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1.
Front Neural Circuits ; 13: 73, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798420

RESUMO

The ventral tegmental area (VTA) reportedly regulates sleep and wakefulness through communication with the lateral hypothalamus (LH). It has also been suggested that adequate anesthesia produced by administration of chloral hydrate, ketamine, or halothane significantly reduces the GABAergic neuronal firing rate within the VTA. However, the exact effects on GABAergic neurons in the VTA and the mechanisms through which these neurons modulate anesthesia through associated neural circuits is still unclear. Here, we used optogenetic and chemogenetic methods to specifically activate or inhibit GABAergic neuronal perikarya in the VTA or their projections to the LH in Vgat-Cre mice. Electroencephalogram (EEG) spectral analyses and burst suppression ratio (BSR) calculations were conducted following administration of 0.8 or 1.0% isoflurane, respectively; and loss of righting reflex (LORR), recovery of righting reflex (RORR), and anesthesia sensitivity were assessed under 1.4% isoflurane anesthesia. The results showed that activation of GABAergic neurons in the VTA increased delta wave power from 40.0 to 46.4% (P = 0.006) and decreased gamma wave power from 15.2 to 11.5% (P = 0.017) during anesthesia maintenance. BSR was increased from 51.8 to 68.3% (P = 0.017). Induction time (LORR) was reduced from 333 to 290 s (P = 0.019), whereas arousal time (RORR) was prolonged from 498 to 661 s (P = 0.007). Conversely, inhibition of VTA GABAergic neurons led to opposite effects. In contrast, optical activation of VTA-LH GABAergic projection neurons increased power of slow delta waves from 44.2 to 48.8% (P = 0.014) and decreased that of gamma oscillations from 10.2 to 8.0%. BSR was increased from 39.9 to 60.2% (P = 0.0002). LORR was reduced from 330 to 232 s (P = 0.002), and RORR increased from 396 to 565 s (P = 0.007). Optical inhibition of the projection neurons caused opposite effects in terms of both the EEG spectrum and the BSR, except that inhibition of this projection did not accelerate arousal time. These results indicate that VTA GABAergic neurons could facilitate the anesthetic effects of isoflurane during induction and maintenance while postponing anesthetic recovery, at least partially, through modulation of their projections to the LH.


Assuntos
Anestesia Geral , Anestésicos Inalatórios/administração & dosagem , Neurônios GABAérgicos/fisiologia , Região Hipotalâmica Lateral/fisiologia , Isoflurano/administração & dosagem , Área Tegmentar Ventral/fisiologia , Animais , Eletroencefalografia , Neurônios GABAérgicos/efeitos dos fármacos , Região Hipotalâmica Lateral/efeitos dos fármacos , Camundongos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Optogenética , Área Tegmentar Ventral/efeitos dos fármacos
2.
Neuropsychopharmacol Rep ; 39(4): 289-296, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31618533

RESUMO

AIM: The lateral hypothalamus (LH) is known as the hunger center, but the mechanisms through which the LH regulates food intake are unclear. Since GABA neurons are reported to project to the LH, the present study investigated the role of GABAergic function in the LH in the regulation of feeding behavior. METHODS: GABA levels in the LH were measured by in vivo microdialysis. Food intake after drug injection into the LH was measured every 1 hour for 4 hours. The mRNA levels were measured using RT-PCR. RESULTS: Food intake significantly increased GABA levels in the LH, suggesting that food intake stimulates GABAergic function in the LH. Injection of the GABAA receptor agonist muscimol into the LH significantly inhibited food intake, whereas injection of the GABAA receptor antagonist bicuculline into the LH did not significantly affect food intake. The inhibitory effect of muscimol injected into the LH was blocked by co-administration of bicuculline. These results indicate that the stimulation of GABAA receptors in the LH inhibits food intake. We next examined whether the stimulation of GABAA receptors affects hypothalamic neuropeptides that are known to regulate feeding behavior. The injection of muscimol significantly decreased preproorexin mRNA in the hypothalamus. CONCLUSION: These results indicate that food intake activates GABAergic function in the LH, which terminates feeding behavior by stimulating GABAA receptors. Moreover, it is suggested that the stimulation of GABAA receptors in the LH reduces food intake through inhibition of orexin neurons.


Assuntos
Ingestão de Alimentos/fisiologia , Região Hipotalâmica Lateral/metabolismo , Orexinas/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Bicuculina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Microdiálise , Muscimol/farmacologia
3.
Biochem Biophys Res Commun ; 519(3): 547-552, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31537386

RESUMO

This study investigated dopaminergic function in the lateral hypothalamus (LH) in the regulation of feeding behavior. Refeeding increased dopamine levels in the LH. Glucose injection also increased dopamine levels in the LH. When the retrograde tracer Fluoro-Gold (FG) was injected into the LH, FG-positive cells were found in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNC), which were mostly tyrosine hydroxylase-positive. Injection of the dopamine D1 receptor agonist SKF 38393, but not the antagonist SCH 23390, into the LH increased food intake. Similarly, injection of the dopamine D2 receptor agonist quinpirole, but not the antagonist l-sulpiride, into the LH increased food intake. The effect of each agonist was blocked by its respective antagonist. Furthermore, injection of quinpirole, but not SKF 38393, decreased the mRNA level of preproorexin. In addition, injection of SKF 38393 decreased the mRNA levels of neuropeptide Y and agouti-related peptide, whereas the injection of quinpirole increased the mRNA level of proopiomelanocortin. These results indicate that food intake activates dopamine neurons projecting from the VTA/SNC to the LH through an increase in blood glucose levels, which terminates food intake by stimulation of dopamine D1 and D2 receptors. It is also possible that stimulation of dopamine D1 and D2 receptors in the LH inhibits feeding behavior through different neuropeptides.


Assuntos
Dopaminérgicos/farmacologia , Dopamina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Região Hipotalâmica Lateral/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Neuropeptídeos/farmacologia , Receptores de Dopamina D1/antagonistas & inibidores , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Agonistas de Dopamina/farmacologia , Região Hipotalâmica Lateral/metabolismo , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Quimpirol/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo
4.
Neuroreport ; 30(14): 927-932, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31469720

RESUMO

Propofol is widely used for induction and maintenance of anaesthesia, which causes a rapid loss of consciousness. So far the mechanisms underlying the effect of propofol are still largely unknown. Here, we found that microinjection of propofol in the lateral hypothalamus caused a significant decrease in wakefulness and an increase in the amount of non-rapid eye movement sleep and rapid eye movement sleep. Application of propofol in the lateral hypothalamus affected the electroencephalogram power spectra with a decrease in theta oscillations and an increase in the delta oscillations. Additionally, using whole-cell patch clamp recording, we found propofol inhibited the excitability of the GABAergic neurons in the lateral hypothalamus, which plays a critical role in controlling wakefulness. Altogether, these findings indicate that propofol targets lateral hypothalamus and generates a hypnotic state, which might involve the inhibition of GABAergic neurons. These results provide a novel mechanism to explain propofol-elicited anaesthesia.


Assuntos
Neurônios GABAérgicos/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Propofol/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos
5.
Biomed Res Int ; 2019: 2389485, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31346513

RESUMO

Acute alcohol exposure induces unconscious condition such as coma whose main physical manifestation is the loss of righting reflex (LORR). Xingnaojing Injection (XNJI), which came from Chinese classic formula An Gong Niu Huang Pill, is widely used for consciousness disorders in China, such as coma. Although XNJI efficiently shortened the duration of LORR induced by acute ethanol, it remains unknown how XNJI acts on ethanol-induced coma (EIC). We performed experiments to examine the effects of XNJI on orexin and adenosine (AD) signaling in the lateral hypothalamic area (LHA) in EIC rats. Results showed that XNJI reduced the duration of LORR, which implied that XNJI promotes recovery form coma. Microdialysis data indicated that acute ethanol significantly increased AD release in the LHA but had no effect on orexin A levels. The qPCR results displayed a significant reduction in the Orexin-1 receptors (OX1R) expression with a concomitant increase in the A1 receptor (A1R) and equilibrative nucleoside transporter type 1 (ENT1) expression in EIC rats. In contrast, XNJI reduced the extracellular AD levels but orexin A levels remained unaffected. XNJI also counteracted the downregulation of the OX1R expression and upregulation of A1R and ENT1 expression caused by EIC. As for ADK expression, XNJI but not ethanol, displayed an upregulation in the LHA in EIC rats. Based on these results, we suggest that XNJI promotes arousal by inhibiting adenosine neurotransmission via reducing AD level and the expression of A1R and ENT1.


Assuntos
Proteínas de Transporte/genética , Coma/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Receptor A1 de Adenosina/genética , Adenosina/genética , Adenosina/metabolismo , Animais , Coma/induzido quimicamente , Coma/genética , Coma/patologia , Transportador Equilibrativo 1 de Nucleosídeo , Etanol/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Receptores de Orexina/genética , Orexinas/genética , Orexinas/metabolismo , Ratos , Reflexo de Endireitamento/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética , Vigília/efeitos dos fármacos
6.
Life Sci ; 232: 116575, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31211999

RESUMO

AIMS: Maternal smoking is considered a risk factor for childhood obesity. In a rat model of tobacco exposure during breastfeeding, we previously reported hyperphagia, overweight, increased visceral fat and hyperleptinemia in adult female offspring. Obesity and eating disorders are associated with impairment in the endocannabinoid (EC) and dopaminergic (DA) systems. Considering that women are prone to eating disorders, we hypothesize that adult female Wistar rats that were exposed to cigarette smoke (CS) during the suckling period would develop EC and DA systems deregulation, possibly explaining the eating disorder in this model. MATERIAL AND METHODS: To mimic maternal smoking, from postnatal day 3 to 21, dams and offspring were exposed to a smoking machine, 4×/day/1 h (CS group). Control animals were exposed to ambient air. Offspring were evaluated at 26 weeks of age. KEY FINDINGS: Concerning the EC system, the CS group had increased expression of diacylglycerol lipase (DAGL) in the lateral hypothalamus (LH) and decreased in the liver. In the visceral adipose tissue, the EC receptor (CB1r) was decreased. Regarding the DA system, the CS group showed higher dopamine transporter (DAT) protein expression in the prefrontal cortex (PFC) and lower DA receptor (D2r) in the arcuate nucleus (ARC). We also assessed the hypothalamic leptin signaling, which was shown to be unchanged. CS offspring showed decreased plasma 17ß-estradiol. SIGNIFICANCE: Neonatal CS exposure induces changes in some biomarkers of the EC and DA systems, which can partially explain the hyperphagia observed in female rats.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Endocanabinoides/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Animais Recém-Nascidos , Fumar Cigarros , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Endocanabinoides/fisiologia , Feminino , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hipotálamo/metabolismo , Lactação/efeitos dos fármacos , Leptina/metabolismo , Lipase Lipoproteica/efeitos dos fármacos , Exposição Materna/efeitos adversos , Obesidade/etiologia , Obesidade/metabolismo , Ratos , Ratos Wistar , Receptores de Canabinoides/efeitos dos fármacos , Fumar , Tabaco
7.
Neuroscience ; 413: 86-98, 2019 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-31202706

RESUMO

Glutamate is the major excitatory neurotransmitter in the brain and plays an essential role in regulating wakefulness. Histaminergic neurons, which are exclusively localized in the tuberomammillary nucleus (TMN) of the hypothalamus, have a pivotal role in the regulation of sleep-wake patterns by sending widespread projections into many brain areas implicated in sleep-wake control. The role of glutamate in histaminergic neurons within the TMN and the resulting sleep-wake profile remains unknown. We found that glutamate, NMDA, AMPA or dihydrokainate, a glutamate-uptake inhibitor, dose-dependently increased wakefulness when microinjected into the rat TMN. Glutamate, NMDA, and AMPA also increased the firing rate of action potentials in TMN histaminergic neurons. The arousal-promoting effect of glutamate was inhibited by NMDA and histamine H1 receptor antagonists. Furthermore, MK-801, an NMDA receptor antagonist, inhibited the firing rate of histaminergic neurons and increased non-rapid eye movement sleep after microinjection into rat TMN. Taken together, these findings demonstrated that glutamate activated histaminergic neurons in the TMN and increased wakefulness in rats, possibly via the action of NMDA and histamine H1 receptors.


Assuntos
Ácido Glutâmico/farmacologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Receptores Histamínicos/metabolismo , Promotores da Vigília/farmacologia , Vigília/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Antagonistas dos Receptores Histamínicos H1/farmacologia , Região Hipotalâmica Lateral/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Sono/efeitos dos fármacos , Sono/fisiologia , Técnicas de Cultura de Tecidos , Vigília/fisiologia
8.
Eur Neuropsychopharmacol ; 29(5): 672-680, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30878320

RESUMO

The lateral hypothalamus (LH) has been described as one of the hypothalamic areas involved in the behavioral and physiological responses triggered by aversive stimuli. Previous studies indicated involvement of the LH in cardiovascular responses to stress. Despite this evidence, the local neurochemical mechanisms involved in LH control of stress responses is still poorly understood. Therefore, in the present study, we investigated the role of GABAergic neurotransmission within the LH in cardiovascular responses induced by an acute session of restraint stress in rats. For this, we evaluated the effect of bilateral microinjection of selective antagonists of either GABAA or GABAB receptors into the LH on arterial pressure increase, heart rate (HR) increase and reduction in tail skin temperature induced by restraint stress. We found that microinjection of the selective GABAA receptor antagonist SR95531 into the LH decreased the increase in HR caused by restraint stress, but without affecting the increase in arterial pressure increase or the reduction in tail skin temperature. Conversely, LH treatment with the selective GABAB receptor antagonist CGP35348 did not affect the restraint-evoked cardiovascular changes. These findings indicate that GABAergic neurotransmission in the LH, acting through activation of local GABAA receptors, plays a facilitatory role in the tachycardic response observed during aversive threats.


Assuntos
Região Hipotalâmica Lateral/metabolismo , Angústia Psicológica , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Estresse Psicológico/metabolismo , Taquicardia/metabolismo , Animais , Antagonistas GABAérgicos/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Microinjeções , Ratos , Ratos Wistar , Estresse Psicológico/psicologia , Taquicardia/psicologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-30885832

RESUMO

Mesotocin (MT) decreases food intake and induces hyperthermia in chicks although hypothalamic mechanisms are unknown. The purpose of this study was thus to investigate effects of receptor antagonists and MT on feeding behavior and hypothalamic physiology. Intracerebroventricular injection of 2.5 nmol into broiler chicks was associated with decreased food intake for 180 min and water intake from 60 to 180 min. Cloacal temperatures were elevated in chicks injected with 0.156 and 0.625 nmol at 30 and 60 min, and up to 180 min in those injected with 2.5 nmol. MT also increased temperatures and decreased food and water intake in chicks from lines selected for low (LWS) or high (HWS) body weight with a higher dose threshold but longer food intake response in HWS chicks. An oxytocin receptor antagonist prevented MT-mediated changes in food intake but not water intake or temperature. Yohimbine, an α2-adrenergic receptor antagonist, did not affect food intake, temperature, or MT-mediated effects. MT increased c-Fos immunoreactivity in the paraventricular nucleus (PVN) and lateral hypothalamus (LH). Hypothalamic agouti-related peptide, corticotropin-releasing factor receptor sub-type 1, and melanocortin receptor 3 mRNAs increased in response to MT. There was increased MT mRNA in the LH and L-aromatic amino acid decarboxylase mRNA in the PVN of MT-injected chicks. In conclusion, MT induced anorexia and hyperthermia and reduced water intake. MT was associated with activation of the PVN and LH and differences in the mRNA abundance of some appetite-associated factors, thus implicating these nuclei and several signaling pathways in the effects observed.


Assuntos
Anorexia/induzido quimicamente , Galinhas/genética , Região Hipotalâmica Lateral/efeitos dos fármacos , Ocitocina/análogos & derivados , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Animais , Descarboxilases de Aminoácido-L-Aromático/genética , Região Hipotalâmica Lateral/metabolismo , Ocitocina/farmacologia , RNA Mensageiro/metabolismo
10.
Neurochem Res ; 44(5): 1152-1158, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30877520

RESUMO

Role of the orexinergic system in pain modulation is well studied and involvement of the spinal orexin-1 receptors is well documented. In this study, we examined role of the spinal orexin-2 receptors in modulation of inflammatory pain in rat. Fifty-one adult male Wistar rats were implanted unilaterally with a guide cannula into the LH and intrathecal tubing in the lumbar space between L4 and L5. Chemical stimulation of LH by carbachol (250 nM/0.5 µL saline) induced remarkable analgesia during the two phases of formalin test and Intrathecal administration of different doses of TCS OX2 29 (10, 30 and 100 µM/ 0.5 µL DMSO) prior to LH stimulation, dose-dependently antagonized the antinociceptive effect of the LH-stimulation during the two phases of formalin test. The effect size of the TCS OX2 29 was η2 = 0.47 and η2 = 0. 87 for the early and late phases of the test, respectively. Also, intrathecal administration of TCS OX2 29 alone (without stimulation of the LH) had no significant effect on formalin induced pain-related behaviors. Our results showed that spinal orexin-2 receptors are involved in modulation of the LH-stimulation induced analgesia in a persistent inflammatory pain model. These findings may suggest spinal orexin-2 receptors in particular and the orexin system in general as a useful therapeutic target for treatment of chronic pains.


Assuntos
Analgesia , Região Hipotalâmica Lateral/efeitos dos fármacos , Receptores de Orexina/metabolismo , Orexinas/farmacologia , Dor/tratamento farmacológico , Animais , Carbacol/farmacologia , Masculino , Núcleo Accumbens/efeitos dos fármacos , Receptores de Orexina/efeitos dos fármacos , Medição da Dor , Ratos Wistar
11.
Gen Comp Endocrinol ; 279: 174-183, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30914266

RESUMO

OBJECTIVE: Cisplatin is an important antineoplastic drug and has side effects such as nausea, vomiting, and dyspepsia. The detailed mechanisms for its side effects are yet not well be illustrated. Our purpose was to investigate the discharges of gastric distention (GD) sensitive neurons regulated by ghrelin and electrical stimulation of the lateral hypothalamus area (LHA) via the dorsal vagal complex (DVC) in cisplatin-treated rats. MATERIALS AND METHODS: Extracellular discharge recording was performed to observe the effects of ghrelin and electrical stimulation of the LHA on discharges of GD neurons in the DVC. RESULTS: GD neurons were recorded in DVC in saline-treated and cisplatin-treated rats and identified as GD-excitatory (GD-E) neurons, which are excited by gastric distension, and GD-inhibitory (GE-I) neurons, which are inhibited by gastric distension. Microinjection of ghrelin into the DVC increased the firing frequency of most GD neurons, while the ratios of excited GD-E and GD-I neurons in cisplatin-treated rats were significantly lower than those in saline-treated rats. The excitatory effect of ghrelin was eliminated completely by DVC pretreatment with ghrelin receptor antagonist [D-Lys-3]-GHRP-6. After electrical stimulation of the LHA, the firing frequency of these neurons significantly increased. This excitatory effect was weaker in cisplatin-treated rats than in saline-treated rats and could be partly blocked by DVC pretreatment with [D-Lys-3]-GHRP-6. CONCLUSION: GD neurons in the DVC could be excited by microinjecting ghrelin into the DVC and electrical stimulation of the LHA, respectively. The excitatory effect was attenuated by cisplatin injected intraperitoneally.


Assuntos
Cisplatino/farmacologia , Grelina/farmacologia , Região Hipotalâmica Lateral/fisiologia , Neurônios/fisiologia , Estômago/inervação , Nervo Vago/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Estimulação Elétrica , Grelina/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Ratos Wistar , Receptores de Grelina/metabolismo , Nervo Vago/efeitos dos fármacos
12.
Neuropharmacology ; 154: 22-33, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30253175

RESUMO

The perifornical/lateral hypothalamic area (LHA) orexin (hypocretin) system is involved in drug-seeking behavior elicited by drug-associated stimuli. Cocaine exposure is associated with presynaptic plasticity at LHA orexin cells such that excitatory input to orexin cells is enhanced acutely and into withdrawal. These changes may augment orexin cell reactivity to drug-related cues during abstinence and contribute to relapse-like behavior. Studies in hypothalamic slices from drug-naïve animals indicate that agonism of group III metabotropic glutamate receptors (mGluRs) reduces presynaptic glutamate release onto orexin cells. Therefore, we examined the group III mGluR system as a potential target to reduce orexin cell excitability in-vivo, including in animals with cocaine experience. First, we verified that group III mGluRs regulate orexin cell activity in behaving animals by showing that intra-LHA infusions of the selective agonist L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4) reduces c-fos expression in orexin cells following 24 h food deprivation. Next, we extended these findings to show that intra-LHA L-AP4 infusions reduced discriminative stimulus-driven cocaine-seeking following withdrawal. Importantly, L-AP4 had no effect on lever pressing for sucrose pellets or general motoric behavior. Finally, using whole-cell patch-clamp recordings from identified orexin cells in orexin-GFP transgenic mice, we show enhanced presynaptic drive to orexin cells following 14d withdrawal and that this plasticity can be normalized by L-AP4. Together, these data indicate that activation of group III mGluRs in LHA reduces orexin cell activity in vivo and may be an effective strategy to suppress cocaine-seeking behavior following withdrawal. These effects are likely mediated, at least in part, by normalization of presynaptic plasticity at orexin cells that occurs as a result of cocaine exposure. This article is part of the Special Issue entitled 'Hypothalamic Control of Homeostasis'.


Assuntos
Comportamento Aditivo/metabolismo , Cocaína/administração & dosagem , Região Hipotalâmica Lateral/metabolismo , Orexinas/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Comportamento Aditivo/prevenção & controle , Região Hipotalâmica Lateral/efeitos dos fármacos , Locomoção/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microinjeções , Propionatos/administração & dosagem , Ratos , Receptores de Glutamato Metabotrópico/agonistas , Autoadministração
13.
Am J Physiol Regul Integr Comp Physiol ; 316(1): R68-R75, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30462527

RESUMO

Dopamine (DA) can promote or inhibit consummatory and reward-related behaviors by activating different receptor subtypes in the lateral hypothalamus and perifornical area (LH/PF). Because orexin neurons are involved in reward and localized in the LH/PF, DA may modulate these neurons to influence reward-related behaviors. To determine the cellular mechanism underlying dopaminergic modulation of orexin neurons, the effect of DA on excitatory transmission to these neurons was investigated using in vitro electrophysiology on rat brain slices. We found that low concentrations (0.1-1 µM) of DA increased evoked excitatory postsynaptic current amplitude while decreasing paired-pulse ratio. In contrast, high concentrations (10-100 µM) of DA did the opposite. The excitatory effect of low DA was blocked by the D1 receptor antagonist SCH-23390, whereas the inhibitory effect of high DA was blocked by the D2 receptor antagonist sulpiride. These results indicate distinct roles of D1 and D2 receptors in bidirectional presynaptic modulation of excitatory transmission. DA had stronger effects on isolated synaptic activity than repetitive ones, suggesting that sensitivity to dopaminergic modulation depends on the level of network activity. In orexin neurons from high-fat diet-fed rats, a high concentration of DA was less effective in suppressing repetitive synaptic activity compared with chow controls. Therefore, in diet-induced obesity, intense synaptic inputs may preferentially reach orexin neurons while intermittent signals are inhibited by high DA levels. In summary, our study provides a cellular mechanism by which DA may exert opposite behavioral effects in the LH/PF through bidirectional modulation of orexin neurons via different DA receptors.


Assuntos
Benzazepinas/farmacologia , Dopamina/farmacologia , Neurônios/efeitos dos fármacos , Orexinas/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Animais , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Receptores de Dopamina D1/efeitos dos fármacos , Transmissão Sináptica/fisiologia
14.
Respir Physiol Neurobiol ; 260: 122-130, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30471436

RESUMO

It has been shown that the lateral hypothalamus/perifornical area (LH/PFA) exerts an important role on arousal-state variations of the central chemoreflex, but the mechanisms that underlie LH/PFA chemoreception are poorly understood. Here we asked whether glutamate inputs on metabotropic receptors in the LH/PFA modulate the hypercapnic ventilatory response. We studied the effects of microinjection of a glutamate metabotropic receptor (mGluR) antagonist ((+)-α-Methyl-4-carboxyphenylglycine; MCPG; 100 mM) and a selective Group II/III mGluR antagonist ((2S)-2-Amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid; LY341495; 5 mM) into the LH/PFA of conscious rats on ventilation in room air and in 7% CO2, during wakefulness and sleep, in the dark and light periods of the diurnal cycle. Microinjection of MCPG and LY341495 increased the hypercapnic ventilatory response in both the light and the dark period during wakefulness, but not during sleep, (p < 0.001). Our data suggest that glutamate, acting on Group II/III metabotropic receptors in the LH/PFA, exerts an inhibitory modulation of the hypercapnic ventilatory response in awake rats.


Assuntos
Dióxido de Carbono/farmacologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Ventilação Pulmonar/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Aminoácidos/farmacologia , Animais , Eletroencefalografia , Eletromiografia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Masculino , Microdiálise , Microinjeções , Ratos , Ratos Wistar , Sono/efeitos dos fármacos , Volume de Ventilação Pulmonar/efeitos dos fármacos , Ventilação/métodos , Vigília/efeitos dos fármacos , Xantenos/farmacologia
15.
Exp Physiol ; 103(12): 1679-1691, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30242927

RESUMO

NEW FINDINGS: What is the central question of this study? ATP is known to modulate the chemosensitivity of some brain areas. However, whether the ATP contributes specifically to the mechanism of chemoreception in the lateral hypothalamus/perifornical area (LH/PFA) remains to be determined. What is the main finding and its importance? ATP, acting on the LH/PFA, enhances the hypercapnic ventilatory response in rats during wakefulness, in the dark period. Our results highlight the importance of ATP as a modulator of central chemoreception and provide new insight regarding the mechanisms involved in LH/PFA chemosensitivity and the sleep-wake differences in the CO2 /H+ -dependent drive to breathe. ABSTRACT: The lateral hypothalamus/perifornical area (LH/PFA) is a central chemoreceptor site, which acts in an arousal state-dependent manner. It has been shown that purinergic signalling through ATP influences the CO2 /H+ responsiveness of other chemosensitive regions, but it is unknown whether ATP is also involved in the mechanisms that underlie LH/PFA chemoreception. Here, we studied the effects of microdialysis of a P2X-receptor agonist [α,ß-methylene ATP (α,ß-meATP), 10 mm] and a non-selective P2-receptor antagonist [pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS), 1 mm] into the LH/PFA of conscious rats on ventilation in room air and in 7% CO2 . In the dark (active) phase, but not in the light, microdialysis of α,ß-meATP caused an augmented hypercapnic ventilatory response during wakefulness, but not during non-REM sleep (P < 0.001). PPADS caused no change in CO2 ventilatory responses in either the dark period or the light period. Our data suggest that ATP in LH/PFA contributes to the hypercapnic ventilatory response in conscious rats during wakefulness in the dark phase of the diurnal cycle.


Assuntos
Trifosfato de Adenosina/metabolismo , Dióxido de Carbono/metabolismo , Células Quimiorreceptoras/metabolismo , Região Hipotalâmica Lateral/metabolismo , Ventilação Pulmonar/fisiologia , Trifosfato de Adenosina/análogos & derivados , Animais , Células Quimiorreceptoras/efeitos dos fármacos , Hipercapnia/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Ventilação Pulmonar/efeitos dos fármacos , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , Ratos , Ratos Wistar , Respiração/efeitos dos fármacos , Sono/efeitos dos fármacos , Sono/fisiologia , Vigília/efeitos dos fármacos , Vigília/fisiologia
16.
Neuropharmacology ; 143: 327-338, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30219501

RESUMO

Histaminergic (HA) neurons located in the tuberomamillary nucleus (TMN) of the posterior hypothalamus fire exclusively during waking and support many physiological functions. We investigated the role of the endovanilloid N-oleoyldopamine (OLDA) in TMN, where dopamine synthesis and its conjugation with oleic acid likely occur. We show that several known targets of OLDA including TRPV1 and cannabinoid receptors are expressed in HA neurons. In contrast to capsaicin, which failed to increase firing of HA neurons in TRPV1 knockout mice (TRPVI KO), OLDA was still able to induce excitation. This excitation was not sensitive to the blockade of cannabinoid receptors 1 and 2 and could result from OLDA interaction with GPR119, as the ligand of GPR119, oleoylethanolamide (OEA), also increased the firing of HA neurons. However, we ruled out this possibility as OEA- (but not OLDA-) excitation was abolished by the PPAR (peroxisome proliferator activated receptor) alpha antagonist MK886. The dopamine uptake blocker nomifensine blanked OLDA-excitation and dopamine receptor antagonists abolished the OLDA action in TRPV1 KO mice. Therefore OLDA excites HA neurons through multiple targets suggesting a central role of the histaminergic system in the behavioral stimulation seen after systemic OLDA application.


Assuntos
Dopamina/análogos & derivados , Histamina/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Dopamina/farmacologia , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/crescimento & desenvolvimento , Região Hipotalâmica Lateral/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Técnicas de Cultura de Tecidos
17.
Neuropharmacology ; 139: 238-256, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29981758

RESUMO

The rat nucleus incertus (NI) contains GABA/peptide-projection neurons responsive to orexin (hypocretin)/orexin receptor-2 (OX2) signalling. Melanin-concentrating hormone (MCH) and orexin neurons often innervate and influence common target areas. Therefore, we assessed the relationship between these hypothalamic peptidergic systems and rat NI, by investigating the presence of an MCH innervation and MCH receptor-1 (MCH1) expression, and neurophysiological and behavioural effects of MCH c.f. orexin-A (OXA), within the NI. We identified lateral hypothalamus (LH), perifornical and sub-zona incerta MCH neurons that innervate NI, and characterised the rostrocaudal distribution of MCH-containing fibres in NI. Single-cell RT-PCR detected MCH1 and OX2 mRNA in NI, and multiplex, fluorescent in situ hybridisation revealed distinct co-expression patterns of MCH1 and OX2 mRNA in NI neurons expressing vesicular GABA transporter (vGAT) mRNA. Patch-clamp recordings revealed 34% of NI neurons tested were hyperpolarised by MCH (1 µM), representing a distinct population from OXA-sensitive NI neurons (35%). Intra-NI OXA infusion (600 pmol) in satiated rats during the light/inactive phase produced increased locomotor activity and food (standard chow) intake, whereas intra-NI MCH infusion (600 pmol) produced only a trend for decreased locomotor activity and no effect on food intake. Furthermore, in satiated or pre-fasted rats tested during the dark/active phase, intra-NI infusion of MCH did not alter the elevated locomotor activity or higher food intake observed. However, quantification of neuropeptide-immunostaining revealed differential diurnal fluctuations in orexin and MCH trafficking to NI. Our findings identify MCH and orexin inputs onto divergent NI populations which may differentially influence arousal and motivated behaviours.


Assuntos
Neurônios/citologia , Neurônios/metabolismo , Receptores de Orexina/metabolismo , Núcleos da Rafe/citologia , Núcleos da Rafe/metabolismo , Receptores do Hormônio Hipofisário/metabolismo , Animais , Nível de Alerta/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hormônios Hipotalâmicos/metabolismo , Masculino , Melaninas/metabolismo , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/efeitos dos fármacos , Orexinas/metabolismo , Hormônios Hipofisários/metabolismo , RNA Mensageiro/metabolismo , Núcleos da Rafe/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Wistar , Técnicas de Cultura de Tecidos , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo , Ácido gama-Aminobutírico/metabolismo
18.
Neuropeptides ; 69: 19-25, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29735274

RESUMO

Orexins are produced in the restricted regions of the lateral hypothalamus (LH). However, orexinergic receptors and projections are localized in wide regions like nucleus accumbens, ventral tegmental area, periaqueductal gray area and spinal cord which are involved in the pain modulation. This study was carried out to investigate the effects of intrathecal administration of orexin-1 receptor antagonist (SB-334867) in the spinal antinociception induced by intra-LH administration of carbachol (cholinergic receptor agonist) in both early and late phases of pain related behaviors in formalin test. In this study, pain-related behaviors (pain scores) were evaluated using the formalin test during 5-min block intervals for a 60-min period in seventy male Wistar rats were given SB-334867 (3, 10, 30 and 100 µM/10 µl) or vehicle (DMSO 12%; 10 µl) intrathecally following intra-LH administration of carbachol (250 nM/rat). Our data showed that intra-LH injection of carbachol attenuated the formalin-induced biphasic pain responses, and intrathecal administration of SB-334867 dose-dependently decreased LH stimulation-induced antinociceptive responses during both phases. Moreover, administration of different doses of SB-334867 during the early phase were more effective than those during the late phase. The antinociceptive role of orexinergic system in the formalin test through a neural pathway from the LH to the spinal cord provides evidence that orexins can be useful in therapeutic targets for pain relief.


Assuntos
Analgésicos/administração & dosagem , Região Hipotalâmica Lateral/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Antagonistas dos Receptores de Orexina/administração & dosagem , Receptores de Orexina/fisiologia , Dor/fisiopatologia , Medula Espinal/efeitos dos fármacos , Animais , Benzoxazóis/administração & dosagem , Região Hipotalâmica Lateral/fisiologia , Injeções Espinhais , Masculino , Naftiridinas , Dor/tratamento farmacológico , Medição da Dor , Ratos Wistar , Medula Espinal/fisiologia , Ureia/administração & dosagem , Ureia/análogos & derivados
19.
Behav Pharmacol ; 29(5): 437-444, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29521667

RESUMO

The present study investigated the effects of estradiol (E2) on ingestive behavior after activation of 5-HT1A receptors in the lateral hypothalamus (LH) of female rats habituated to eat a wet mash diet. Ovariectomized rats treated with corn oil (OVX) or estradiol cypionate (OVX+E) received local injections into the LH of vehicle or an agonist of 5-HT1A receptors, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT; at a dose of 6 nmol). To determine the involvement of these receptors in food intake, some animals were pretreated with N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY-100635, a 5-HT1A receptor full antagonist, at a dose of 0.37 nmol), followed by the injection of the agonist 8-OH-DPAT or its vehicle. The results showed that the injection of 8-OH-DPAT into the LH of OVX rats significantly increased food intake, and the duration and frequency of this behavior. The pretreatment with E2 suppressed the hyperphagic response induced by 8-OH-DPAT in OVX animals. The inhibition of 5-HT1A receptors after pretreatment with WAY-100635 blocked the hyperphagic effects evoked by 8-OH-DPAT in OVX. These results indicate that the activity of LH 5-HT1A receptors could be affected by blood E2 levels.


Assuntos
Estradiol/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/fisiologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Ingestão de Alimentos/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/metabolismo , Feminino , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hipotálamo/efeitos dos fármacos , Ovariectomia , Piperazinas , Piridinas , Ratos , Ratos Wistar , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
20.
CNS Neurol Disord Drug Targets ; 17(2): 106-112, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29542425

RESUMO

BACKGROUND & OBJECTIVE: Adult neurogenesis, a specific form of brain plasticity in mammals that occurs in the subventricular zone, is subject to complex regulation. Hypocretin/orexin neurons are implicated in the regulation of sleep and arousal states, among other functions. Here we report for the first time the presence of orexinergic projections within the adult rat subventricular zone. Post-mortem retrograde tracing combined with immunofluorescence indicated orexinergic projections toward the subventricular zone. To establish the relationship between the depletion of orexin neurons and the number of proliferating cells in the subventricular zone, we labeled mitotic cells. Histological analysis revealed proliferating cells to be in close contact with orexinergic fibers. Neurotoxinlesioning of orexin neurons in the lateral hypothalamus significantly activated precursor cell proliferation in the subventricular zone. Furthermore, cell proliferation in both normal and lesioned animals failed to reveal newly born orexin neurons in the lateral hypothalamus. CONCLUSION: Based on these findings, we suggest that the adult subventricular zone is affected by orexinergic signaling, the functional implication of which must be further elucidated.


Assuntos
Proliferação de Células , Ventrículos Laterais/citologia , Neurogênese/fisiologia , Neurônios/metabolismo , Orexinas/deficiência , Saporinas/deficiência , Animais , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/fisiologia , Masculino , Vias Neurais/fisiologia , Técnicas de Rastreamento Neuroanatômico , Neurogênese/efeitos dos fármacos , Ratos
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