RESUMO
Memory retrieval can become difficult over time, but it is important to note that memories that appear to be forgotten might still be stored in the brain, as shown by their occasional spontaneous retrieval. Histamine in the central nervous system is a promising target for facilitating the recovery of memory retrieval. Our previous study demonstrated that histamine H3 receptor (H3R) inverse agonists/antagonists, activating histamine synthesis and release, enhance activity in the perirhinal cortex and help in retrieving forgotten long-term object recognition memories. However, it is unclear whether enhancing histaminergic activity alone is enough for the recovery of memory retrieval, considering that H3Rs are also located in other neuron types and affect the release of multiple neurotransmitters. In this study, we employed a chemogenetic method to determine whether specifically activating histamine neurons in the tuberomammillary nucleus facilitates memory retrieval. In the novel object recognition test, control mice did not show a preference for objects based on memory 1 week after training, but chemogenetic activation of histamine neurons before testing improved memory retrieval. This selective activation did not affect the locomotor activity or anxiety-related behavior. Administering an H2R antagonist directly into the perirhinal cortex inhibited the recovery of memory retrieval induced by the activation of histamine neurons. Furthermore, we utilized the Barnes maze test to investigate whether chemogenetic activation of histamine neurons influences the retrieval of forgotten spatial memories. Control mice explored all the holes in the maze equally 1 week after training, whereas mice with chemogenetically activated histamine neurons spent more time around the target hole. These findings indicate that chemogenetic activation of histamine neurons in the tuberomammillary nucleus can promote retrieval of seemingly forgotten object recognition and spatial memories.
Assuntos
Histamina , Neurônios , Animais , Histamina/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Masculino , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos Endogâmicos C57BL , Camundongos , Ansiedade/fisiopatologia , Região Hipotalâmica Lateral/fisiologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Antagonistas dos Receptores H2 da Histamina/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologiaRESUMO
Despite the therapeutic potential of chemogenetics, the method lacks comprehensive preclinical validation, hindering its progression to human clinical trials. We aimed to validate a robust but simple in vivo efficacy assay in rats which could support chemogenetic drug discovery by providing a quick, simple and reliable animal model. Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation. Subcutaneous deschloroclozapine in rats transfected with AAV9 resulted in a substantial reduction of food-intake, comparable to the efficacy of exenatide. We estimated that the effect of deschloroclozapine lasts 1-3 h post-administration. AAV5, oral administration of deschloroclozapine, and clozapine-N-oxide were also effective but with slightly less potency. The strongest effect on food-intake occurred within the first 30 min after re-feeding, suggesting this as the optimal experimental endpoint. This study demonstrates that general chemogenetic silencing of the LH can be utilized as an optimal, fast and reliable in vivo experimental model for conducting preclinical proof-of-concept studies in order to validate the in vivo effectiveness of novel chemogenetic treatments. We also hypothesize based on our results that universal LH silencing with existing and human translatable genetic neuroengineering techniques might be a viable strategy to affect food intake and influence obesity.
Assuntos
Clozapina , Dependovirus , Ingestão de Alimentos , Região Hipotalâmica Lateral , Estudo de Prova de Conceito , Animais , Clozapina/análogos & derivados , Clozapina/farmacologia , Ratos , Ingestão de Alimentos/efeitos dos fármacos , Região Hipotalâmica Lateral/efeitos dos fármacos , Dependovirus/genética , Masculino , Exenatida/farmacologia , HumanosRESUMO
Parkinson's Disease (PD) patients experience sleeping disorders in addition to the disease-defining symptomology of movement dysfunctions. The prevalence of PD is sex-based and presence of sleeping disorders in PD also shows sex bias with a stronger phenotype in males. In addition to loss of dopamine-containing neurons in the striatum, arousal-related, orexin-containing neurons in the lateral hypothalamus (LH) are lost in PD, which could contribute to state-related disorders. As orexin has been shown to be involved in sleeping disorders and to have neuroprotective effects, we asked whether orexin could protect sleep-related LH neurons from damage putatively from the protein α-synuclein (α-syn), which is found at high levels in the PD brain and that we have shown is associated with putatively excitotoxic rises in intracellular calcium in brainstem sleep-controlling nuclei, especially in males. Accordingly, we monitored intracellular calcium transients induced by α-syn and whether concurrent exposure to orexin affected those transients in LH cells of the mouse brain slice using calcium imaging. Further, we used an assay of cell death to determine whether LH cell viability was influenced when α-syn and orexin were co-applied when compared to exposure to α-syn alone. We found that excitatory calcium events induced by α-syn were reduced in amplitude and frequency when orexin was co-applied, and when data were evaluated by sex, this effect was found to be greater in females. In addition, α-syn exposure was associated with cell death that was higher in males, and interestingly, reduced cell death was noted when orexin was present, which did not show a sex bias. We interpret our findings to indicate that orexin is protective to α-syn-mediated damage to hypothalamic neurons, and the actions of orexin on α-syn-induced cellular effects differ between sexes, which could underlie sex-based differences in sleeping disorders in PD.
Assuntos
Cálcio , Morte Celular , Região Hipotalâmica Lateral , Neurônios , Orexinas , alfa-Sinucleína , Animais , Orexinas/metabolismo , Orexinas/farmacologia , Masculino , Camundongos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Feminino , Região Hipotalâmica Lateral/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , alfa-Sinucleína/metabolismo , Morte Celular/efeitos dos fármacos , Cálcio/metabolismo , Camundongos Endogâmicos C57BL , Caracteres SexuaisRESUMO
Excessive consumption of palatable foods that are rich in fats and sugars has contributed to the increasing prevalence of obesity worldwide. Similar to addictive drugs, such foods activate the brain's reward circuit, involving mesolimbic dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and the prefrontal cortex. Neuroadaptations occurring in this circuit are hypothesized to contribute to uncontrolled consumption of such foods, a common feature of most of eating disorders and obesity. The rostromedial tegmental nucleus (RMTg), also named tail of the VTA (tVTA), is an inhibitory structure projecting to the VTA and the lateral hypothalamus (LH), two key brain regions in food intake regulation. Prior research has demonstrated that the RMTg responds to addictive drugs and influences their impact on mesolimbic activity and reward-related behaviors. However, the role of the RMTg in food intake regulation remains largely unexplored. The present study aimed to investigate the role of the RMTg and its projections to the VTA and the LH in regulating food intake in rats. To do so, we examined eating patterns of rats with either bilateral excitotoxic lesions of the RMTg or specific lesions of RMTg-VTA and RMTg-LH pathways. Rats were exposed to a 6-week 'free choice high-fat and high-sugar' diet, followed by a 4-week palatable food forced abstinence and a 24 h re-access period. Our results indicate that an RMTg-VTA pathway lesion increases fat consumption following 6 weeks of diet and at time of re-access. The RMTg-LH pathway lesion produces a milder effect with a decrease in global calorie intake. These findings suggest that the RMTg influences palatable food consumption and relapse through its projections to the VTA.
Assuntos
Área Tegmentar Ventral , Animais , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Ingestão de Alimentos/fisiologia , Região Hipotalâmica Lateral/fisiologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Gorduras na Dieta , Vias Neurais/fisiologia , Vias Neurais/efeitos dos fármacos , Recompensa , Comportamento Alimentar/fisiologia , Comportamento Alimentar/efeitos dos fármacosRESUMO
Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine's food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.
Assuntos
Fármacos Antiobesidade , Compostos Bicíclicos Heterocíclicos com Pontes , Neurônios GABAérgicos , Obesidade , Animais , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Ratos , Camundongos , Fármacos Antiobesidade/farmacologia , Masculino , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Camundongos Transgênicos , Redução de Peso/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
The adipocyte-derived hormone, leptin, plays a key role in the maintenance of energy homeostasis. Leptin binds to the long form of its receptor, which is predominantly expressed in various hypothalamic regions, including the lateral hypothalamic area (LH) and supraoptic nucleus (SO). Several studies have suggested that leptin directly activates neuronal nitric oxide synthase, leading to increased nitric oxide production. We used histochemistry for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) as a marker for nitric oxide synthase activity and assessed the effect of leptin on nitrergic neurons in the LH and SO of rats. We found that intraperitoneal administration of leptin led to a significant increase in the number of NADPH-d-positive neurons in the LH and SO. In addition, the intensity (optical density) of NADPH-d staining in LH and SO neurons was significantly elevated in rats that received leptin compared with saline-treated rats. These findings suggest that nitrergic neurons in the LH and SO may be implicated in mediating the central effects of leptin.
Assuntos
Região Hipotalâmica Lateral , Leptina , Neurônios Nitrérgicos , Núcleo Supraóptico , Animais , Leptina/farmacologia , Leptina/metabolismo , Masculino , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Ratos , Núcleo Supraóptico/efeitos dos fármacos , Núcleo Supraóptico/metabolismo , Neurônios Nitrérgicos/efeitos dos fármacos , Neurônios Nitrérgicos/metabolismo , NADPH Desidrogenase/metabolismo , Ratos Wistar , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Sprague-DawleyRESUMO
Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain. We have previously shown that glucoprivation, induced by an anti-glycolygic agent 2-deoxy-D-glucose (2DG), activates perifornical lateral hypothalamus (PeFLH) neurons and that expression of NPY in the VLM CA/NPY neurons is required for glucoprivic feeding. We therefore hypothesized that glucoprivic feeding and possibly other CRRs require NPY-sensitive PeFLH neurons. To test this, we used the ribosomal toxin conjugate NPY-saporin (NPY-SAP) to selectively lesion NPY receptor-expressing neurons in the PeFLH of male rats. We found that NPY-SAP destroyed a significant number of PeFLH neurons, including those expressing orexin, but not those expressing melanin-concentrating hormone. The PeFLH NPY-SAP lesions attenuated 2DG-induced feeding but did not affect 2DG-induced increase in locomotor activity, sympathoadrenal hyperglycemia, or corticosterone release. The 2DG-induced feeding response was also significantly attenuated in NPY-SAP-treated female rats. Interestingly, PeFLH NPY-SAP lesioned male rats had reduced body weights and decreased dark cycle feeding, but this effect was not seen in female rats. We conclude that a NPY projection to the PeFLH is necessary for glucoprivic feeding, but not locomotor activity, hyperglycemia, or corticosterone release, in both male and female rats.
Assuntos
Comportamento Alimentar , Hipotálamo , Neurônios , Neuropeptídeo Y , Ratos Sprague-Dawley , Animais , Feminino , Masculino , Ratos , Desoxiglucose/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Glucose/metabolismo , Região Hipotalâmica Lateral/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Melaninas/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neuropeptídeo Y/metabolismo , Neuropeptídeo Y/farmacologia , Neuropeptídeos/metabolismo , Orexinas/metabolismo , Hormônios Hipofisários/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Receptores de Neuropeptídeo Y/genética , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Saporinas/farmacologiaRESUMO
The lateral hypothalamus (LH) sends neural pathways to structures involved on predatorrelated defensive behaviours, escape and antinociception. The aim of this study was to investigate the role played by µ-opioid receptors located on LH neurons in defensive behaviour and unconditioned fearinduced antinociception elicited by electric stimulation of LH. To achieve the goals, the µ1-opioid receptor selective antagonist naloxonazine was administered at different concentrations in the LH, and the defensive behaviour and fearinduced antinociception elicited by electrical stimulation of LH were evaluated. The electrical stimulation of LH caused escape behaviour followed by defensive antinociception. Microinjections of naloxonazine in a concentration of 5.0 µg/0.2 µL in the LH decreased the aversive stimulusinduced escape behaviour thresholds, but diminished defensive antinociception. These findings suggest that µ-opioid receptors of LH can be critical to panic attackrelated symptoms and facilitate the unconditioned fearinduced antinociception produced by LH neurons activation.
Assuntos
Comportamento Animal , Região Hipotalâmica Lateral , Transtorno de Pânico , Receptores Opioides mu , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Bicuculina/farmacologia , Medo/fisiologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Naloxona/análogos & derivados , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Nociceptividade , Pânico/fisiologia , Transtorno de Pânico/metabolismo , Transtorno de Pânico/psicologia , Ratos , Ratos Wistar , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/metabolismoRESUMO
The endocannabinoid neurotransmission acting via local CB1 receptor in the bed nucleus of the stria terminalis (BNST) has been implicated in behavioral and physiological responses to emotional stress. However, the neural network related to this control is poorly understood. In this sense, the lateral hypothalamus (LH) is involved in stress responses, and BNST GABAergic neurons densely innervate this hypothalamic nucleus. However, a role of BNST projections to the LH in physiological responses to stress is unknown. Therefore, using male rats, we investigated the role of LH GABAergic neurotransmission in the regulation of cardiovascular responses to stress by CB1 receptors within the BNST. We observed that microinjection of the selective CB1 receptor antagonist AM251 into the BNST decreased the number of Fos-immunoreactive cells within the LH of rats submitted to acute restraint stress. Treatment of the BNST with AM251 also enhanced restraint-evoked tachycardia. Nevertheless, arterial pressure increase and sympathetically-mediated cutaneous vasoconstriction to restraint was not affected by CB1 receptor antagonism within the BNST. The effect of AM251 in the BNST on restraint-evoked tachycardia was abolished in animals pretreated with the selective GABAA receptor antagonist SR95531 in the LH. These results indicate that regulation of cardiovascular responses to stress by CB1 receptors in the BNST is mediated by GABAergic neurotransmission in the LH. Present data also provide evidence of the BNST endocannabinoid neurotransmission as a mechanism involved in LH neuronal activation during stressful events.
Assuntos
Endocanabinoides/fisiologia , Região Hipotalâmica Lateral/fisiologia , Angústia Psicológica , Núcleos Septais/fisiologia , Animais , Antagonistas de Receptores de Canabinoides/administração & dosagem , Antagonistas GABAérgicos/administração & dosagem , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Modelos Neurológicos , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Piridazinas/administração & dosagem , Ratos , Ratos Wistar , Núcleos Septais/efeitos dos fármacos , Estresse Psicológico/fisiopatologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Taquicardia/fisiopatologiaRESUMO
During the last few decades, the consumption of low-calorie sweeteners, as a substitute for caloric sweeteners, has sharply increased. Although research shows that caloric versus low-calorie sweeteners can have differential effects on the brain, it is unknown which neuronal populations are responsible for detecting the difference between the two types of sweeteners. Using in vivo two-photon calcium imaging, we investigated how drinking sucrose or sucralose (a low-calorie sweetener) affects the activity of glutamatergic neurons in the lateral hypothalamus. Furthermore, we explored the consequences of consuming a free-choice high fat diet on the calorie detection abilities of these glutamatergic neurons. We found that glutamatergic neurons indeed can discriminate sucrose from water and sucralose, and that consumption of a free-choice high fat diet shifts the glutamatergic neuronal response from sucrose-specific to sucralose-specific, thereby disrupting calorie detection. These results highlight the disruptive effects of a diet high in saturated fat on calorie detection in the lateral hypothalamus.
Assuntos
Ingestão de Energia/fisiologia , Região Hipotalâmica Lateral/fisiopatologia , Animais , Dieta com Restrição de Gorduras/métodos , Dieta Hiperlipídica/métodos , Feminino , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Edulcorantes/administração & dosagemRESUMO
Acupuncture modulates the mesolimbic dopamine (DA) system; an area implicated in drug abuse. However, the mechanism by which peripheral sensory afferents, during acupuncture stimulation, modulate this system needs further investigation. The lateral hypothalamus (LH) has been implicated in reward processing and addictive behaviors. To investigate the role of the LH in mediating acupuncture effects, we evaluated the role of LH and spinohypothalamic neurons on cocaine-induced psychomotor activity and NAc DA release. Systemic injection of cocaine increased locomotor activity and 50 kHz ultrasonic vocalizations (USVs), which were attenuated by mechanical stimulation of needles inserted into HT7 but neither ST36 nor LI5. The acupuncture effects were blocked by chemical lesions of the LH or mimicked by activation of LH neurons. Single-unit extracellular recordings showed excitation of LH and spinohypothalamic neurons following acupuncture. Our results suggest that acupuncture recruits the LH to suppress the mesolimbic DA system and psychomotor responses following cocaine injection.
Assuntos
Cocaína/farmacologia , Dopamina/metabolismo , Neurônios Aferentes/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Acupuntura/métodos , Animais , Humanos , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Locomoção/efeitos dos fármacos , Agulhas , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/patologia , Ratos , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/terapiaRESUMO
A growing body of literature implicates noradrenergic (NE) signaling in the modulation of ethanol consumption. However, relatively few studies have detailed specific brain pathways that mediate NE-associated binge-like ethanol consumption. To begin to fill this gap in the literature, male and female C57BL6/J and TH-ires-cre mice underwent pharmacological and chemogenetic testing, respectively, in combination with "drinking in the dark" procedures to model binge-like consumption of ethanol or sucrose solutions. First, we showed that intraperitoneal administration of the NE reuptake inhibitor, reboxetine, blunted binge-like ethanol intake in C57BL6/J mice. Chemogenetic activation of locus coeruleus (LC) tyrosine hydroxylase (TH)-expressing neurons blunted binge-like ethanol intake regardless of sex. Chemogenetic activation of LC projections to the lateral hypothalamus (LH), a region implicated in ethanol consumption, blunted binge-like ethanol drinking without altering sucrose intake in ethanol-experienced or ethanol-naïve mice. In C57BL/6 J mice, LH-targeted microinfusion of an α1-adrenergic receptor (AR) agonist blunted binge-like ethanol intake across both sexes, while LH infusion of a ß-AR agonist blunted binge-like ethanol intake in females exclusively. Finally, in mice with high baseline ethanol intake both an α1- AR agonist and an α-2 AR antagonist blunted binge-like ethanol intake. The present results provide novel evidence that increased NE tone in a circuit arising from the LC and projecting to the LH reduces binge-like ethanol drinking in mice, and may represent a novel approach to treating binge or heavy drinking prior to the development of dependence. This article is part of the special Issue on "Neurocircuitry Modulating Drug and Alcohol Abuse".
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Região Hipotalâmica Lateral/metabolismo , Locus Cerúleo/metabolismo , Norepinefrina/metabolismo , Reboxetina/farmacologia , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Feminino , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/fisiopatologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/fisiopatologia , Masculino , Camundongos , Vias Neurais , Tirosina 3-Mono-OxigenaseRESUMO
The lateral hypothalamus (LH) orexinergic neurons project to numerous brain regions implicated in pain perception, including the CA1 part of the hippocampal formation. Moreover, the roles of orexin receptors (OXRs) in the CA1 in anti-analgesic consequences of the LH chemical stimulation by carbachol, muscarinic receptor agonist, in acute pain have not been clarified. The current research showed OXRs antagonist administration's effect in the CA1 on analgesia elicited by the LH chemical stimulation in a tail-flick test as an acute model of pain. The control groups, including vehicle-control groups, were given intra-LH administration of saline (0.5 µL), following intra-CA1 infusion of DMSO (12 %; 0.5 µL), and carbachol-control groups were treated with carbachol (250 nM/0.5 µL saline) into the LH following DMSO in the CA1. Treated groups received SB334867 (1, 3, 10, and 30 nM/0.5 µL DMSO) or TCS OX2 29 (0.1, 1, 10, and 20 nM/0.5 µL DMSO) as OX1R or OX2R antagonist, respectively, in the CA1 prior intra-LH administration of carbachol. After all injections, all rats underwent the tail-flick test over a 60-min time. Infusion of SB334867 or TCS OX2 29 in the CA1 impaired the analgesic consequences following chemical stimulation of the LH in acute pain. Meanwhile suppressive impact of the OX1R or OX2R antagonist on the analgesic impact of LH chemical stimulation was approximately identical. The current investigation provided a new document about the critical involvement of hippocampal orexinergic system in the modulatory role of the LH-CA1 path in pain perception.
Assuntos
Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Região Hipotalâmica Lateral/metabolismo , Agonistas Muscarínicos/farmacologia , Nociceptividade/fisiologia , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/efeitos dos fármacos , Receptores de Orexina/metabolismo , Animais , Benzoxazóis/farmacologia , Região CA1 Hipocampal/efeitos dos fármacos , Carbacol/farmacologia , Dimetil Sulfóxido/farmacologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Isoquinolinas/farmacologia , Masculino , Agonistas Muscarínicos/administração & dosagem , Naftiridinas/farmacologia , Nociceptividade/efeitos dos fármacos , Antagonistas dos Receptores de Orexina/administração & dosagem , Receptores de Orexina/agonistas , Piridinas/farmacologia , Ratos , Ratos Wistar , Estimulação Química , Ureia/análogos & derivados , Ureia/farmacologiaRESUMO
Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LHPV) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LHPV neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LHPV neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LHPV projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LHPV activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LHPV neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.
Assuntos
Comportamento Animal , Região Hipotalâmica Lateral/fisiopatologia , Nociceptividade , Dor/fisiopatologia , Dor/psicologia , Analgésicos Opioides/uso terapêutico , Animais , Animais Geneticamente Modificados , Comportamento Animal/efeitos dos fármacos , Sinalização do Cálcio , Modelos Animais de Doenças , Tolerância a Medicamentos , Feminino , Neurônios GABAérgicos/metabolismo , Ácido Glutâmico/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Morfina/farmacologia , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Técnicas de Rastreamento Neuroanatômico , Nociceptividade/efeitos dos fármacos , Optogenética , Dor/metabolismo , Dor/prevenção & controle , Parvalbuminas/genética , Parvalbuminas/metabolismoRESUMO
Several studies have reported that nicotine, the main bioactive component of tobacco, exerts a marked negative energy balance. Apart from its anorectic action, nicotine also modulates energy expenditure, by regulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. These effects are mainly controlled at the central level by modulation of hypothalamic neuropeptide systems and energy sensors, such as AMP-activated protein kinase (AMPK). In this study, we aimed to investigate the kappa opioid receptor (κOR)/dynorphin signaling in the modulation of nicotine's effects on energy balance. We found that body weight loss after nicotine treatment is associated with a down-regulation of the κOR endogenous ligand dynorphin precursor and with a marked reduction in κOR signaling and the p70 S6 kinase/ribosomal protein S6 (S6K/rpS6) pathway in the lateral hypothalamic area (LHA). The inhibition of these pathways by nicotine was completely blunted in κOR deficient mice, after central pharmacological blockade of κOR, and in rodents where κOR was genetically knocked down specifically in the LHA. Moreover, κOR-mediated nicotine effects on body weight do not depend on orexin. These data unravel a new central regulatory pathway modulating nicotine's effects on energy balance.
Assuntos
Região Hipotalâmica Lateral/metabolismo , Nicotina/farmacologia , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Peso Corporal , Dinorfinas/metabolismo , Metabolismo Energético , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-DawleyRESUMO
The orexinergic connection between the lateral hypothalamus (LH) and the ventral tegmental area (VTA) is involved in modulating the reward circuit. The conditioned place preference (CPP) can be induced by microinjection of carbachol, a cholinergic agonist, into the LH. The current research was conducted to understand whether intra-VTA orexin receptors (OXRs) could influence the duration of the extinction period or maintenance of the intra-LH carbachol-induced CPP. To this end, the rats unilaterally received intra-LH carbachol (250 nM) within a 3-day conditioning period. Animals that have already passed the conditioning test were unilaterally administered by intra-VTA microinjection of SB334867, an OX1R antagonist, or TCS OX2 29, an OX2R antagonist during the extinction phase of the LH stimulation-induced CPP. For the first time, our data indicated that daily intra-VTA administration of either SB334867 (30 nM) or TCS OX2 29 (10 and 30 nM) during the extinction period decreased the maintenance of intra-LH carbachol-induced CPP. In conclusion, OXRs in the VTA play crucial roles in the maintenance of reward processes.
Assuntos
Benzoxazóis/farmacologia , Isoquinolinas/farmacologia , Naftiridinas/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/efeitos dos fármacos , Piridinas/farmacologia , Ureia/análogos & derivados , Animais , Benzoxazóis/administração & dosagem , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Isoquinolinas/administração & dosagem , Masculino , Naftiridinas/administração & dosagem , Antagonistas dos Receptores de Orexina/administração & dosagem , Receptores de Orexina/metabolismo , Piridinas/administração & dosagem , Ratos , Ratos Wistar , Recompensa , Ureia/administração & dosagem , Ureia/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismoRESUMO
Neurons containing neuropeptide S (NPS) and orexins are activated during stress. Previously, we reported that orexins released during stress, via orexin OX1 receptors (OX1 Rs), contribute to the reinstatement of cocaine seeking through endocannabinoid/CB1 receptor (CB1 R)-mediated dopaminergic disinhibition in the ventral tegmental area (VTA). Here, we further demonstrated that NPS released during stress is an up-stream activator of this orexin-endocannabinoid cascade in the VTA, leading to the reinstatement of cocaine seeking. Mice were trained to acquire cocaine conditioned place preference (CPP) by context-pairing cocaine injections followed by the extinction training with context-pairing saline injections. Interestingly, the extinguished cocaine CPP in mice was significantly reinstated by intracerebroventricular injection (i.c.v.) of NPS (1 nmol) in a manner prevented by intraperitoneal injection (i.p.) of SHA68 (50 mg/kg), an NPS receptor antagonist. This NPS-induced cocaine reinstatement was prevented by either i.p. or intra-VTA microinjection (i.vta.) of SB-334867 (15 mg/kg, i.p. or 15 nmol, i.vta.) and AM 251 (1.1 mg/kg, i.p. or 30 nmol, i.vta.), antagonists of OX1 Rs and CB1 Rs, respectively. Besides, NPS (1 nmol, i.c.v.) increased the number of c-Fos-containing orexin neurons in the lateral hypothalamus (LH) and increased orexin-A level in the VTA. The latter effect was blocked by SHA68. Furthermore, a 30-min restraint stress in mice reinstated extinguished cocaine CPP and was prevented by SHA68. These results suggest that NPS is released upon stress and subsequently activates LH orexin neurons to release orexins in the VTA. The released orexins then reinstate extinguished cocaine CPP via an OX1 R- and endocannabinoid-CB1 R-mediated signaling in the VTA.
Assuntos
Cocaína/efeitos adversos , Endocanabinoides/metabolismo , Neuropeptídeos/metabolismo , Orexinas/metabolismo , Restrição Física , Animais , Benzoxazóis/farmacologia , Condicionamento Clássico , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microinjeções , Naftiridinas/farmacologia , Receptores de Orexina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ureia/análogos & derivados , Ureia/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismoRESUMO
Anxiety commonly co-occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL- and not BLA- and vHipp-NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL-NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.
Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Agonistas dos Receptores Histamínicos/administração & dosagem , Núcleo Accumbens/fisiopatologia , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Receptores Histamínicos H3/metabolismo , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiopatologia , Animais , Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/fisiopatologia , Transtornos de Ansiedade/psicologia , Modelos Animais de Doenças , Glutamatos/metabolismo , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Humanos , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/fisiopatologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/etiologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/psicologia , Optogenética , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Transgênicos , Técnicas Estereotáxicas , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
RATIONALE: Prior research suggests that the neural pathway from the lateral hypothalamic area (LHA) to the paraventricular nucleus of the thalamus (PVT) mediates the attribution of incentive salience to Pavlovian reward cues. However, a causal role for the LHA and the neurotransmitters involved have not been demonstrated in this regard. OBJECTIVES: To examine (1) the role of LHA in the acquisition of Pavlovian conditioned approach (PavCA) behaviors, and (2) the role of PVT orexin 1 receptors (OX1r) and orexin 2 receptors (OX2r) in the expression of PavCA behaviors and conditioned reinforcement. METHODS: Rats received excitotoxic lesions of the LHA prior to Pavlovian training. A separate cohort of rats characterized as sign-trackers (STs) or goal-trackers (GTs) received the OX1r antagonist SB-334867, or the OX2r antagonist TCS-OX2-29, into the PVT, to assess their effects on the expression of PavCA behavior and on the conditioned reinforcing properties of a Pavlovian reward cue. RESULTS: LHA lesions attenuated the development of sign-tracking behavior. Administration of either the OX1r or OX2r antagonist into the PVT reduced sign-tracking behavior in STs. Further, OX2r antagonism reduced the conditioned reinforcing properties of a Pavlovian reward cue in STs. CONCLUSIONS: The LHA is necessary for the development of sign-tracking behavior; and blockade of orexin signaling in the PVT attenuates the expression of sign-tracking behavior and the conditioned reinforcing properties of a Pavlovian reward cue. Together, these data suggest that LHA orexin inputs to the PVT are a key component of the circuitry that encodes the incentive motivational value of reward cues.
Assuntos
Sinais (Psicologia) , Região Hipotalâmica Lateral/fisiologia , Núcleos da Linha Média do Tálamo/fisiologia , Motivação/fisiologia , Receptores de Orexina/fisiologia , Recompensa , Animais , Benzoxazóis/administração & dosagem , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Isoquinolinas/administração & dosagem , Masculino , Núcleos da Linha Média do Tálamo/efeitos dos fármacos , Motivação/efeitos dos fármacos , Naftiridinas/administração & dosagem , Antagonistas dos Receptores de Orexina/administração & dosagem , Piridinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Ureia/administração & dosagem , Ureia/análogos & derivadosRESUMO
Orexinergic projections originated from the lateral hypothalamus (LH) to the ventral tegmental area (VTA) play essential role in reward-related behaviors. Our previous studies show that intra-LH injection of carbachol, as a cholinergic agonist, induces conditioned place preference (CPP) in rats. This study aimed to determine whether chemical stimulation of the LH alone can induce reinstatement or not, and whether intra-VTA orexin receptors are involved in the reinstatement of intra-LH carbachol-induced CPP in the rats. The animals were unilaterally treated by carbachol (250 nM) in the LH during 3-day conditioning phase. Then, they underwent an extinction phase without receiving carbachol, and on the reinstatement day, animals received a different priming dose of carbachol in the separate groups. Extinguished animals unilaterally received intra-VTA administration of SB334867 or TCS OX2 29 as orexin-1 or orexin-2 receptor antagonists to evaluate the role of orexin receptors before effective priming dose of carbachol on the reinstatement day. Findings showed that intra-LH microinjection of a priming dose of carbachol (25 and 50 nM) induced the reinstatement of LH chemical stimulation-induced CPP. Moreover, it was indicated that, intra-VTA administration of either SB334867 or TCS OX2 29 (10 and 30 nM) before to intra-LH injection of the priming dose of carbachol (50 nM) dose-dependently inhibited the reinstatement of intra-LH carbachol-induced CPP. Also, the orexin-2 receptor antagonist was a little more effective than orexin-1 receptor antagonist for inhibiting the reinstatement of LH chemical stimulation-induced CPP. The consequences propose that both orexin receptors in the VTA play roles in the reinstatement of intra-LH carbachol-induced CPP.