Raphe pallidus neurons mediate prostaglandin E2-evoked increases in brown adipose tissue thermogenesis

To elucidate central neural pathways contributing to the febrile component of the acute phase response to pyrogenic insult, I sought to determine whether activation of neurons in the rostral raphe pallidus (RPa) is required for the increase in brown adipose tissue (BAT) thermogenesis evoked by i.c.v. prostaglandin E(2) (PGE(2)) in urethane-chloralose-anesthetized, ventilated rats. BAT sympathetic nerve activity (SNA; +224% of control), BAT temperature (+1.8 degrees C), expired CO(2) (+1.3%), mean arterial pressure (+23 mm Hg), and heart rate (+73 beats per minute) were significantly increased after i.c.v. PGE(2) (2 microg). Microinjection of either the GABA(A) receptor agonist, muscimol (2 mM, 60 nl), or glycine (0.5M, 60 nl) into RPa resulted in a prompt reversal of the PGE(2)-evoked stimulation of BAT SNA, BAT thermogenesis and heart rate, with these variables returning to control levels prior to i.c.v. PGE(2) following the long-lasting, muscimol-induced inhibition of RPa neurons. In conclusion, activation of neurons in RPa, possibly BAT sympathetic premotor neurons, is essential for the increases in BAT SNA and BAT thermogenesis stimulated by i.c.v. administration of PGE(2). The increased heart rate likely contributing to an augmented cardiac output supporting the increased BAT thermogenesis in response to PGE(2) is also dependent on neurons in RPa. These results contribute to our understanding of central neural substrates for the augmented thermogenesis during fever.     

Synergistic interactions between airway afferent nerve subtypes regulating the cough reflex in guinea-pigs

In urethane–chloralose anaesthetized, neuromuscularly blocked, artificially ventilated rats, we demonstrated that activation of carotid chemoreceptors inhibits the elevated levels of brown adipose tissue (BAT) sympathetic nerve activity (SNA) evoked by hypothermia, by microinjection of prostaglandin E₂ into the medial preoptic area or by disinhibition of neurones in the raphe pallidus area (RPa). Peripheral chemoreceptor stimulation with systemic administration of NaCN (50 μg in 0.1 ml) or with hypoxic ventilation (8% O₂–92% N₂, 30 s) completely inhibited BAT SNA. Arterial chemoreceptor-evoked inhibition of BAT SNA was eliminated by prior bilateral transections of the carotid sinus nerves or by prior inhibition of neurones within the commissural nucleus tractus solitarii (commNTS) with glycine (40 nmol/80 nl) or with the GABA_A receptor agonist muscimol (160 pmol/80 nl; 77 ± 10% attenuation), or by prior blockade of ionotropic excitatory amino acid receptors in the commNTS with kynurenate (8 nmol/80 nl; 82 ± 10% attenuation). Furthermore, activation of commNTS neurones following local microinjection of bicuculline (30 pmol/60 nl) completely inhibited the elevated level of BAT SNA resulting from disinhibition of neurones in the RPa. These results demonstrate that hypoxic stimulation of arterial chemoreceptor afferents leads to an inhibition of BAT SNA and BAT thermogenesis through an EAA-mediated activation of second-order, arterial chemoreceptor neurones in the commNTS. Peripheral chemoreceptor-evoked inhibition of BAT SNA could directly contribute to (or be permissive for) the hypoxia-evoked reductions in body temperature and oxygen consumption that serve as an adaptive response to decreased oxygen availability.     

Medullary pathways mediating specific sympathetic responses to activation of dorsomedial hypothalamus

We sought to determine which medullary sympathetic premotor neurons mediate the cardiovascular and thermogenic effects resulting from activation of neurons in the dorsomedial hypothalamus (DMH) in urethane/chloralose-anesthetized, artificially ventilated rats. Unilateral disinhibition of neurons in the DMH with microinjection of bicuculline (2 mM, 30 nl) caused significant increases in brown adipose tissue sympathetic nerve activity (BAT SNA, +828+/-169% of control, n=16), cardiac SNA (+516+/-82% of control, n=16), renal SNA (RSNA, +203+/-25% of control, n=28) and, accompanied by increases in BAT temperature (+1.6+/-0.3 degrees C, n=11), end-tidal CO(2) (+0.7+/-0.1%, n=15), heart rate (+113+/-7 beats/min, n=32), arterial pressure (+19+/-2 mm Hg, n=32) and plasma epinephrine and norepinephrine concentrations. Inhibition of neurons in the rostral raphe pallidus (RPa) with microinjection of muscimol (6 mM, 60 nl) abolished the increases in BAT SNA and BAT temperature and reduced the tachycardia induced by disinhibition of DMH neurons. Inhibition of neurons in the RVLM with microinjection of muscimol (6 mM, 60 nl) markedly reduced the increase in RSNA, but did not affect the evoked tachycardia or the increase in arterial pressure. Combined glutamic acid decarboxylase (GAD-67) immunocytochemistry and pseudorabies viral retrograde tracing from BAT indicated close appositions between GABAergic terminals and DMH neurons in sympathetic pathways to BAT. In conclusion, these results demonstrate the existence of a tonically active, GABAergic inhibitory input to neurons in the DMH and that blockade of this inhibition increases sympathetic outflow to thermogenic and cardiovascular targets by activating functionally specific populations of sympathetic premotor neurons: the excitation of BAT SNA and BAT thermogenesis is mediated through putative sympathetic premotor neurons in the RPa, while the activation in RSNA is dependent on those in RVLM. These data increase our understanding of the central pathways mediating changes in sympathetically mediated thermogenesis that is activated in thermoregulation, stress responses and energy balance.     

Serotonin potentiates sympathetic responses evoked by spinal NMDA

In urethane–chloralose anaesthetized, neuromuscularly blocked, ventilated rats, we examined the effects on sympathetic outflow to brown adipose tissue (BAT) of separate and simultaneous spinal microinjections of NMDA and serotonin. Microinjection of NMDA (12 pmol) into the right T4 spinal intermediolateral nucleus (IML) immediately increased ipsilateral brown adipose tissue (BAT) sympathetic nerve activity (SNA; peak: +546% of control), BAT thermogenesis (+0.8°C) and heart rate (+53 beats min⁻¹), whereas microinjection of a lower dose of NMDA (1.2 pmol) did not change any of the recorded variables. Microinjection of 5-hydroxytryptamine (5-HT, 2 nmol) into the T4 IML increased BAT SNA (peak: +342% of control) at a long latency (mean onset: 23min). The long latency 5-HT-evoked increase in BAT SNA was prevented by microinjection of methysergide (600 pmol) into the T4 IML. The increases in BAT SNA evoked by T4 IML microinjections of NMDA (12 pmol) were significantly potentiated (two to three times larger than the response to NMDA alone) following T4 IML microinjections of 5-HT (100 pmol to 2 nmol, but not 20 pmol). Also, microinjection of 5-HT (200 pmol) converted the subthreshold dose of NMDA (1.2 pmol) into an effective dose for increasing BAT SNA and heart rate. The 5-HT-mediated potentiation of the increase in BAT SNA evoked by microinjection of NMDA into the T4 IML was reversed by microinjection of methysergide (600 pmol) into the T4 IML. These results demonstrate that BAT SNA and thermogenesis can be driven by activation of spinal excitatory amino acid or 5-HT receptors and that concomitant activation of spinal NMDA and 5-HT receptors can act synergistically to markedly increase BAT SNA and thermogenesis.     

Preoptic mechanism for cold-defensive responses to skin cooling

We recently identified a somatosensory pathway that transmits temperature information from the skin to a median subregion of the preoptic area (POA), a thermoregulatory centre. Here, we investigated in vivo the local neuronal circuit in the rat POA that processes the thermosensory information and outputs thermoregulatory effector signals. Skin cooling-evoked increases in sympathetic thermogenesis in brown adipose tissue, in metabolism and in heart rate were reversed by inhibition of neurons in the median preoptic nucleus (MnPO). Glutamatergic stimulation or disinhibition of MnPO neurons evoked thermogenic, metabolic and cardiac responses that mimicked the cold-defensive responses to skin cooling and were reversed by antagonizing GABA_A receptors in the medial preoptic area (MPO), which is thought to contain neurons providing thermoregulatory output to effectors. These results suggest that GABA inhibition of output neurons in the MPO by MnPO neurons that are activated by cool sensory signals from the skin is a core thermoregulatory mechanism within the POA that is essential for the feedforward defence of body temperature against cold challenges in the environment.     

Microinjection of prostaglandin E2 and muscimol into the preoptic area in conscious rats: comparison of effects on plasma adrenocorticotrophic hormone (ACTH), body temperature, locomotor activity, and cardiovascular function

The preoptic area (POA) is thought to play an important role in thermoregulation and fever. Local application of prostaglandin E2 (PGE2) to this region elicits increases in core body temperature, heart rate, and plasma levels of adrenocorticotrophic hormone (ACTH). Similar effects on body temperature and heart rate have also been reported after local application of the GABAA receptor agonist muscimol to the preoptic area. The purpose of this study was to assess and compare the effects of microinjection of PGE2 and muscimol into the preoptic area in the same chronically instrumented conscious rats on plasma levels of ACTH. Injection of either PGE2 (150 pmol/100 nL) or muscimol (20 or 80 pmol/100 nL) into the same sites in the preoptic area evoked increases in body temperature, heart rate, blood pressure, and plasma levels of ACTH, while significant increases in locomotor activity were apparent only after muscimol. These data confirm and extend previous findings and support the notion that neurons in the region of the preoptic area exert tonic inhibition on downstream mechanisms capable of increasing the activity of the hypothalamic-pituitary-adrenal (HPA) axis as well as sympathetic thermogenic and cardiac activity.     

Prostaglandin E2 fever mediated by inhibition of the GABAergic transmission in the region immediately adjacent to the organum vasculosum of the lamina terminalis

Unilateral microinjection of prostaglandin (PG)E(2) into a region immediately adjacent to the organum vasculosum of the lamina terminalis (peri-OVLT) in the preoptic area elicited thermogenic, tachycardic, cutaneous vasoconstrictive, and hyperthermic responses simultaneously in urethane-chloralose-anesthetized rats. The magnitude of these responses increased dose-dependently over the range of 57 fmol-2.8 pmol, except for the vasoconstrictive response. Microinjection of a GABA(A) receptor antagonist, bicuculline methiodide or gabazine (5-20 pmol), into the PGE(2)-sensitive site in the peri-OVLT region also elicited responses similar to those induced by PGE(2). Although administration of a GABA(A) receptor agonist, muscimol (10 pmol), microinjected into the same site alone usually had no effect on the rate of whole-body O(2) consumption, heart rate or colon and skin temperatures, all PGE(2)-induced responses were blocked 10 min after the muscimol pretreatment and recovered at 50-90 min. Pretreatment with the vehicle, saline, had no effect on the PGE(2)-induced responses. These results suggest that spontaneous release of GABA and tonic activation of GABA(A) receptors in the peri-OVLT region prevent the elevation in the body core temperature under normal circumstances and that PGE(2)-induced febrile responses are mediated, at least in part, by inhibition of the GABAergic transmission in this area.     

Heat loss responses and blockade of prostaglandin E2-induced thermogenesis elicited by α1-adrenergic activation in the rostromedial preoptic area

The unilateral microinjection of noradrenaline (NA), but not vehicle solution, into the rostromedial preoptic area (POA) elicited simultaneous increases in cutaneous temperatures of the tail and sole of the foot and decreases in the whole-body O₂ consumption rate, heart rate, and colonic temperature in urethane–chloralose-anesthetized rats, suggesting a coordinate increase in heat loss and decrease in heat production. The magnitude of these responses increased dose-dependently over the range of 1–100 pmol, except for the metabolic and bradycardic responses. Similar hypothermic responses were elicited by the microinjection of 40 pmol methoxamine (an α₁-adrenergic agonist), but not by that of clonidine (an α₂-agonist) or isoproterenol (a β-agonist). Sites at which microinjection of NA elicited hypothermic responses were in the vicinity of the organum vasculosum of the lamina terminalis including the median preoptic nucleus, whereas no thermal or metabolic response was elicited when NA was microinjected into the lateral POA or caudal part of the medial POA. The microinjection of 130 fmol prostaglandin (PG) E₂ into the NA-sensitive site always elicited thermogenic, tachycardic, and hyperthermic responses. Furthermore, the PGE₂-induced febrile responses were greatly attenuated by prior administration of NA at the same site. These results demonstrate that NA in the rostromedial POA exerts α₁-adrenoceptor-mediated hypothermic effects and opposes PGE₂-induced fever.     

Hypothalamic neuronal histamine regulates sympathetic nerve activity and expression of uncoupling protein 1 mRNA in brown adipose tissue in rats

To clarify how hypothalamic neuronal histamine regulates peripheral energy expenditure, we investigated the effect of infusion of histamine into the third cerebral ventricle or discrete hypothalamic regions on sympathetic nerve activity and expression of uncoupling protein 1 (UCP1) mRNA in brown adipose tissue (BAT). Infusion of histamine (200 nmol) into the third cerebral ventricle of anesthetized rats significantly increased the electrophysiological activity of sympathetic nerves (P<0.01) and UCP1 mRNA expression in the BAT (P<0.05). Microinjection of histamine (10 nmol) into the paraventricular nucleus (PVN) and preoptic area (POA) produced similar significant increases in BAT sympathetic nerve activity (P<0.01 for each). By contrast, injection of histamine into the ventromedial hypothalamic nucleus or lateral hypothalamic area had no effect. We conclude that hypothalamic neuronal histamine may regulate energy expenditure in BAT through the activation of sympathetic nerves. The PVN and/or POA appear to be the principal hypothalamic sites that mediate the stimulatory effect of histamine on this efferent pathway.     

Central control of thermogenesis in mammals

Thermogenesis, the production of heat energy, is an essential component of the homeostatic repertoire to maintain body temperature in mammals and birds during the challenge of low environmental temperature and plays a key role in elevating body temperature during the febrile response to infection. The primary sources of neurally regulated metabolic heat production are mitochondrial oxidation in brown adipose tissue, increases in heart rate and shivering in skeletal muscle. Thermogenesis is regulated in each of these tissues by parallel networks in the central nervous system, which respond to feedforward afferent signals from cutaneous and core body thermoreceptors and to feedback signals from brain thermosensitive neurons to activate the appropriate sympathetic and somatic efferents. This review summarizes the research leading to a model of the feedforward reflex pathway through which environmental cold stimulates thermogenesis and discusses the influence on this thermoregulatory network of the pyrogenic mediator, prostaglandin E(2), to increase body temperature. The cold thermal afferent circuit from cutaneous thermal receptors ascends via second-order thermosensory neurons in the dorsal horn of the spinal cord to activate neurons in the lateral parabrachial nucleus, which drive GABAergic interneurons in the preoptic area to inhibit warm-sensitive, inhibitory output neurons of the preoptic area. The resulting disinhibition of thermogenesis-promoting neurons in the dorsomedial hypothalamus and possibly of sympathetic and somatic premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, activates excitatory inputs to spinal sympathetic and somatic motor circuits to drive thermogenesis.     

Involvement of the purinergic system in central cardiovascular modulation at the level of the nucleus ambiguus of anaesthetized rats

Anatomical studies have demonstrated the existence of purinergic P2 receptors in the nucleus ambiguus (NA), a site containing cardiac vagal motoneurons. However, very little is known about the functional role of these receptors in central cardiac vagal regulation. The aims of our study were to evaluate the following: (1) the blood pressure and heart rate responses following purinoceptor activation within the NA; (2) the role of purinoceptors and excitatory amino acid (EAA) receptors in mediating the cardiovascular responses evoked by ATP and L-glutamate stimulation of NA; and (3) the role of NA purinoceptors in mediating the cardiovascular responses of the Bezold-Jarisch reflex. In anaesthetized rats, microinjection of L-glutamate (5.0 nmol/50 nl) into the NA induced a marked and immediate onset bradycardia with minimal change in arterial pressure. Microinjection of ATP into the NA induced a dose-dependent (0.31-6.0 nmol/50 nl) bradycardia and pressor responses. It is noteworthy that the bradycardia occurred either before or simultaneously with a pressor response (when present), indicating that it was not a baroreceptor reflex mediated response due to the rise in arterial pressure. The pressor response was prevented by α(1)-adrenergic blockade with prazosin, whereas muscarinic blockade with methyl-atropine abolished the evoked bradycardia. Ipsilateral microinjection of PPADS (a P2 receptor antagonist; 500 pmol/100 nl) into the NA significantly attenuated the ATP-induced bradycardia but spared the pressor response. In contrast, PPADS in the NA had no effect on the L-glutamate-evoked bradycardic response. Ipsilateral injection of kynurenic acid (a non-selective EAA receptor antagonist; 10 nmol/50 nl) into the NA totally blocked the bradycardia induced by l-glutamate and partly attenuated the ATP induced bradycardia. Finally, both the depressor and the bradycardic responses of the Bezold-Jarisch reflex were attenuated significantly (P < 0.01 and P < 0.05, respectively) following bilateral microinjection of PPADS into the NA. These results identify ATP and purinergic P2 receptors within the ventrolateral medulla as excitatory to cardiovagal neurons. Additionally, our data show that P2 receptors within the ventrolateral medulla are integral to the cardiovascular responses of the Bezold-Jarisch reflex.     

Nitric oxide mediates noradrenaline-induced hypothermic responses and opposes prostaglandin E2-induced fever in the rostromedial preoptic area

Noradrenaline (NA) microinjected into the rostromedial preoptic area (POA) elicits heat loss responses and opposes prostaglandin E₂-induced fever. Here, I tested the hypothesis that local synthesis and release of nitric oxide (NO) mediates the NA-induced effects. The unilateral microinjection of the NO donor sodium nitroprusside (SNP, 8.4 nmol), but not that of saline solution, into the NA-sensitive site elicited an increase in tail skin temperature and decreases in the whole-body O₂ consumption rate, heart rate, and colonic temperature simultaneously in urethane–chloralose-anesthetized rats. Pretreatment with SNP greatly attenuated the thermogenic, tachycardic, and hyperthermic effects of prostaglandin E₂ (140 fmol) microinjected into the same site. Furthermore, the NA-induced hypothermic responses were largely blocked by a prior microinjection of an NO synthase inhibitor N^G-monomethyl-l-arginine (l-NMMA, 5 nmol), but not by that of its inactive enantiomer, N^G-monomethyl-d-arginine (d-NMMA, 5 nmol), at the same site. These results suggest that the hypothermic and antipyretic effects of NA are mediated by NO in the rostromedial POA.     

Activation of lateral hypothalamic neurons stimulates brown adipose tissue thermogenesis

The lateral hypothalamic area, containing orexin neurons, is involved in several aspects of autonomic regulation, including thermoregulation and energy expenditure. To determine if activation of lateral hypothalamic area neurons influences sympathetically-regulated thermogenesis in brown adipose tissue, we microinjected bicuculline (120 pmol, 60 nl, unilateral) into the lateral hypothalamic area in urethane/chloralose-anesthetized, artificially-ventilated rats. Disinhibition of neurons in lateral hypothalamic area evoked a significant increase (+1309%) in brown adipose tissue sympathetic nerve activity accompanied by parallel increases in brown adipose tissue temperature (+2.0 degrees C), in expired CO2 (+0.6%), in heart rate (+88 bpm) and in mean arterial pressure (+11 mm Hg). Subsequent microinjections of glycine (30 nmol, 60 nl) to inhibit local neurons in raphe pallidus or in dorsomedial hypothalamus or of glutamate receptor antagonists into dorsomedial hypothalamus promptly reversed the increases in brown adipose tissue sympathetic nerve activity, brown adipose tissue temperature and heart rate evoked by disinhibition of neurons in lateral hypothalamic area. We conclude that neurons in the lateral hypothalamic area can influence brown adipose tissue sympathetic nerve activity, brown adipose tissue thermogenesis and heart rate through pathways that are dependent on the activation of neurons in dorsomedial hypothalamus and raphe pallidus.     

Afferent connections of the caudal raphe pallidus nucleus in rats: a study using the fluorescent retrograde tracers fluorogold and true-blue

Afferent connections to the caudal region of the nucleus raphe pallidus (RPa) in rats were studied using fluorogold and true-blue as tracers. Due to its ability to produce limited injection sites, true-blue proved to be more appropriate than fluorogold for studying long distance connections in a narrow structure such as the RPa. Fluorescent, retrogradely-labeled perikarya were found in the preoptic area (median, medial and lateral nuclei), hypothalamus (anterior, dorsal, lateral and posterior areas, and the peri- and paraventricular nuclei), zona incerta, central gray (dorsal, ventral and ventro-lateral), reticular formation of the brainstem, trigeminal spinal nuclei and in the spinal cord (laminae V-X at thoracic, lumbar and sacral levels). This connection pattern suggests the involvement of the RPa in autonomic, somatic and endocrine functions.     

EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses

Fever is a result of the action of prostaglandin E2 (PGE2) on the brain and appears to require EP3 prostaglandin receptors (EP3Rs), but the specific neurons on which PGE2 acts to produce fever have not been definitively established. Here we report that selective genetic deletion of the EP3Rs in the median preoptic nucleus of mice resulted in abrogation of the fever response. These observations demonstrate that the EP3R-bearing neurons in the median preoptic nucleus are required for fever responses.     

Changes in cerebral cortex size are governed by fibroblast growth factor during embryogenesis

We show that fibroblast growth factor 2 (FGF2) and FGF receptors are transiently expressed by cells of the pseudostratified ventricular epithelium (PVE) during early neurogenesis. A single microinjection of FGF2 into cerebral ventricles of rat embryos at E15.5 increased the volume and total number of neurons in the adult cerebral cortex by 18% and 87%, respectively. Microinjection of FGF2 by the end of neurogenesis, at E20.5, selectively increased the number of glia. Mice lacking the FGF2 gene had fewer cortical neurons and glia at maturity. BrdU studies in FGF2-microinjected and FGF2-null animals suggested that FGF2 increases the proportion of dividing cells in the PVE without affecting the cell-cycle length. Thus, FGF2 increases the number of rounds of division of cortical progenitors.     

Modulation of tonic immobility in guinea pig PAG by homocysteic acid, a glutamate agonist

Tonic immobility (TI) is an innate defensive behavior elicited by physical restriction and postural inversion, and is characterized by a profound and temporary state of motor inhibition. The participation of the periaqueductal gray matter (PAG) in TI modulation has previously been described. In addition, the excitatory amino acids (EAA) are important mediators involved in the adjustment of several defensive responses produced by PAG. In the present study, we investigated the effect of microinjection of the EAA agonist dl-homocysteic acid (DLH) and the N-methyl-d-aspartate (NMDA) receptor antagonist (MK-801) into the ventrolateral and dorsal PAG over the duration of TI in guinea pigs. Microinjection of 15 nmol/0.2 microl of DLH into the ventrolateral PAG (vlPAG) and 30 nmol/0.2 microl of DLH into the dorsal PAG (dPAG) promoted an increase and decrease in TI duration, respectively. These responses were blocked by prior microinjection of the NMDA receptor antagonist, MK-801 (3.6 nmol/0.2 microl) at the same site. Microinjection of MK-801 alone into the vlPAG and dPAG did not alter the duration of TI episodes. These results suggest that NMDA receptors are involved in the modulation of TI in both the vlPAG and dPAG. In addition, PAG excitatory amino acids modulate the TI response via columnar organization of the PAG. In this manner, the vlPAG facilitates TI modulation whereas dPAG has an inhibitory role in TI.     

Tonic activity of alpha1 adrenergic receptors of the medial preoptic area contributes towards increased sleep in rats

Several studies have suggested that noradrenergic afferents to the medial preoptic area might be involved in hypnogenesis and in lowering the body temperature, and that the alpha1 adrenergic receptors might be mediating these responses. This study was undertaken to find out the changes in sleep-wakefulness and body temperature in rats, when these adrenergic receptors of the medial preoptic area are blocked by alpha1 selective antagonist, prazosin. Adult male Wistar rats were chronically implanted with electrooculogram, electroencephalogram and electromyogram electrodes for sleep-wakefulness assessment, and a bilateral guide cannula for microinjection of prazosin at the medial preoptic area. A radio-transmitter was implanted in the abdomen for telemetric measurement of body temperature in four groups of rats. Sleep-wakefulness was also assessed telemetrically in four other groups of rats. Sleep-wakefulness recordings from these rats were done in a specialized chamber, where they could move about freely and select the ambient temperature which they prefer. Prazosin induced a dose dependent increase in wake period and in body temperature, when microinjected into the medial preoptic area. Results suggest that preoptic alpha1 adrenergic receptors mediate hypnogenic and hypothermic responses. It is proposed that the noradrenergic afferents to the medial preoptic area, by tonic activation of alpha1 adrenergic receptors, contribute towards increase in sleep especially during the daytime.     

Cutaneous vasodilation elicited by disinhibition of the caudal portion of the rostral ventromedial medulla of the free-behaving rat

Putative sympathetic premotor neurons controlling cutaneous vasomotion are contained within the rostral ventromedial medulla (RVMM) between levels corresponding, rostrally, to the rostral portion of the nucleus of the facial nerve (RVMM(fn)) and, caudally, to the rostral pole of the inferior olive (RVMM(io)). Cutaneous vasoconstrictor premotor neurons in the RVMM(fn) play a major role in mediating thermoregulatory changes in cutaneous vasomotion that regulate heat loss. To determine the role of neurons in the RVMM(io) in regulating cutaneous blood flow, we examined the changes in the tail and paw skin temperature of free-behaving rats following chemically-evoked changes in the activity of neurons in the RVMM(io). Microinjection of the GABA_A agonist, muscimol, within either the RVMM(fn) or the RVMM(io) induced a massive peripheral vasodilation; microinjection of the GABA_A antagonist bicuculline methiodide within the RVMM(fn) reversed the increase in cutaneous blood flow induced by warm exposure and, unexpectedly, disinhibition of RVMM(io) neurons produced a rapid cutaneous vasodilation. We conclude that the tonically-active neurons driving cutaneous vasoconstriction, likely sympathetic premotor neurons previously described in the RVMM(fn), are also located in the RVMM(io). However, in the RVMM(io), these are accompanied by a population of neurons that receives a tonically-active GABAergic inhibition in the conscious animal and that promotes a cutaneous vasodilation upon relief of this inhibition. Whether the vasodilator neurons located in the RVMM(io) play a role in thermoregulation remains to be determined.     

Serotoninergic receptors in the anteroventral preoptic region modulate the hypoxic ventilatory response

Hypothalamus is a site of integration of the hypoxic and thermal stimuli on breathing and there is evidence that serotonin (5-HT) receptors in the anteroventral preoptic region (AVPO) mediate hypoxic hypothermia. Once 5-HT is involved in the hypoxic ventilatory response (HVR), we investigated the participation of the 5-HT receptors (5-HT1, 5-HT2 and 5-HT7) in the AVPO in the HVR. To this end, pulmonary ventilation (V(E)) of rats was measured before and after intra-AVPO microinjection of methysergide (a 5-HT1 and 5-HT2 receptor antagonist), WAY-100635 (a 5-HT1A receptor antagonist) and SB-269970 (a 5-HT7 receptor antagonist), followed by 60 min of hypoxia exposure (7% O2). Intra-AVPO microinjection of vehicles or 5-HT antagonists did not change V(E) during normoxic conditions. Exposure of rats to 7% O2 evoked typical hypoxia-induced hyperpnea after vehicle microinjection, which was not affected by methysergide. WAY-100635 and SB-269970 treatment caused an increased HVR, due to a higher tidal volume. Therefore, the current data provide the evidence that 5-HT acting on 5-HT1A and 5-HT7 receptors in the AVPO exert an inhibitory modulation on the HVR.