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1.
Am J Physiol Regul Integr Comp Physiol ; 321(6): R938-R950, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34704845

RESUMO

Systemic administration of dopamine (DA) receptor agonists leads to falls in body temperature. However, the central thermoregulatory pathways modulated by DA have not been fully elucidated. Here we identified a source and site of action contributing to DA's hypothermic action by inhibition of brown adipose tissue (BAT) thermogenesis. Nanoinjection of the type 2 and type 3 DA receptor (D2R/D3R) agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), in the rostral raphe pallidus area (rRPa) inhibits the sympathetic activation of BAT evoked by cold exposure or by direct activation of N-methyl-d-aspartate (NMDA) receptors in the rRPa. Blockade of D2R/D3R in the rRPa with nanoinjection of SB-277011A increases BAT thermogenesis, consistent with a tonic release of DA in the rRPa contributing to inhibition of BAT thermogenesis. Accordingly, D2Rs are expressed in cold-activated and serotonergic neurons in the rRPa, and anatomical tracing studies revealed that neurons in the posterior hypothalamus (PH) are a source of dopaminergic input to the rRPa. Disinhibitory activation of PH neurons with nanoinjection of gabazine inhibits BAT thermogenesis, which is reduced by pretreatment of the rRPa with SB-277011A. In conclusion, the rRPa, the site of sympathetic premotor neurons for BAT, receives a tonically active, dopaminergic input from the PH that suppresses BAT thermogenesis.


Assuntos
Tecido Adiposo Marrom/inervação , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Hipotálamo Posterior/metabolismo , Inibição Neural , Núcleo Pálido da Rafe/metabolismo , Termogênese , Animais , Agonistas de Dopamina/administração & dosagem , Neurônios Dopaminérgicos/efeitos dos fármacos , Antagonistas GABAérgicos/administração & dosagem , Hipotálamo Posterior/efeitos dos fármacos , Injeções , Masculino , Vias Neurais/metabolismo , Núcleo Pálido da Rafe/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Termogênese/efeitos dos fármacos
2.
Brain Res ; 1764: 147480, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33861997

RESUMO

It has been suggested that cannabis consumption during adolescence may be an initial step to cocaine use in adulthood. Indeed, previous preclinical data show that adolescent exposure to cannabinoids (both natural and synthetic) potentiates cocaine self-administration in rats. Here we aimed at gaining a deeper understanding of the cellular activation patterns induced by cocaine as revealed by Fos imaging and how these patterns may change due to adolescent exposure to THC. Male and female Wistar rats were administered every other day THC (3 mg/kg i.p.) or vehicle from postnatal day 28-44. At adulthood (PND90) they were given an injection of cocaine (20 mg/kg i.p.) or saline and sacrificed 90 min later. Cocaine-induced Fos activation was measured by immunohistochemistry as an index of cellular activation. We found that cocaine-induced activation in the motor cortex was stronger in THC-exposed rats. Moreover, there was significant sex-dependent interaction between cocaine and adolescent THC exposure in the dorsal hypothalamus, suggesting that cocaine induced a more robust cellular activation in THC-exposed females but not in THC-treated males. Other THC- and cocaine-induced effects were also evident. These results add to the previous literature suggesting that the behavioral, cellular, molecular, and brain-activating actions of cocaine are modulated by early experience with cannabinoids and provide additional knowledge that may explain the enhanced actions of cocaine in rats exposed to cannabinoids during their adolescence.


Assuntos
Química Encefálica/efeitos dos fármacos , Cocaína/farmacologia , Dronabinol/farmacologia , Genes fos/efeitos dos fármacos , Alucinógenos/farmacologia , Envelhecimento , Animais , Comportamento Animal/efeitos dos fármacos , Interações Medicamentosas , Feminino , Hipotálamo Posterior/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Córtex Motor/efeitos dos fármacos , Córtex Motor/metabolismo , Ratos , Ratos Wistar , Caracteres Sexuais
3.
Brain Res ; 1754: 147239, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33412148

RESUMO

Previously it was reported that central orexin (OX) and arachidonic acid (AA) signaling pathways played an active role in the control of the cardiovascular system. It was also reported that they have exhibited their cardiovascular control role by using similar central or peripheral mechanisms. However, there has been no study demonstrating the interaction between OX and AA signaling pathways in terms of cardiovascular control. The current study was designed to investigate the possible mediation of the central cyclooxygenase (COX) and lipoxygenase (LOX) pathways in OX-induced cardiovascular effects in the rats. Intracerebroventricular injection of OX increased blood pressure and heart rate in a dose-dependent manner in normotensive male Sprague Dawley rats. Moreover, the microdialysis study revealed that intracerebroventricular injected OX caused a time-dependent increase in the extracellular total prostaglandin concentrations in the posterior hypothalamus. Interestingly, central pretreatment with a non-selective COX inhibitor, ibuprofen, or a non-selective LOX inhibitor, nordihydroguaiaretic acid, partially reversed pressor and tachycardic cardiovascular responses evoked by central administration of OX. In summary, our findings show that the central treatment with OX causes pressor and tachycardic cardiovascular responses along with an increase in posterior hypothalamic extracellular total prostaglandin concentrations. Furthermore, our results also demonstrate that central COX and LOX pathways mediate, at least in part, centrally administered OX-evoked pressor and tachycardic responses, as well.


Assuntos
Ciclo-Oxigenase 2/efeitos dos fármacos , Lipoxigenases/efeitos dos fármacos , Orexinas/farmacologia , Vasoconstritores/farmacologia , Animais , Ácido Araquidônico/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/metabolismo , Ciclo-Oxigenase 2/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Hipotálamo Posterior/efeitos dos fármacos , Lipoxigenases/metabolismo , Masculino , Orexinas/metabolismo , Ratos Sprague-Dawley
4.
Psychoneuroendocrinology ; 119: 104720, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32563174

RESUMO

Anxiety disorders are among the most prevalent categories of mental illnesses. The gut-brain axis, along with gastrointestinally-derived neuropeptides, like glucagon-like peptide-1 (GLP-1), are emerging as potential key regulators of emotionality, including anxiety behavior. However, the neuroanatomical substrates from which GLP-1 exerts its anxiogenic effect remain poorly characterized. Here we focus on a relatively new candidate nucleus, the supramammillary nucleus (SuM), located just caudal to the lateral hypothalamus and ventral to the ventral tegmental area. Our focus on the SuM is supported by previous data showing expression of GLP-1R mRNA throughout the SuM and activation of the SuM during anxiety-inducing behaviors in rodents. Data show that chemogenetic activation of neurons in the SuM results in an anxiolytic response in male and female rats. In contrast, selective activation of SuM GLP-1R, by microinjection of a GLP-1R agonist exendin-4 into the SuM resulted in potent anxiety-like behavior, measured in both open field and elevated plus maze tests in male and female rats. This anxiogenic effect of GLP-1R activation persisted after high-fat diet exposure. Importantly, reduction of GLP-1R expression in the SuM, by AAV-shRNA GLP-1R knockdown, resulted in a clear anxiolytic response; an effect only observed in female rats. Our data identify a new neural substrate for GLP-1 control of anxiety-like behavior and indicate that the SuM GLP-1R are sufficient for anxiogenesis in both sexes, but necessary only in females.


Assuntos
Ansiedade/psicologia , Receptor do Peptídeo Semelhante ao Glucagon 1/fisiologia , Hipotálamo Posterior/fisiologia , Animais , Ansiedade/genética , Ansiedade/fisiopatologia , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Exenatida/farmacologia , Feminino , Técnicas de Silenciamento de Genes , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Hipotálamo Posterior/efeitos dos fármacos , Masculino , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos
5.
Neuroscience ; 409: 261-275, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30930128

RESUMO

Injection of the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHAL) into the rat rostral and caudal supramammillary nucleus (SUM) provided expected patterns of projections into the hippocampus and the septal region. In addition, unexpectedly intense projections were observed into the claustrum defined by parvalbumin expression. Injections of the retrograde tracer fluorogold (FG) into the hippocampus and the region of the claustrum showed that the cells of origin of these projections distributed similarly within the borders of the SUM. The SUM is usually involved in control of hippocampal theta activity, but the observation of intense projections into the claustrum indicates that it may also influence isocortical processes. Therefore, the SUM may coordinate sensory processing in the isocortex with memory formation in the hippocampus.


Assuntos
Claustrum/fisiologia , Hipotálamo Posterior/fisiologia , Neurônios/fisiologia , Animais , Claustrum/efeitos dos fármacos , Hipotálamo Posterior/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Técnicas de Rastreamento Neuroanatômico , Marcadores do Trato Nervoso/farmacologia , Neurônios/efeitos dos fármacos , Ratos
6.
Eur Neuropsychopharmacol ; 27(11): 1120-1131, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28939165

RESUMO

Acute γ-aminobutyric acid (GABA) disinhibition in the posterior hypothalamus (PH) elicits defensive reactions that are considered anxiety- and panic attack-like behaviour, and these defensive reactions are followed by antinociception. Evidence indicates that the PH connects with the medial prefrontal cortex, particularly the anterior cingulate cortex (ACC), which seems to regulate these unconditioned fear-induced defensive responses. However, few studies have shown the participation of cortical regions in the control of behavioural and antinociceptive responses organised by diencephalic structures. It has been suggested that the glutamatergic system can mediate this cortical influence, as excitatory imbalance is believed to play a role in both defensive mechanisms. Thus, the aim of the present study was to investigate the involvement of ACC glutamatergic connections via blockade of local N-methyl-D-aspartate (NMDA) receptors to elaborate panic-like defensive behaviours and unconditioned fear-induced antinociception organised by PH neurons. Wistar rats were treated with microinjections of 0.9% NaCl or LY235959 (a selective NMDA receptor antagonist) in the ACC at different concentrations (2, 4 and 8 nmol/0.2µL), followed by GABAA receptor blockade in the PH. Defensive reactions were analysed for 20min, and the nociceptive threshold was then measured at 10-min intervals for 60min. Pretreatment of the ACC with LY235959 reduced both panic-like defensive behaviour and fear-induced antinociception evoked by PH GABAergic disinhibition. Our findings suggest that ACC NMDA receptor-signalled glutamatergic inputs play a relevant role in the organisation of anxiety- and panic attack-like behaviours and in fear-induced antinociception.


Assuntos
Reação de Fuga/fisiologia , Medo/fisiologia , Giro do Cíngulo/metabolismo , Hipotálamo Posterior/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/fisiologia , Análise de Variância , Animais , Bicuculina/análogos & derivados , Bicuculina/farmacologia , Relação Dose-Resposta a Droga , Reação de Fuga/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo/efeitos dos fármacos , Antagonistas de Receptores de GABA-A/farmacologia , Giro do Cíngulo/efeitos dos fármacos , Hipotálamo Posterior/efeitos dos fármacos , Isoquinolinas/farmacologia , Masculino , Microinjeções , Medição da Dor , Pânico/efeitos dos fármacos , Pânico/fisiologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
7.
Brain Struct Funct ; 222(1): 113-129, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-26951288

RESUMO

Previous studies from our group have shown that cytotoxic lesions in the ventral portion of the anteromedial thalamic nucleus (AMv), one of the main targets of the hypothalamic predator-responsive circuit, strongly impairs contextual fear responses to an environment previously associated with a predator. The AMv is in a position to convey information to cortico-hippocampal-amygdalar circuits involved in the processing of fear memory. However, it remains to be determined whether the nucleus is involved in the acquisition or subsequent expression of contextual fear. In the present investigation, we addressed this question by inactivating the rat AMv with muscimol either prior to cat exposure or prior to exposure to the cat-related context. Accordingly, AMv pharmacological inactivation prior to cat exposure did not interfere with innate fear responses, but it drastically reduced contextual conditioning to the predator-associated environment. On the other hand, AMv inactivation prior to exposure to the environment associated with the predator threat did not affect contextual fear responses. The behavioral results were further supported by the demonstration that AMv inactivation prior to cat exposure also blocked the activation of sites critically involved in the expression of anti-predatory contextual defensive responses (i.e., the dorsal premammillary nucleus and the dorsolateral periaqueductal gray) in animals exposed to the predator-associated context. The AMv projections were also examined, and the results of this investigation outline important paths that can influence hippocampal circuitry and raise new ideas for anterior thalamic-hippocampal paths involved in emotional learning.


Assuntos
Núcleos Anteriores do Tálamo/fisiologia , Medo/fisiologia , Memória/fisiologia , Animais , Núcleos Anteriores do Tálamo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Gatos , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Medo/efeitos dos fármacos , Agonistas de Receptores de GABA-A/administração & dosagem , Hipotálamo Posterior/efeitos dos fármacos , Hipotálamo Posterior/fisiologia , Masculino , Memória/efeitos dos fármacos , Muscimol/administração & dosagem , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/fisiologia , Comportamento Predatório , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar
8.
J Neurosurg ; 126(4): 1158-1164, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27341042

RESUMO

OBJECTIVE Deep brain stimulation (DBS) of the posterior hypothalamus (PH) has been reported to be effective for aggressive behavior in a number of isolated cases. Few of these case studies have analyzed single-unit recordings in the human PH and none have quantitatively analyzed single units in the red nucleus (RN). The authors report on the properties of ongoing neuronal discharges in bilateral trajectories targeting the PH and the effectiveness of DBS of the PH as a treatment for aggressive behavior. METHODS DBS electrodes were surgically implanted in the PH of 1 awake patient with Sotos syndrome and 3 other anesthetized patients with treatment-resistant aggressivity. Intraoperative extracellular recordings were obtained from the ventral thalamus, PH, and RN and analyzed offline to discriminate single units and measure firing rates and firing patterns. Target location was based on the stereotactic coordinates used by Sano et al. in their 1970 study and the location of the dorsal border of the RN. RESULTS A total of 138 units were analyzed from the 4 patients. Most of the PH units had a slow, irregular discharge (mean [± SD] 4.5 ± 2.7 Hz, n = 68) but some units also had a higher discharge rate (16.7 ± 4.7 Hz, n = 15). Two populations of neurons were observed in the ventral thalamic region as well, one with a high firing rate (mean 16.5 ± 6.5 Hz, n = 5) and one with a low firing rate (mean 4.6 ± 2.8 Hz, n = 6). RN units had a regular firing rate with a mean of 20.4 ± 9.9 Hz and displayed periods of oscillatory activity in the beta range. PH units displayed a prolonged period of inhibition following microstimulation compared with RN units that were not inhibited. Patients under anesthesia showed a trend for lower firing rates in the PH but not in the RN. All 4 patients displayed a reduction in their aggressive behavior after surgery. CONCLUSIONS During PH DBS, microelectrode recordings can provide an additional mechanism to help identify the PH target and surrounding structures to be avoided such as the RN. PH units can be distinguished from ventral thalamic units based on their response to focal microstimulation. The RN has a characteristic higher firing rate and a pattern of beta oscillations in the spike trains. The effect of the anesthetic administered should be considered when using microelectrode recordings. The results of this study, along with previous reports, suggest that PH DBS may be an effective treatment for aggression.


Assuntos
Agressão/fisiologia , Estimulação Encefálica Profunda , Hipotálamo Posterior/fisiopatologia , Neurônios/fisiologia , Núcleo Rubro/fisiopatologia , Potenciais de Ação/efeitos dos fármacos , Adolescente , Anestesia , Criança , Feminino , Humanos , Hipotálamo Posterior/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Núcleo Rubro/efeitos dos fármacos , Síndrome de Sotos/fisiopatologia , Síndrome de Sotos/terapia , Técnicas Estereotáxicas , Resultado do Tratamento , Adulto Jovem
9.
Neuropharmacology ; 113(Pt A): 367-385, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27717879

RESUMO

The medial prefrontal cortex can influence unconditioned fear-induced defensive mechanisms organised by diencephalic neurons that are under tonic GABAergic inhibition. The posterior hypothalamus (PH) is involved with anxiety- and panic attack-like responses. To understand this cortical mediation, our study characterised anterior cingulate cortex (ACC)-PH pathways and investigated the effect of ACC local inactivation with lidocaine. We also investigated the involvement of PH ionotropic glutamate receptors in the defensive behaviours and fear-induced antinociception by microinjecting NBQX (an AMPA/kainate receptor antagonist) and LY235959 (a NMDA receptor antagonist) into the PH. ACC pretreatment with lidocaine decreased the proaversive effect and antinociception evoked by GABAA receptor blockade in the PH, which suggests that there may be descending excitatory pathways from this cortical region to the PH. Microinjections of both NBQX and LY235959 into the PH also attenuated defensive and antinociceptive responses. This suggests that the blockade of AMPA/kainate and NMDA receptors reduces the activity of glutamatergic efferent pathways. Both inputs from the ACC to the PH and glutamatergic hypothalamic short links disinhibited by intra-hypothalamic GABAA receptors blockade are potentially implicated. Microinjection of a bidirectional neurotracer in the PH showed a Cg1-PH pathway and PH neuronal reciprocal connections with the periaqueductal grey matter. Microinjections of an antegrade neurotracer into the Cg1 showed axonal fibres and glutamatergic vesicle-immunoreactive terminal boutons surrounding both mediorostral-lateroposterior thalamic nucleus and PH neuronal perikarya. These data suggest a critical role played by ACC-PH glutamatergic pathways and AMPA/kainate and NMDA receptors in the panic attack-like reactions and antinociception organised by PH neurons.


Assuntos
Medo/fisiologia , Giro do Cíngulo/fisiologia , Hipotálamo Posterior/fisiologia , Medição da Dor/métodos , Dor/prevenção & controle , Animais , Bicuculina/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Medo/efeitos dos fármacos , Medo/psicologia , Giro do Cíngulo/efeitos dos fármacos , Hipotálamo Posterior/efeitos dos fármacos , Masculino , Microinjeções , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Dor/psicologia , Medição da Dor/efeitos dos fármacos , Quinoxalinas/administração & dosagem , Ratos , Ratos Wistar
10.
Neuropharmacology ; 110(Pt A): 396-406, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27496691

RESUMO

The obesity epidemic continues unabated and currently available pharmacological treatments are not sufficiently effective. Combining gut/brain peptide, GLP-1, with estrogen into a conjugate may represent a novel, safe and potent, strategy to treat diabesity. Here we demonstrate that the central administration of GLP-1-estrogen conjugate reduced food reward, food intake, and body weight in rats. In order to determine the brain location of the interaction of GLP-1 with estrogen, we avail of single-photon emission computed tomography imaging of regional cerebral blood flow and pinpoint a brain site unexplored for its role in feeding and reward, the supramammillary nucleus (SUM) as a potential target of the conjugated GLP-1-estrogen. We confirm that conjugated GLP-1 and estrogen directly target the SUM with site-specific microinjections. Additional microinjections of GLP-1-estrogen into classic energy balance controlling nuclei, the lateral hypothalamus (LH) and the nucleus of the solitary tract (NTS) revealed that the metabolic benefits resulting from GLP-1-estrogen injections are mediated through the LH and to some extent by the NTS. In contrast, no additional benefit of the conjugate was noted on food reward when the compound was microinjected into the LH or the NTS, identifying the SUM as the only neural substrate identified here to underlie the reward reducing benefits of GLP-1 and estrogen conjugate. Collectively we discover a surprising neural substrate underlying food intake and reward effects of GLP-1 and estrogen and uncover a new brain area capable of regulating energy balance and reward.


Assuntos
Peso Corporal/fisiologia , Estrogênios/metabolismo , Alimentos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipotálamo Posterior/metabolismo , Recompensa , Animais , Mapeamento Encefálico , Fármacos do Sistema Nervoso Central/farmacologia , Circulação Cerebrovascular/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Estrogênios/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Hipotálamo Posterior/diagnóstico por imagem , Hipotálamo Posterior/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Motivação/efeitos dos fármacos , Motivação/fisiologia , Ratos Sprague-Dawley , Tomografia Computadorizada de Emissão de Fóton Único
11.
Auton Autacoid Pharmacol ; 36(1-2): 3-13, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27555117

RESUMO

In a rat model, the baroreceptor reflex can be assessed by graded infusions of either phenylephrine or sodium nitroprusside with continuous hemodynamic monitoring. Microinjection of the cholinergic agonist carbachol (CCh) into the posterior hypothalamic nucleus (PHN) evokes an increase in mean arterial pressure and a change in heart rate. Lower doses of CCh evoke only tachycardia, whereas middle and higher doses evoke a biphasic change in heart rate of tachycardia followed by bradycardia. The bradycardia following the microinjection of CCh into the PHN can be attenuated by the previous administration of the vasopressin V1 receptor antagonist [d(CH2 )5 Tyr(Me)] arginine vasopressin (AVPX). Circulating arginine vasopressin (AVP) has been shown to increase the sensitivity of the baroreceptor reflex by stimulating vasopressin V1 receptors in the area postrema. The attenuation by AVPX of the bradycardia that results following the high doses of CCh suggests that AVP is released into the circulation following stimulation of cholinergic systems within the PHN. Thus, microinjection of a high dose of CCh (11 nmol) into the PHN alters the sensitivity of the baroreceptor reflex by increasing peripheral levels of AVP.


Assuntos
Barorreflexo/fisiologia , Carbacol/administração & dosagem , Agonistas Colinérgicos/administração & dosagem , Hipotálamo Posterior/fisiologia , Microinjeções , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hipotálamo Posterior/efeitos dos fármacos , Masculino , Microinjeções/métodos , Ratos , Ratos Sprague-Dawley
12.
Eur J Neurosci ; 44(6): 2324-33, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27421240

RESUMO

Data obtained in in vitro experiments and urethane anaesthetized animals have revealed that the mechanisms responsible for the generation of hippocampal cholinergic theta rhythm are specifically affected by the administration of broad spectrum gap junctions (GJs) blocker - carbenoxolone (CBX). The aim of this study was to examine the effect of GJs modulation on the production of posterior hypothalamic theta. Specifically, we were interested in evaluating whether CBX could attenuate the theta rhythm recorded from the supramammillary nucleus and posterior hypothalamic nuclei, in both in vitro and in vivo preparations. The data we obtained from in vitro and in vivo preparations demonstrated that the administration of CBX did not suppress cholinergically induced theta in posterior hypothalamic area (PHa) slices nor the theta rhythm observed in the PHa of urethane anaesthetized rats. Moreover, the application of trimethylamine, while very effective in the enhancement of hippocampal theta rhythm, did not produce any changes in theta oscillations observed in either in vitro or in vivo posterior hypothalamic area preparations. These data show that electrical coupling via GJs is not involved in theta rhythm generation in the PHa. Surprisingly, we observed a significant enhancement of theta activity in response to the carbenoxolone administration in both in vitro and in vivo PHa preparations. The theta rhythm enhancement detected in those experiments was attenuated by the application of spironolactone (mineralocorticoid receptors antagonist). We suggest that the observed excitatory effects of CBX on posterior hypothalamic oscillatory activity in the theta band could be mediated by mineralocorticoid receptors.


Assuntos
Hipotálamo Posterior/fisiologia , Ritmo Teta , Animais , Carbenoxolona/farmacologia , Junções Comunicantes/efeitos dos fármacos , Hipotálamo Posterior/efeitos dos fármacos , Masculino , Ratos , Receptores de Mineralocorticoides/metabolismo , Ritmo Teta/efeitos dos fármacos
13.
Brain Res ; 1646: 551-559, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27353451

RESUMO

The theta rhythm discovered in the posterior hypothalamus area (PHa) differs from theta observed in the hippocampal formation. In comparison to hippocampal spontaneous theta, the theta recorded in the PHa is rarely registered, has lower amplitude, often disappears, and sometimes returns after a few minutes. These features indicate that spontaneous theta recorded in the PHa is not an appropriate experimental model to search for the correlation between PHa cell discharges and local field potential. In this paper we present standard experimental conditions necessary to record theta-related cells in the PHa in anesthetized rats. Three pharmacological agents were used in the experiments to induce PHa theta rhythm in urethanized rats: carbachol (CCH), carbenoxolone and kainic acid, which are potent enough to induce well-synchronized PHa theta. However, CCH was found to be the best pharmacological tool to induce PHa theta oscillations, due to its longest duration of action and lack of preliminary epileptogenic effects. It seems that CCH-induced theta can be the most suitable pharmacological model for experiments with the use of protocol of long-lasting recordings of PHa theta-related cell discharges.


Assuntos
Potenciais de Ação , Hipotálamo Posterior/fisiologia , Neurônios/fisiologia , Ritmo Teta , Potenciais de Ação/efeitos dos fármacos , Animais , Carbacol/administração & dosagem , Carbenoxolona/administração & dosagem , Agonistas Colinérgicos/administração & dosagem , Eletroencefalografia , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Hipotálamo Posterior/efeitos dos fármacos , Ácido Caínico/administração & dosagem , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Ritmo Teta/efeitos dos fármacos
14.
Hippocampus ; 26(10): 1354-69, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27326660

RESUMO

Kowalczyk et al. (Hippocampus 2014; 24:7-20) were probably the first to conduct a systemic study of posterior hypothalamic area (PHa) theta rhythm in anesthetized rats. They demonstrated that local PHa theta field potentials were tail-pinch resistant and could be generated in urethane-anesthetized rats independently of ongoing hippocampal formation theta rhythm. These in vivo data were also confirmed in PHa slice preparations perfused with cholinergic agonist, carbachol. In the current experiments we extend our earlier observations concerning PHa theta rhythm. Specifically, PHa field potentials were analyzed in relation to the ongoing local cell firing repertoire. Single-unit discharge patterns of cells localized in the posterior hypothalamic and supramammillary nuclei were characterized according to the criteria that was developed previously to classify theta-related cells in the hippocampal formation. The present study demonstrated that in addition to the earlier described theta-related cells (theta-on, theta-off and gating cells) the PHa also contains cells discharging in a very regular manner, which were labelled "timing cells". This type of neuron has not been previously documented. We suggest that "timing cells" form a part of the ascending brainstem synchronizing pathway, provideing a regular rhythmic signal which facilitates the transduction of tonic discharges of cells localized in the brain stem into theta-frequency rhythmic discharges. © 2016 Wiley Periodicals, Inc.


Assuntos
Potenciais de Ação/fisiologia , Hipotálamo Posterior/fisiologia , Neurônios/fisiologia , Ritmo Teta/fisiologia , Potenciais de Ação/efeitos dos fármacos , Anestesia , Animais , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Eletrocorticografia , Hipotálamo Posterior/efeitos dos fármacos , Masculino , Microeletrodos , Neurônios/efeitos dos fármacos , Ratos Wistar , Ritmo Teta/efeitos dos fármacos , Técnicas de Cultura de Tecidos
15.
Sci Rep ; 6: 20206, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26831220

RESUMO

Corticotropin releasing factor (CRF), a peptide hormone involved in the stress response, holds a key position in cardiovascular regulation. Here, we report that the central effect of CRF on cardiovascular activities is mediated by the posterior hypothalamic nucleus (PH), an important structure responsible for stress-induced cardiovascular changes. Our present results demonstrate that CRF directly excites PH neurons via two CRF receptors, CRFR1 and CRFR2, and consequently increases heart rate (HR) rather than the mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). Bilateral vagotomy does not influence the tachycardia response to microinjection of CRF into the PH, while ß adrenergic receptor antagonist propranolol almost totally abolishes the tachycardia. Furthermore, microinjecting CRF into the PH primarily increases neuronal activity of the rostral ventrolateral medulla (RVLM) and rostral ventromedial medulla (RVMM), but does not influence that of the dorsal motor nucleus of the vagus nerve (DMNV). These findings suggest that the PH is a critical target for central CRF system in regulation of cardiac activity and the PH-RVLM/RVMM-cardiac sympathetic nerve pathways, rather than PH-DMNV-vagus pathway, may contribute to the CRF-induced tachycardia.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Hipotálamo Posterior/citologia , Hipotálamo Posterior/metabolismo , Neurônios/metabolismo , Taquicardia/etiologia , Taquicardia/metabolismo , Animais , Pressão Sanguínea , Hormônio Liberador da Corticotropina/farmacologia , Expressão Gênica , Frequência Cardíaca , Hipotálamo Posterior/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/inervação , Masculino , Bulbo/efeitos dos fármacos , Bulbo/metabolismo , Microinjeções , Neurônios/efeitos dos fármacos , Ratos , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Sistema Nervoso Simpático , Taquicardia/fisiopatologia , Vagotomia
16.
Exp Physiol ; 100(6): 617-27, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25809871

RESUMO

NEW FINDINGS: What is the central question of this study? Does ex vivo administration of endothelin-1 and endothelin-3 regulate noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate-salt hypertensive rats compared with normotensive rats? What is the main finding and its importance? Endothelin-1 and endothelin-3 enhanced diverse mechanisms leading to increased noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate-salt hypertensive rats. Unveiling the role of brain endothelins in hypertension would probably favour the development of new therapeutic targets for the treatment of essential hypertension, which still represents a challenging disease with high mortality. Brain catecholamines participate in diverse biological functions regulated by the hypothalamus. We have previously reported that endothelin-1 and endothelin-3 (ET-1 and ET-3) modulate catecholaminergic activity in the anterior and posterior hypothalamus of normotensive rats. The aim of the present study was to evaluate the interaction between endothelins and noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We assessed the effects of ET-1 and ET-3 on tyrosine hydroxylase activity and expression, neuronal noradrenaline (NA) release, neuronal NA transporter (NAT) activity and expression, monoamine oxidase activity and NA endogenous content and utilization (as a marker of turnover) in the posterior hypothalamus of DOCA-salt hypertensive rats. In addition, levels of ETA and ETB receptors were assayed in normotensive and hypertensive rats. Results showed that tyrosine hydroxylase activity and total and phosphorylated levels, NAT activity and content, NA release, monoamine oxidase activity and NA utilization were increased in DOCA-salt rats. Both ET-1 and ET-3 further enhanced all noradrenergic parameters except for total tyrosine hydroxylase level and NA endogenous content and utilization. The expression of ETA receptors was increased in the posterior hypothalamus of DOCA-salt rats, but ETB receptors showed no changes. These results show that ET-1 and ET-3 upregulate noradrenergic activity in the posterior hypothalamus of DOCA-salt hypertensive rats. Our findings suggest that the interaction between noradrenergic transmission and the endothelinergic system in the posterior hypothalamus may be involved in the development and/or maintenance of hypertension in this animal model.


Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Acetato de Desoxicorticosterona , Endotelina-1/administração & dosagem , Endotelina-3/administração & dosagem , Hipertensão/metabolismo , Hipotálamo Posterior/efeitos dos fármacos , Norepinefrina/metabolismo , Cloreto de Sódio na Dieta , Transmissão Sináptica/efeitos dos fármacos , Neurônios Adrenérgicos/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Hipotálamo Posterior/metabolismo , Hipotálamo Posterior/fisiopatologia , Masculino , Monoaminoxidase/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Fosforilação , Ratos Sprague-Dawley , Receptor de Endotelina A/efeitos dos fármacos , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/efeitos dos fármacos , Receptor de Endotelina B/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
17.
Auton Neurosci ; 187: 63-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25468497

RESUMO

Histamine, acting centrally as a neurotransmitter, evokes a reversal of hemorrhagic hypotension in rats due to the activation of the sympathetic and the renin-angiotensin systems as well as the release of arginine vasopressin and proopiomelanocortin-derived peptides. We demonstrated previously that central nicotinic cholinergic receptors are involved in the pressor effect of histamine. The aim of the present study was to examine influences of centrally administrated histamine on acetylcholine (ACh) release at the posterior hypothalamus-a region characterized by location of histaminergic and cholinergic neurons involved in the regulation of the sympathetic activity in the cardiovascular system-in hemorrhage-hypotensive anesthetized rats. Hemodynamic and microdialysis studies were carried out in Sprague-Dawley rats. Hemorrhagic hypotension was induced by withdrawal of a volume of 1.5 ml blood/100 g body weight over a period of 10 min. Acute hemorrhage led to a severe and long-lasting decrease in mean arterial pressure (MAP), heart rate (HR), and an increase in extracellular posterior hypothalamic ACh and choline (Ch) levels by 56% and 59%, respectively. Intracerebroventricularly (i.c.v.) administered histamine (50, 100, and 200 nmol) dose- and time-dependently increased MAP and HR and caused an additional rise in extracellular posterior hypothalamic ACh and Ch levels at the most by 102%, as compared to the control saline-treated group. Histamine H1 receptor antagonist chlorpheniramine (50 nmol; i.c.v.) completely blocked histamine-evoked hemodynamic and extracellular posterior hypothalamic ACh and Ch changes, whereas H2 and H3/H4 receptor blockers ranitidine (50 nmol; i.c.v.) and thioperamide (50 nmol; i.c.v.) had no effect. In conclusion, centrally administered histamine, acting via H1 receptors, increases ACh release at the posterior hypothalamus and causes a pressor and tachycardic response in hemorrhage-hypotensive anesthetized rats.


Assuntos
Acetilcolina/metabolismo , Hemorragia , Agonistas dos Receptores Histamínicos/uso terapêutico , Histamina/uso terapêutico , Hipotensão/complicações , Hipotálamo Posterior/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Clorfeniramina/farmacologia , Colina/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Hemorragia/patologia , Antagonistas dos Receptores Histamínicos/farmacologia , Hipotálamo Posterior/metabolismo , Masculino , Microdiálise , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
18.
Respir Physiol Neurobiol ; 205: 66-76, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25448396

RESUMO

To investigate the role of posterior hypothalamus and central neurotransmitters in the pulmonary edema due to hypobaric hypoxia, rats were placed in a high altitude simulation chamber (barometric pressure-294.4 mmHg) for 24 h. Exposure to hypobaric hypoxia resulted in increases in mean arterial blood pressure, renal sympathetic nerve activity, right ventricular systolic pressure, lung wet to dry weight ratio and Evans blue dye leakage. There was a significant attenuation in these responses to hypobaric hypoxia (a) after lesioning posterior hypothalamus and (b) after chronic infusion of GABAA receptor agonist muscimol into posterior hypothalamus. No such attenuation was evident with the chronic infusion of the nitric oxide donor SNAP into the posterior hypothalamus. It is concluded that in hypobaric hypoxia, there is over-activity of posterior hypothalamic neurons probably due to a local decrease in GABA-ergic inhibition which increases the sympathetic drive causing pulmonary hypertension and edema.


Assuntos
Doença da Altitude/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Hipotálamo Posterior/fisiopatologia , Hipóxia/fisiopatologia , Animais , Modelos Animais de Doenças , Agonistas de Receptores de GABA-A/farmacologia , Hipotálamo Posterior/efeitos dos fármacos , Masculino , Muscimol/farmacologia , Doadores de Óxido Nítrico/farmacologia , Edema Pulmonar/fisiopatologia , Ratos , Ratos Wistar , S-Nitroso-N-Acetilpenicilamina/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia
19.
Am J Physiol Regul Integr Comp Physiol ; 307(6): R704-10, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25031227

RESUMO

Histamine neurons are active during waking and largely inactive during sleep, with minimal activity during rapid-eye movement (REM) sleep. Caffeine, the most widely used stimulant, causes a significant increase of sleep onset latency in rats and humans. We hypothesized that caffeine increases glutamate release in the posterior hypothalamus (PH) and produces increased activity of wake-active histamine neurons. Using in vivo microdialysis, we collected samples from the PH after caffeine administration in freely behaving rats. HPLC analysis and biosensor measurements showed a significant increase in glutamate levels beginning 30 min after caffeine administration. Glutamate levels remained elevated for at least 140 min. GABA levels did not significantly change over the same time period. Histamine level significantly increased beginning 30 min after caffeine administration and remained elevated for at least 140 min. Immunostaining showed a significantly elevated number of c-Fos-labeled histamine neurons in caffeine-treated rats compared with saline-treated animals. We conclude that increased glutamate levels in the PH activate histamine neurons and contribute to caffeine-induced waking and alertness.


Assuntos
Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Ácido Glutâmico/metabolismo , Liberação de Histamina/efeitos dos fármacos , Hipotálamo Posterior/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Técnicas Biossensoriais , Cromatografia Líquida de Alta Pressão , Hipotálamo Posterior/metabolismo , Masculino , Microdiálise , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Vigília/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo
20.
Eur J Neurosci ; 40(2): 2344-51, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24862453

RESUMO

Research suggests a causal link between estrogens and mood. Here, we began by examining the effects of estradiol (E2 ) on rat innate and conditioned defensive behaviors in response to cat odor. Second, we utilized whole-cell patch clamp electrophysiological techniques to assess noradrenergic effects on neurons within the dorsal premammillary nucleus of the hypothalamus (PMd), a nucleus implicated in fear reactivity, and their regulation by E2 . Our results show that E2 increased general arousal and modified innate defensive reactivity to cat odor. When ovariectomized females treated with E2 as opposed to oil were exposed to cat odor, they showed elevations in risk assessment and reductions in freezing, indicating a shift from passive to active coping. In addition, animals previously exposed to cat odor showed clear cue + context conditioning 24 h later. However, although E2 persisted in its effects on general arousal in the conditioning task, its effects on fear disappeared. In the patch clamp experiments noradrenergic compounds that typically induce fear clearly excited PMd neurons, producing depolarizations and action potentials. E2 treatment shifted some excitatory effects of noradrenergic agonists to inhibitory, possibly by differentially affecting α- and ß-adrenoreceptors. In summary, our results implicate E2 in general arousal and fear reactivity, and suggest these may be governed by changes in noradrenergic responsivity in the PMd. These effects of E2 may have ethological relevance, serving to promote mate seeking even in contexts of ambiguous threat and shed light on the involvement of estrogen in mood and its associated disorders.


Assuntos
Ansiedade/metabolismo , Estradiol/farmacologia , Estrogênios/farmacologia , Medo , Hipotálamo Posterior/fisiologia , Potenciais de Ação , Agonistas Adrenérgicos/farmacologia , Animais , Ansiedade/fisiopatologia , Condicionamento Clássico , Feminino , Hipotálamo Posterior/efeitos dos fármacos , Ratos , Ratos Long-Evans
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