Dorsomedial medullary 5-HT2 receptors mediate immediate onset of initial hyperventilation, airway dilation, and ventilatory decline during hypoxia in mice

The dorsomedial medulla oblongata (DMM) includes the solitary tract nucleus and the hypoglossal nucleus, to which 5-HT neurons project. Effects of 5-HT in the DMM on ventilatory augmentation and airway dilation are mediated via 5-HT2 receptors, which interact with the CO2 drive. The interaction may elicit cycles between hyperventilation with airway dilation and hypoventilation with airway narrowing. In the present study, effects of 5-HT2 receptors in the DMM on hypoxic ventilatory and airway responses were investigated, while 5-HT release in the DMM was monitored. Adult male mice were anesthetized, and then a microdialysis probe was inserted into the DMM. The mice were placed in a double-chamber plethysmograph. After recovery from anesthesia, the mice were exposed to hypoxic gas (7% O2 in N2) for 5 min with or without a 5-HT2 receptor antagonist (LY-53857) perfused in the DMM. 5-HT release in the DMM was increased by hypoxia regardless of the presence of LY-53857. Immediate onset and the peak of initial hypoxic hyperventilatory responses were delayed. Subsequent ventilatory decline and airway dilation during initial hypoxic hyperventilation were suppressed with LY-53857. These results suggest that 5-HT release increased by hypoxia acts on 5-HT2 receptors in the DMM, which contributes to the immediate onset of initial hypoxic hyperventilation, airway dilation, and subsequent ventilatory decline. Hypoxic ventilatory and airway responses mediated via 5-HT2 receptors in the DMM may play roles in immediate rescue and defensive adaptation for hypoxia and may be included in periodic breathing and the pathogenesis of obstructive sleep apnea.

Role of serotonergic input to the ventrolateral medulla in expression of the 10-Hz sympathetic nerve rhythm

We studied the changes in inferior cardiac sympathetic nerve discharge (SND) produced by unilateral microinjections of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists into the ventrolateral medulla (VLM) of urethane-anesthetized, baroreceptor-denervated cats. Microinjection of the 5-HT2 receptor antagonist LY-53857 (10 mM) into either the rostral or caudal VLM significantly reduced ( P ≤ 0.05) the 10-Hz rhythmic component of basal SND without affecting its lower-frequency, aperiodic component. The selective depression of 10-Hz power was accompanied by a statistically significant decrease in mean arterial pressure (MAP). Microinjection of LY-53857 into the VLM also attenuated the increase in 10-Hz power that followed tetanic stimulation of depressor sites in the caudal medullary raphé nuclei. Microinjection of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-amino-propane (DOI; 10 μM) into the VLM selectively enhanced 10-Hz SND, and intravenous DOI (1 mg/kg) partially reversed the reduction in 10-Hz SND produced by 5-HT2 receptor blockade in the VLM. Microinjection of the 5-HT1A receptor agonist, 8-hydroxy-2-(di- n-propylamino)tetralin (8-OHDPAT; 10 mM), into either the rostral or caudal VLM also selectively attenuated 10-Hz SND and significantly reduced MAP. The reduction in 10-Hz SND produced by 8-OHDPAT was partially reversed by intravenous WAY-100635 (1 mg/kg), which selectively blocks 5-HT1A receptors. These results support the view that serotonergic inputs to the VLM play an important role in expression of the 10-Hz rhythm in SND.

Compensatory airway dilation and additive ventilatory augmentation mediated by dorsomedial medullary 5-hydroxytryptamine 2 receptor activity and hypercapnia

5-HT2 receptor activity in the hypoglossal nucleus and hypercapnia is associated with airway dilation. 5-HT neurons in the medullary raphe and hypercapnia are responsible for tidal volume change. In this study, the effects of 5-HT2 receptors in the dorsomedial medulla oblongata (DMM), which receives projections from the medullary raphe, and hypercapnia on airway resistance and respiratory variables were studied in mice while monitoring 5-HT release in the DMM. A microdialysis probe was inserted into the DMM of anesthetized adult mice. Each mouse was placed in a double-chamber plethysmograph. After recovery from anesthesia, the mice were exposed to stepwise increases in CO2 inhalation (5%, 7%, and 9% CO2 in O2) at 8-min intervals with a selective serotonin reuptake inhibitor, fluoxetine, or fluoxetine plus a 5-HT2 receptor antagonist, LY-53857 in the DMM. In response to fluoxetine plus LY-53857 coperfusion, specific airway resistance was increased, and tidal volume and minute ventilation were decreased. CO2 inhalation with fluoxetine plus LY-53857 coperfusion in the DMM largely decreased airway resistance and additively increased minute ventilation. Thus, 5-HT2 receptor activity in the DMM increases basal levels of airway dilation and ventilatory volume, dependent on central inspiratory activity and the volume threshold of the inspiratory off-switch mechanism. Hypercapnia with low 5-HT2 receptor activity in the DMM largely recovers airway dilation and additively increases ventilatory volume. Interaction between 5-HT2 receptor activity in the DMM and CO2 drive may elicit a cycle of hyperventilation with airway dilation and hypoventilation with airway narrowing.

Serotonergic involvement in stress-induced vasopressin and oxytocin secretion

OBJECTIVE: To investigate the involvement of serotonin (5-hydroxytryptamine - 5-HT) receptors in mediation of stress-induced arginine vasopressin (AVP) and oxytocin (OT) secretion in male rats. DESIGN: Experiments on laboratory rats with control groups. METHODS: Different stress paradigms were applied after pretreatment with intracerebroventricular infusion of saline or different 5-HT antagonists. RESULTS: Restraint stress (5 min), hypotensive hemorrhage or dehydration for 24 h increased AVP secretion fivefold and OT secretion threefold. Swim stress for 3 min had no effect on AVP secretion, but increased OT secretion threefold. Ether vapor or hypoglycemia had no effect on AVP or OT secretion. The restraint stress-induced AVP response was inhibited by pretreatment with the 5-HT(2A+2C) antagonists ketanserin (KET) and LY-53857 (LY) and the 5-HT(3+4) antagonist ICS-205930 (ICS), whereas the 5-HT(1A) antagonist WAY-100635 (WAY) had no effect. The OT response to restraint stress was inhibited by WAY, KET and LY but not by ICS. KET and LY inhibited OT response to dehydration, and LY inhibited OT response to hemorrhage. Neither of the antagonists affected AVP responses to dehydration or hemorrhage, nor the swim stress-induced OT response. CONCLUSION: 5-HT(2A), 5-HT(2C) and possibly 5-HT(3) and 5-HT(4) receptors, but not 5-HT(1A) receptors, are involved in the restraint stress-induced AVP secretion. 5-HT does not seem to be involved in the dehydration- or hemorrhage-induced AVP response. The restraint stress-induced OT response seems to be mediated via 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors. The dehydration and hemorrhage-induced OT responses are at least mediated by the 5-HT(2A) and 5-HT(2C) receptors. The 5-HT(3) and 5-HT(4) receptors are not involved in stress-induced OT secretion.

Neuroendocrine and cardiovascular effects of serotonin: selective role of brain angiotensin on vasopressin

Central serotonin (5-HT) and angiotensin (ANG II) stimulate arginine vasopressin (AVP), oxytocin (OT), and adrenocorticotropin (ACTH) secretion and increase blood pressure. Studies were conducted in conscious rats to determine whether neuroendocrine activation by 5-HT requires a brain angiotensinergic intermediate pathway. In the first study, ANG II formation was inhibited by the angiotensin-converting enzyme inhibitor enalapril before injection of the 5-HT releaser/uptake inhibitor d-fenfluramine. Fenfluramine (2 mg/kg ip) stimulated AVP, OT, corticosterone, and prolactin (PRL) secretion (P<0.01). Enalapril (60 mg/l in drinking water for 4 days and 10 mg/kg ip 2 h before the rats were killed) inhibited only the AVP response (P<0.01) to d-fenfluramine. In the second study, the effect of intracerebroventricular injection of the 5-HT2A/2C antagonist LY-53857 (10 microgram), or the ANG II AT1 antagonist DuP-753 (10 microgram), on intracerebroventricular 5-HT (10 microgram)-stimulated AVP, OT, ACTH, PRL, renin secretion, mean arterial pressure (MAP) and heart rate (HR) was tested. LY-53857 inhibited the AVP, OT, and ACTH responses to 5-HT (P<0.01), whereas DuP-753 inhibited only the AVP response (P<0.01). Intraventricular injection of 5-HT increased MAP and decreased HR. The MAP response was not affected by LY-53857 or DuP-753, and at no time did MAP decline below starting levels. The decreased HR was inhibited by LY-53857 but not by DuP-753. These results demonstrate that 5-HT-induced AVP secretion is mediated selectively via brain angiotensinergic mechanisms by way of the AT1 receptor.

Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue

Pharmacological manipulation of brain serotonergic [5-hydroxytryptamine (5-HT)] activity affects run time to exhaustion in the rat. These effects may be mediated by neurochemical, hormonal, or substrate mechanisms. Groups of rats were decapitated during rest, after 1 h of treadmill running (20 m/min, 5% grade), and at exhaustion. Immediately before exercise rats were injected intraperitoneally with 1 mg/kg of quipazine dimaleate (QD; a 5-HT agonist), 1.5 mg/kg of LY 53857 (LY; a 5-HT antagonist), or the vehicle (V; 0.9% saline). LY increased and QD decreased time to exhaustion (approximately 28 and 32%, respectively; P < 0.05). At fatigue, QD animals had greater plasma glucose, liver glycogen, and muscle glycogen concentrations but lower plasma free fatty acid concentration than did V and LY animals (P < 0.05). In general, plasma corticosterone and catecholamine levels during exercise in QD and LY rats were similar to those in V rats. Brain 5-HT and 5-hydroxyindole-3-acetic acid concentrations were higher at 1 h of exercise than at rest (P < 0.05), and the latter increased even further at fatigue in the midbrain and striatum (P < 0.05). Brain dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were higher at 1 h of exercise (P < 0.05) but were similar to resting levels at fatigue. QD appeared to block the increase in DA and DOPAC at 1 h of exercise, and LY prevented the decrease in DA and DOPAC at fatigue (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

5-Hydroxytryptamine potentiates vasoconstrictor effect of endothelin-1

Interactions between 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) relative to contraction of rat aortic rings were examined in this study. Pretreatment of rings with threshold concentration of 5-HT potentiated the subsequent contractile response to ET-1. However, pretreatment with threshold concentration of ET-1 did not potentiate the contractile response to 5-HT. The 5-HT receptor antagonist LY 53857 blocked the synergistic contractile effects of 5-HT and ET-1 on rat aortic rings. Indomethacin and the thromboxane A2/endoperoxide receptor antagonist SQ 29548 also attenuated (P less than 0.05) the synergistic contractile effects of 5-HT and ET-1, suggesting release of thromboxane A2 or expression of thromboxane A2 receptors during this interaction. The calcium channel blocker verapamil also decreased the synergistic contractile effects of 5-HT and ET-1. Contraction of aortic rings by 5-HT alone was abolished by LY 53857 and attenuated by verapamil, diltiazem, and SQ 29548. Decrease in the force of contraction by verapamil as well as diltiazem indicates activation of voltage-dependent calcium channels during 5-HT-mediated contraction and perhaps during amplification of the vasoconstrictor activity of ET-1 by 5-HT.

Receptor mediation of microvascular responses to serotonin in striated muscle

Serotonin constricts large arterioles and dilates small arterioles in striated muscle. Our study aimed to identify the receptors that mediate this differential response. Rats were anesthetized with pentobarbital sodium, and the cremaster muscle was prepared for videomicroscopy. Serotonin, applied topically, caused a constriction of large (A1) arterioles that was attenuated by cyproheptadine, methysergide, and LY 53857 but not by MDL 7222, phentolamine, propranolol, or diphenhydramine. The 5-hydroxytryptamine (5-HT)-induced constriction of A1 arterioles was mimicked by alpha-CH3-5-HT but not by 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) or 5-carboxamidotryptamine (5-CT). In addition, 5-HT caused a dilation of small (A3 or A4) arterioles that was blocked by cyproheptadine and methysergide but not by LY 53857, MDL 7222, phentolamine, or propranolol. Diphenhydramine caused a slight increase in the small arteriole mean effective concentration to serotonin but did not change the maximal response. The serotonin-induced dilation of small arterioles was mimicked by 5-CT but not by alpha-CH3-5-HT or 8-OH-DPAT. These data indicate that the 5-HT-induced constriction of large A1 arterioles is mediated via a 5-HT2 or 5-HT1C receptor, whereas 5-HT-induced dilation of smaller arterioles appears to be mediated by a 5-HT1-like receptor.

Vasopressin and autonomic mechanisms mediate cardiovascular actions of central serotonin

Intracerebroventricular administration of serotonin (5-HT) to conscious rats increases mean arterial pressure (MAP) and decreases heart rate. To determine the mechanisms involved, 5-HT (2.5 micrograms) was injected intracerebroventricularly into conscious rats pretreated with various neurotransmitter and hormone antagonists. The selective 5-HT2 antagonist LY 53857 abolished the increase in MAP and the bradycardia elicited by 5-HT. The increase in MAP produced by 5-HT was potentiated by chlorisondamine (a ganglionic antagonist), unaffected by prazosin (an alpha 1-antagonist) or a vasopressin V1 antagonist alone, but eliminated by the combined pretreatment with prazosin plus the vasopressin antagonist. In contrast, the bradycardia was eliminated by either the vasopressin V1 antagonist or chlorisondamine. In conclusion, 5-HT injected into the lateral cerebral ventricle of conscious rats induces sympathoexcitation and the release of vasopressin, which results in an increase in MAP; 5-HT also elicits a bradycardia mediated through an interaction of the autonomic nervous system with circulating vasopressin.