAT into the RPa has been shown to greatly inhibit the increased BAT sympathetic activity and tachycardia evoked by systemic injection of leptin,23 which acts, at least in part, on neurons in the DMH.24,25 Similarly, the increase in RSNA evoked by DMH activation is mediated primarily by neurons in the RVLM,3,4,7 which also contains 5-HT1A receptors.19 Furthermore, microinjection of 8-OH-DPAT into the RVLM suppresses the reflex increase in splanchnic sympathetic activity evoked by stimulation of somatic nociceptive afferent nerves.35 Thus, the DMH-evoked increase in RSNA (or in the activity of other sympathetic pathways mediated by the RVLM) could also be suppressed by activation of 5-HT1A receptors within the RVLM itself. It is very interesting to note that Miyawaki et al35 also found, consistent with the findings in the present study, that 8-OH-DPAT microinjection into the RVLM did not inhibit the baroreceptor- and chemoreceptor-sympathetic reflexes.
Thus, it is possible that the suppression of the DMH-evoked increase in MAP, HR, and RSNA is attributable entirely to an action on 5-HT1A receptors within the key medullary nuclei (RPa and RVLM) that mediate the sympathetic components of the response. However, even if this is the case, 5-HT1A receptors at higher levels of the brain may also be capable of inhibiting all or part of the response. For example, the lateral periaqueductal gray in the midbrain mediates at least part of the response evoked from the DMH,36 and this region also contains 5-HT1A receptors37 which, when activated, cause inhibition of periaqueductal gray neurons.38 Furthermore, there are 5-HT1A receptors within the DMH itself.20 Because the DMH response was evoked by blockade of GABAergic inhibitory receptors, it follows that the DMH sympathoexcitatory neurons that generate this response must receive tonic excitatory as well as tonic inhibitory synaptic inputs. Therefore, it is conceivable that the tonic excitatory inputs could be suppressed by activation of 5-HT1A receptors within the DMH, as has been shown to occur in the locus coeruleus.39 Further studies are needed to determine the role of 5-HT1A receptors in supramedullary regions on the DMH-evoked response.
In general, activation of 5-HT1A receptors causes hyperpolarization and inhibition of neurons.26 Such receptors may be autoreceptors on serotonergic neurons, or else postsynaptic receptors on nonserotonergic neurons.26 It could be argued that 8-OH-DPAT suppresses the DMH-evoked increase in RSNA via direct inhibition of RVLM neurons, but if so, such neurons would have to be a separate population from RVLM neurons that mediate baroreceptor and chemoreceptor reflex responses. However, this seems unlikely because we found previously that 5 out of a sample of 6 identified barosensitive spinally projecting RVLM neurons were powerfully excited by DMH activation.7 Thus, there appears to be a powerful convergence of inputs from the DMH and baroreceptors onto RVLM sympathetic premotor neurons. A more likely possibility, then, is that 8-OH-DPAT acts presynaptically to selectively suppress DMH-evoked excitation of RVLM sympathetic premotor neurons, while leaving intact excitatory and inhibitory inputs from chemoreceptors and baroreceptors, respectively. As mentioned above, a similar selective action of 5-HT1A receptors in the RVLM, in inhibiting the somatosympathetic reflex but not baroreceptor- or chemoreceptor-sympathetic reflexes, has been demonstrated previously by Miyawaki et al.35 These authors also proposed that this is likely to be a presynaptic effect, but further studies are needed to determine the precise cellular mechanism that underlies this selectivity.
Perspectives
There is much evidence, from studies in human and animal models, that 5-HT1A receptors have a major role in modulating behavioral and physiological changes associated with stress and anxiety,26 which is believed to be a significant risk factor for hypertension.1 5-HT1A receptor agonists have an anxiolytic effect, as demonstrated in human and animal studies.40 The present study focused on the sympathoexcitatory response evoked by activation of DMH neurons, but our results also raise the important question as to whether other stress-induced responses that are mediated by the DMH, including respiratory effects and hormonal responses such as the release of ACTH,2 may also be suppressed by administration of 5-HT1A receptor agonists. In addition, a further question is whether the suppression of the DMH-evoked sympathoexcitatory response is specific to that particular nucleus or alternatively is a general effect on sympathoexcitatory responses evoked by activation of other hypothalamic nuclei, such as the paraventricular nucleus, which also play a role in mediating stress-induced responses.41 Future studies will also be needed to determine the precise sites and cellular mechanisms of action of 5-HT1A receptor agonists in modulating stress-induced physiological responses.
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Acknowledgments |
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This study was supported by the National Health and Medical Research Council of Australia. We thank Suzanne Killinger for excellent technical assistance.
Received March 30, 2005; first decision April 18, 2005; accepted April 29, 2005.
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References |
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1. Esler M, Lambert G, Brunner-La Rocca HP, Vaddadi G, Kaye D. Sympathetic nerve activity and neurotransmitter release in humans: translation from pathophysiology into clinical practice. Acta Physiol Scand. 2003; 177: 275–284.[CrossRef][Medline] [Order article via Infotrieve]
2. DiMicco JA, Samuels BC, Zaretskaia MV, Zaretsky DV. The dorsomedial hypothalamus and the response to stress: part renaissance, part revolution. Pharmacol Biochem Behav. 2002; 71: 469–480.[CrossRef][Medline] [Order article via Infotrieve]
3. Cao WH, Fan W, Morrison SF. Medullary pathways mediating specific sympathetic responses to activation of dorsomedial hypothalamus. Neuroscience. 2004; 126: 229–240.[CrossRef][Medline] [Order article via Infotrieve]
4. Fontes MAP, Tagawa T, Polson JW, Cavanagh SJ, Dampney RAL. Descending pathways mediating cardiovascular response from dorsomedial hypothalamic nucleus. Am J Physiol. 2001; 280: H2891–H2901.
5. Bailey TW, Dimicco JA. Chemical stimulation of the dorsomedial hypothalamus elevates plasma ACTH in conscious rats. Am J Physiol. 2001; 280: R8–R15.
6. Greenwood B, DiMicco JA. Activation of the hypothalamic dorsomedial nucleus stimulates intestinal motility in rats. Am J Physiol. 1995; 268: G514–G521.[Medline] [Order article via Infotrieve]
7. Horiuchi J, McAllen RM, Allen AM, Killinger S, Fontes MAP, Dampney RAL. Descending vasomotor pathways from the dorsomedial hypothalamic nucleus: role of medullary raphe and RVLM. Am J Physiol. 2004; 287: R824–R832.
8. Shekhar A, Hingtgen JN, DiMicco JA. GABA receptors in the posterior hypothalamus regulate experimental anxiety in rats. Brain Res. 1990; 512: 81–88.[CrossRef][Medline] [Order article via Infotrieve]
9. Stotz-Potter EH, Morin SM, DiMicco JA. Effect of microinjection of muscimol into the dorsomedial or paraventricular hypothalamic nucleus on air stress-induced neuroendocrine and cardiovascular changes in rats. Brain Res. 1996; 742: 219–224.[CrossRef][Medline] [Order article via Infotrieve]
10. Stotz-Potter EH, Willis LR, DiMicco JA. Muscimol acts in dorsomedial but not paraventricular hypothalamic nucleus to suppress cardiovascular effects of stress. J Neurosci. 1996; 16: 1173–1179.
11. Nalivaiko E, Blessing WW. Raphe region mediates changes in cutaneous vascular tone elicited by stimulation of amygdala and hypothalamus in rabbits. Brain Res. 2001; 891: 130–137.[CrossRef][Medline] [Order article via Infotrieve]
12. Olivier B, Zethof T, Pattij T, van Boogaert M, van Oorschot R, Leahy C, Oosting R, Bouwknecht A, Veening J, van der Gugten J, Groenink L. Stress-induced hyperthermia and anxiety: pharmacological validation. Eur J Pharmacol. 2003; 463: 117–132.[CrossRef][Medline] [Order article via Infotrieve]
13. Madden CJ, Morrison SF. Excitatory amino acid receptors in the dorsomedial hypothalamus mediate prostaglandin-evoked thermogenesis in brown adipose tissue. Am J Physiol. 2004; 286: R320–R325.
14. Zaretskaia MV, Zaretsky DV, DiMicco JA. Role of the dorsomedial hypothalamus in thermogenesis and tachycardia caused by microinjection of prostaglandin E2 into the preoptic area in anesthetized rats. Neurosci Lett. 2003; 340: 1–4.[CrossRef][Medline] [Order article via Infotrieve]
15. Madden CJ, Morrison SF. Excitatory amino acid receptor activation in the raphe pallidus area mediates prostaglandin-evoked thermogenesis. Neuroscience. 2003; 122: 5–16.[CrossRef][Medline] [Order article via Infotrieve]
16. Samuels BC, Zaretsky DV, DiMicco JA. Tachycardia evoked by disinhibition of the dorsomedial hypothalamus in rats is mediated through medullary raphe. J Physiol. 2002; 538: 941–946.
17. Zaretsky DV, Zaretskaia MV, Samuels BC, Cluxton LK, DiMicco JA. Microinjection of muscimol into raphe pallidus suppresses tachycardia associated with air stress in conscious rats. J Physiol. 2003; 546: 243–250.
18. Morrison SF. Raphe pallidus neurons mediate prostaglandin E2-evoked increases in brown adipose tissue thermogenesis. Neuroscience. 2003; 121: 17–24.[CrossRef][Medline] [Order article via Infotrieve]
19. Helke CJ, Capuano S, Tran N, Zhuo H. Immunocytochemical studies of the 5-HT(1A) receptor in ventral medullary neurons that project to the intermediolateral cell column and contain serotonin or tyrosine hydroxylase immunoreactivity. J Comp Neurol. 1997; 379: 261–270.[CrossRef][Medline] [Order article via Infotrieve]
20. Frankfurt M, Mendelson SD, McKittrick CR, McEwen BS. Alterations of serotonin receptor binding in the hypothalamus following acute denervation. Brain Res. 1993; 601: 349–352.[CrossRef][Medline] [Order article via Infotrieve]
21. Blessing WW. 5-Hydroxytryptamine 1A receptor activation reduces cutaneous vasoconstriction and fever associated with the acute inflammatory response in rabbits. Neuroscience. 2004; 123: 1–4.[CrossRef][Medline] [Order article via Infotrieve]
22. McCall RB, Clement ME. Role of serotonin1A and serotonin2 receptors in the central regulation of the cardiovascular system. Pharmacol Rev. 1994; 46: 231–243.[Medline] [Order article via Infotrieve]
23. Morrison SF. Activation of 5-HT1A receptors in raphe pallidus inhibits leptin-evoked increases in brown adipose tissue thermogenesis. Am J Physiol. 2004; 286: R832–R837.
24. Elias CF, Kelly JF, Lee CE, Ahima RS, Drucker DJ, Saper CB, Elmquist JK. Chemical characterization of leptin-activated neurons in the rat brain. J Comp Neurol. 2000; 423: 261–281.[CrossRef][Medline] [Order article via Infotrieve]
25. Marsh AJ, Fontes MAP, Killinger S, Pawlak DB, Polson JW, Dampney RAL. Cardiovascular responses evoked by leptin acting on neurons in the ventromedial and dorsomedial hypothalamus. Hypertension. 2003; 42: 488–493.
26. Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999; 38: 1083–1152.[CrossRef][Medline] [Order article via Infotrieve]
27. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 4th ed. New York, NY: Academic Press; 1998.
28. Tagawa T, Horiuchi J, Potts PD, Dampney RAL. Sympathoinhibition after angiotensin receptor blockade in the rostral ventrolateral medulla is independent of glutamate and gamma-aminobutyric acid receptors. J Auton Nerv Syst. 1999; 77: 21–30.[CrossRef][Medline] [Order article via Infotrieve]
29. Gebber GL. Basis for phase relations between baroreceptor and sympathetic nervous discharge. Am J Physiol. 1976; 230: 263–270.
30. Gradin K, Pettersson A, Hedner T, Persson B. Acute administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT-receptor agonist, causes a biphasic blood pressure response and a bradycardia in the normotensive Sprague-Dawley rat and in the spontaneously hypertensive rat. J Neural Transm. 1985; 62: 305–319.[CrossRef][Medline] [Order article via Infotrieve]
31. Ootsuka Y, Blessing WW. 5-Hydroxytryptamine 1A receptors inhibit cold-induced sympathetically mediated cutaneous vasoconstriction in rabbits. J Physiol. 2003; 552: 303–314.
32. Nosjean A, Guyenet PG. Role of ventrolateral medulla in sympatholytic effect of 8-OHDPAT in rats. Am J Physiol. 1991; 260: R600–R609.[Medline] [Order article via Infotrieve]
33. Lovick TA. Systemic and regional hemodynamic responses to microinjection of 5-HT agonists in the rostral ventrolateral medulla in the rat. Neurosci Lett. 1989; 107: 157–161.[CrossRef][Medline] [Order article via Infotrieve]
34. Head GA, Williams NS. Hemodynamic effects of central angiotensin I, II and III in conscious rabbits. Am J Physiol. 1992; 263: R845–R851.[Medline] [Order article via Infotrieve]
35. Miyawaki T, Goodchild AK, Pilowsky PM. Rostral ventral medulla 5-HT1A receptors selectively inhibit the somatosympathetic reflex. Am J Physiol. 2001; 280: R1261–R1268.
36. da Silva LG, de Menezes RC, dos Santos RA, Campagnole-Santos MJ, Fontes MAP. Role of periaqueductal gray on the cardiovascular response evoked by disinhibition of the dorsomedial hypothalamus. Brain Res. 2003; 984: 206–214.[CrossRef][Medline] [Order article via Infotrieve]
37. Pazos A, Palacios JM. Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res. 1985; 346: 205–230.[CrossRef][Medline] [Order article via Infotrieve]
38. Behbehani MM, Liu H, Jiang M, Pun RY, Shipley MT. Activation of serotonin1A receptors inhibits midbrain periaqueductal gray neurons of the rat. Brain Res. 1993; 612: 56–60.[CrossRef][Medline] [Order article via Infotrieve]
39. Aston-Jones G, Akaoka H, Charlety P, Chouvet G. Serotonin selectively attenuates glutamate-evoked activation of noradrenergic locus coeruleus neurons. J Neurosci. 1991; 11: 760–769.[Abstract]
40. Handley SL. 5-Hydroxytryptamine pathways in anxiety and its treatment. Pharmacol Ther. 1995; 66: 103–148.[CrossRef][Medline] [Order article via Infotrieve]
41. Sawchenko PE, Brown ER, Chan RK, Ericsson A, Li HY, Roland BL, Kovacs KJ. The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress. Prog Brain Res. 1996; 107: 201–222.[Medline] [Order article via Infotrieve]
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