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Activation of protein kinases after cocaine administration controls psychomotor behaviours by interacting with metabotropic receptors in the brain. This study identified how c-Jun N-terminal kinase (JNK) interacts with metabotropic glutamate receptor 5 (mGluR5) in vitro and in the caudate and putamen (CPu). The potential role of this interaction in the regulation of psychomotor behaviour was also evaluated after administration of cocaine. Active JNK phosphorylates a threonine residue at position 1055 in the carboxyl terminus (CT) of mGluR5 in vitro. The binding of active JNK to the D-motif within CT2 is necessary for that phosphorylation. Interaction of phosphorylated JNK and mGluR5 occurs in the CPu. Unilateral interference of the interaction decreases the repeated cocaine-induced increases in locomotor activity and conditioned place preference. These findings suggest that activation of JNK has the capability to interact with mGluR5 in the CPu. Phosphorylation of mGluR5 following the JNK-mGluR5 interaction may be responsible for the potentiation of behavioural sensitisation and cocaine-wanting behaviour in response to cocaine administration.
Assuntos
Cocaína , Receptor de Glutamato Metabotrópico 5 , Encéfalo/metabolismo , Cocaína/metabolismo , Cocaína/farmacologia , Fosforilação , Putamen/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismoRESUMO
Transient receptor potential vanilloid 1 (TRPV1) has been implicated in peripheral inflammation and is a mediator of the inflammatory response to various noxious stimuli. However, the interaction between TRPV1 and N-methyl-D-aspartate (NMDA) receptors in the regulation of inflammatory pain remains poorly understood. This study aimed to investigate the analgesic effects of intrathecal administration of capsazepine, a TRPV1 antagonist, on carrageenan-induced inflammatory pain in mice and to identify its interactions with NMDA receptors. Inflammatory pain was induced by intraplantar injection of 2% carrageenan in male ICR mice. To investigate the analgesic effects of capsazepine, pain-related behaviors were evaluated using von Frey filaments and a thermal stimulator placed on the hind paw. TRPV1 expression and NMDA receptor phosphorylation in the spinal cord and glutamate concentration in the spinal cord and serum were measured. Intrathecal treatment with capsazepine significantly attenuated carrageenan-induced mechanical allodynia and thermal hyperalgesia. Moreover, carrageenan-enhanced glutamate and phosphorylation of NMDA receptor subunit 2B in the spinal cord were suppressed by capsazepine administration. These results indicate that TRPV1 and NMDA receptors in the spinal cord are associated with inflammatory pain transmission, and inhibition of TRPV1 may reduce inflammatory pain via NMDA receptors.
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Capsaicina/análogos & derivados , Hiperalgesia/metabolismo , Inflamação , Dor/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Canais de Cátion TRPV/metabolismo , Analgésicos/farmacologia , Animais , Capsaicina/farmacologia , Carragenina/efeitos adversos , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Dor/induzido quimicamente , Fosforilação , Medula Espinal/metabolismoRESUMO
The Shenmen point (acupuncture point heart 7: HT7), located in the heart meridian, is frequently used to treat mental disorders, including drug addiction, anxiety, and depression. This study aimed to determine how HT7 regulates anxiety and negative emotions caused by repeated alcohol administration, focusing on the amygdala and paraventricular nucleus (PVN). Repeated administration of alcohol (ETOH; 2 g/kg, i.p. injection, 16% v/v) for 14 days increased the corticosterone (CORT) levels, and HT7 stimulation reduced the plasma CORT levels. HT7 stimulation mitigated anxiety-like behaviors and reduced 22-kHz ultrasonic vocalizations in rats receiving repeated ETOH injections. HT7 stimulation increased the amygdala expression of mature brain-derived neurotropic factor (mBDNF) and phosphorylated tropomyosin receptor kinase B (pTrkB) and decreased the PVN corticotropin-releasing hormone (CRH) expression. Amygdala microinjections of the TrkB antagonist ANA-12 (0.1 pmol/1 µL) reversed the increase in PVN CRH levels. The reduced PVN CRH levels were regulated by CRH-expressing neurons in the amygdala, and the increased amygdala CRH levels were affected by the HT7-stimulation induced increases in mBDNF. HT7 stimulation alleviates increased stress hormone levels and mitigates anxiety and negative emotions caused by repeated ETOH administration. These results provide scientific support for the clinical use of acupuncture to treat various alcoholism-induced diseases.
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Terapia por Acupuntura , Ansiedade/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Etanol/administração & dosagem , Transdução de Sinais , Ultrassom , Vocalização Animal , Pontos de Acupuntura , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/sangue , Comportamento Animal , Corticosterona/sangue , Teste de Labirinto em Cruz Elevado , Etanol/sangue , Masculino , Núcleo Hipotalâmico Paraventricular/metabolismo , Fosforilação , Ratos Wistar , Receptor trkB/metabolismoRESUMO
BACKGROUND: Electroacupuncture (EA) is often used in clinical settings due to its analgesic effect, but its safety has not been verified due to the lack of clear criteria. This study examined the critical range of the corrosion of stainless steel types STS304 and STS316, which have been used clinically, and the relationship between needle corrosion and cell necrosis. METHOD: The critical point of corrosion for STS304 and STS316 was identified by varying the time, frequency, and stimulation intensity. In a tissue necrosis experiment, EA stimulation was applied to rats using STS316 needles with different thicknesses at maximum intensity for 60 min, and the presence of corrosion and tissue necrosis was determined. A cytotoxicity experiment was also conducted and assessed the needles and tissue necrosis. RESULTS: The results showed that STS316 was more stable than STS304 and that only coated needles corroded. Furthermore, tissue necrosis was observed regardless of corrosion, and slight cell necrosis was associated with needles with corrosion. CONCLUSIONS: This study demonstrated that non-coated STS316 was the most stable for EA stimulation and that corrosion byproducts and cell necrosis were not directly related.
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Eletroacupuntura/instrumentação , Agulhas/efeitos adversos , Pontos de Acupuntura , Animais , Eletroacupuntura/efeitos adversos , Eletroacupuntura/métodos , Masculino , Necrose/etiologia , Necrose/patologia , Ratos , Ratos Sprague-Dawley , Aço Inoxidável/efeitos adversos , Aço Inoxidável/análiseRESUMO
BACKGROUND: Phosphorylation state of dopamine- and cAMP-regulated phosphoprotein, molecular weight 32 kDa (DARPP32) is crucial to understand drug-mediated synaptic plasticity. In this study, mechanisms underlying repeated cocaine-stimulated phosphorylation of DARPP32 at threonine 75 (pDARPP32-Thr75) were determined by investigating the hypothesis that activation of protein kinases and phosphatases coupled to glutamate signaling is necessary for the regulation of pDARPP32-Thr75 after repeated cocaine administration. METHODS: Intracaudate drug infusions into the rat dorsal striatum followed by Western immunoblot analysis were mainly performed to test this hypothesis. RESULTS: The results demonstrated that 7 repeated daily intraperitoneal injections of cocaine (20mg/kg) upregulated the expression of pDARPP32-Thr75. Increases in the cytosolic Ca(2+) concentrations followed by Ca(2+)-dependent protein kinase activation through stimulation of Ca(2+) channels in striatal neurons were necessary for the phosphorylation. Activation of protein phosphatases further regulated the phosphorylation state by deactivating pDARPP32-Thr75 and upstream protein kinases. CONCLUSION: These findings suggest that activation of protein kinases and phosphatases coupled to glutamate receptors controls the phosphorylation state of DARPP32-Thr75 after repeated exposure to cocaine in the dorsal striatum in a Ca(2+)-dependent manner.
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Cálcio/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Animais , Canais de Cálcio/metabolismo , Cátions Bivalentes/metabolismo , Corpo Estriado/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/genética , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Masculino , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Quinases/metabolismo , Ratos Sprague-Dawley , Receptores de Glutamato/metabolismo , Canais de Sódio/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
We previously found that the dopamine D2-type receptors (D2 and D3 receptors), coupled to protein kinase G (PKG), upregulate locomotor activity after repeated cocaine administration. In this study, D4 receptors, another type of D2 receptor also coupled to PKG, were examined to determine their requirement in the regulation of locomotor activity after repeated cocaine administration. The results demonstrated that repeated injections of cocaine (20 mg/kg), given once a day for seven consecutive days, significantly increased extracellular dopamine concentrations. Intra-caudate infusion of the D4 receptor agonist, PD168077 (10 nmol), and the PKG inhibitor, KT5823 (2 nmol), significantly decreased the repeated cocaine-induced increase in dopamine levels and locomotor activity. However, intra-caudate infusion of KT5823, but not PD168077, decreased ∆FosB immunoreactivity elevated by repeated cocaine administration. These findings suggest that D4 receptors linked to PKG could be a key modulator for dopamine release required for changes in locomotor activity caused by repeated cocaine exposure.
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Cocaína/administração & dosagem , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Inibidores da Captação de Dopamina/administração & dosagem , Dopamina/metabolismo , Atividade Motora/efeitos dos fármacos , Receptores de Dopamina D4/metabolismo , Análise de Variância , Animais , Benzamidas/farmacologia , Carbazóis/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/genética , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Óxido Nítrico Sintase Tipo I/metabolismo , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D4/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
The chronic use of the novel synthetic cathinone mexedrone, like other psychoactive drugs, can be considered addictive, with a high potential for abuse and the ability to cause psychological dependence in certain users. However, little is known about the neurobehavioral effects of mexedrone in association with its potential for abuse. We investigated the abuse potential for mexedrone abuse through multiple behavioral tests. In addition, serotonin transporter (SERT) levels were measured in the synaptosome of the dorsal striatum, and serotonin (5-HT) levels were measured in the dorsal striatum of acute mexedreone (50 mg/kg)-treated mice. To clarify the neuropharmacological mechanisms underlying the locomotor response of mexedrone, the 5-HT2A receptor antagonist M100907 (0.5 or 1.0 mg/kg) was administered prior to the acute injection of mexedrone in the locomotor activity experiment in mice. Mexedrone (10-50 mg/kg) produced a significant place preference in mice and mexedrone (0.1-0.5 mg/kg/infusion) maintained self-administration behavior in rats in a dose-dependent manner. In the drug discrimination experiment, mexedrone (5.6-32 mg/kg) was fully substituted for the discriminative stimulus effects of cocaine in rats. Mexedrone increased locomotor activity, and these effects were reversed by pretreatment with M100907. Acute mexedrone significantly increased c-Fos expression in the dorsal striatum and decreased SERT levels in the synaptosome of the dorsal striatum of mice, resulting in an elevation of 5-HT levels. Taken together, our results provide the possibility that mexedrone has abuse potential, which might be mediated, at least in part, by the activation of the serotonergic system in the dorsal striatum.
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Cocaína , Fluorbenzenos , Metanfetamina/análogos & derivados , Piperidinas , Catinona Sintética , Ratos , Camundongos , Masculino , Animais , Ratos Sprague-Dawley , Serotonina/metabolismo , Cocaína/farmacologia , Relação Dose-Resposta a DrogaRESUMO
PURPOSE: In castrate resistant prostate cancer cells we investigated the cytotoxic effect of simvastatin and the mechanism involved. MATERIALS AND METHODS: After treating PC3 and DU-145 cells with simvastatin, cell viability and apoptosis were determined using tetrazolium salt based colorimetric assay and annexin-V-fluorescein isothiocyanate/propidium iodide double staining assay, respectively. To determine whether simvastatin affects the nuclear factor-κB pathway, we assessed IκBα and phosphorylated IκBα expression, and p65 and phosphorylated p65 subcellular localization by Western blot analysis. Also, changes in nuclear factor-κB transcriptional activity were assessed using a luciferase reporter assay. RESULTS: After treating PC3 and DU-145 cells with 0, 20 or 40 µM simvastatin for 24, 48 or 72 hours, the proportion of viable cells decreased and the proportion of apoptotic cells increased in a dose and time dependent manner. Western blot analysis showed that simvastatin inhibited IκBα phosphorylation and degradation. It also demonstrated that simvastatin increased p65 protein levels in cytoplasmic fractions and decreased phosphorylated p65 protein levels in nuclear fractions but did not change p65 protein levels in cytoplasm. Luciferase reporter assay showed that simvastatin dose dependently reduced nuclear factor-κB activity. Reverse transcriptase-polymerase chain reaction and Western blot revealed that simvastatin inhibited nuclear factor-κB regulated cIAP-1 and 2, cFLIP-S and XIAP expression in dose and time dependent fashion. CONCLUSIONS: Simvastatin inhibited castrate resistant prostate cancer cell growth by inducing apoptosis. These effects were probably mediated by the inhibition of IκBα phosphorylation and nuclear translocation of p50/p65 dimer in the nuclear factor-κB pathway.
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Apoptose/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , NF-kappa B/fisiologia , Neoplasias da Próstata/patologia , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Células Tumorais CultivadasRESUMO
Introduction: We and others have shown that electrical stimulation of the PC-6 acupoint over the wrist relieves hypertension by stimulating afferent sensory nerve fibers and activating the central endogenous opioid system. Warm needle acupuncture has long been utilized to treat various diseases in clinics. Methods: Here, we developed a temperature-controllable warm needle acupuncture instrument (WAI) and investigated the peripheral mechanism underlying the effect of warm needle acupuncture at PC-6 on hypertension in a rat model of immobilization stress-induced hypertension. Results: Stimulation with our newly developed WAI and traditional warm needle acupuncture attenuated hypertension development. Such effects were reproduced by capsaicin (a TRPV1 agonist) injection into PC-6 or WAI stimulation at 48°C. In contrast, PC-6 pretreatment with the TRPV1 antagonist capsazepine blocked the antihypertensive effect of WAI stimulation at PC-6. WAI stimulation at PC-6 increased the number of dorsal root ganglia double-stained with TRPV1 and CGRP. QX-314 and capsaicin perineural injection into the median nerve for chemical ablation of small afferent nerve fibers (C-fibers) prevented the antihypertensive effect of WAI stimulation at PC-6. Additionally, PC-6 pretreatment with RTX ablated the antihypertensive effect of WAI stimulation. Conclusion: These findings suggest that warm needle acupuncture at PC-6 activates C-fiber of median nerve and the peripheral TRPV1 receptors to attenuate the development of immobilization stress-induced hypertension in rats.
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Introduction: Since the analgesic effect of acupuncture stimulation is derived from different mechanisms depending on the type of pain, it is important to know which acupuncture points to stimulate. In this study, to confirm the effect of acupuncture stimulation on acute pain from a neurological point of view, somatosensory evoked potential and sensory threshold changes were evaluated to identify the nerve range that is affected by acupuncture stimulation on LI4 (Hapgok acupuncture point, of the radial nerve) during acute pain. Methods: The subjects were 40 healthy men and women aged 19-35 years. The study was designed as a randomly controlled, crossover trial with acupuncture stimulation at LI4 as the intervention. The washout period for acupuncture stimulation was 2 weeks, and the subjects were divided into two groups, i.e., an acupuncture stimulation group and a nonstimulation group, with 10 men and 10 women in each group. Somatosensory evoked potential measurement was carried out for 5 min by alternately applying 2 HZ-pulse electrical stimulation to the thumb and the little finger of the hand acupunctured with a 64-channel electroencephalogram. The verbal rating scale was used before and after each acupuncture stimulation session. Result and discussion: The results of the study confirmed that the somatosensory evoked potential amplitude value of the thumb was significantly decreased and that the intensity of sensory stimulation corresponding to a verbal rating scale score of 6 was significantly increased only in the thumb after acupuncture stimulation. Therefore, the results show that acupuncture treatment for acute pain is more effective when direct acupuncture stimulation is applied to the painful area.
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Acupuncture stimulation can protect the brain against caffeine-induced sleep disruption. This study investigated whether electroacupuncture stimulation acupuncture point HT7 alleviates sleep disruption by regulating mBDNF and ER stress in the medial septum. Acute exposure to caffeine (15 mg/kg, i.p.) increased the wake time and decreased REM sleep, which HT7 stimulation alleviated. HT7 stimulation ameliorated the acute caffeine exposure-induced increase in the expression of BiP, an endoplasmic reticulum stress response protein, in the rat medial septum. Interestingly, HT7 stimulation induced the expression of mBDNF and pTrkB in the medial septum. The next experiment investigated whether TrkB phosphorylated by HT7 stimulation induced BiP expression in the rat medial septum. Before electroacupuncture stimulation at HT7, ANA-12 was administered to caffeine-treated rats. In rats administered ANA-12 in the medial septum, HT7 stimulation did not reduce BiP expression. These findings suggest that HT7 stimulation improves wake time and REM sleep dysfunction by regulating the BDNF-mediated endoplasmic reticulum stress response in the medial septum. These results indicate that the alleviation of endoplasmic reticulum stress in the medial septum by HT7 stimulation and the subsequent amelioration of insomnia may depend on phosphorylated TrkB activation.
Assuntos
Eletroacupuntura , Animais , Ratos , Cafeína/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estresse do Retículo Endoplasmático , Ratos Sprague-Dawley , SonoRESUMO
Background: The energy flow at acupuncture point is important for understanding the mechanism of acupuncture treatment. However, there are few studies on energy at acupuncture point, and related studies have limitation in explaining the energy flow in all meridians. Thus, we aimed to understand the properties of electrical energy at acupuncture point in twelve meridians by measuring the biopotential at acupuncture and non-acupuncture points. Methods: For each meridian, twenty subjects were participated, and biopotential was measured at five transport points and their adjacent non-acupuncture points. In each subject, both 'non-stimulation' and 'stimulation' experiments were conducted in random order. The data were analyzed in two parts: biopotential variability and biopotential difference between acupuncture and non-acupuncture points. Results: The biopotential variability at acupuncture point was increased by acupuncture stimulation, and it was related to the activation of Qi flow by acupuncture stimulation. The biopotential difference between acupuncture and non-acupuncture points was formed in the direction related to the Qi flow theory, and this biopotential difference tended to decrease by acupuncture stimulation. Conclusion: The study on biopotential can provide a foundation for research on energy flow mechanism of acupuncture stimulation, and it is expected to overcome limitation of qualitative explanation in traditional medicine.
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BACKGROUND: Most ETOH addiction preclinical studies have focused on the rewards of chronic ETOH self-administration or the ETOH reinstatement model. Acute ETOH administration studies are scarce despite the potential of ETOH to cause sedation, intoxication and reduced acute functional tolerance. Here, we established a rat model of acute ETOH administration induced by an intraperitoneal injection of 1 g/kg ethanol and assessed the similarities in physiological and behavioral effects between acupuncture and Sigma1 R antagonists. METHODS: Male Wistar rats (300-330 g) received pretreatment with (1) saline injection, (2) saline + mechanical stimulation using a mechanical acupuncture instrument (MAI) for acupuncture at the Shenmen (HT7), (3) ETOH (1 g/kg) injection, (4) ETOH + HT7, or (5) the selective σ1 R antagonist BD 1047 (3, 10, or 30 mg/kg, intraperitoneal (IP) injection). ETOH (1 g/kg) or saline was IP injected after 10 min. Then, ETOH-induced immobility was evaluated in an open field arena, ultrasonic vocalizations (USVs) indicating ethanol-induced emotional changes were recorded in a recording chamber, and the rats were sacrificed for the analysis of protein levels of σ1 R in several regions of the brain. RESULTS: Acute ethanol exposure increased the immobile time, 22-kHz USVs, and protein levels of σ1 R in the ventral tegmental area (VTA). However, pretreatment with acupuncture at HT7 induced recovery of immobile time, reduced 22-kHz USVs, and regulated the protein levels of σ1 R in the VTA. These effects have similarities with IP injection of BD 1047 (10 mg/kg). CONCLUSION: This study showed that acupuncture at HT7 regulates immobility and 22-kHz USVs via Sigma1 R in the VTA upon acute ETOH exposure.
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OBJECTIVES: Insomnia is one of the most common sleep disorders and is difficult to completely treat because of the undesirable side effects of hypnotics. The present study was designed to investigate the hypnotic effect of acupuncture stimulation at HT7 on caffeine-induced sleep disorders and locomotor activity in rats. We also evaluated neuronal activity changes in the arousal region of the basal forebrain. METHODS: Rats received intraperitoneal injections of caffeine, and then electroencephalogram power spectrum analysis and locomotor activity measurements were performed. Stimulation at HT7 was performed using a mechanical acupuncture instrument (MAI) before caffeine injection, and its effects on caffeine-induced changes in sleep architecture, locomotor activity and c-Fos expression were examined. RESULTS: Caffeine injection (7.5 mg/kg) produced a significant decrease in slow-wave sleep and an increase in wake time compared with saline injection. Caffeine injection also increased locomotor activity and c-Fos expression in the medial septum-vertical limb of the diagonal band of Broca (MS-VDB), one of the arousal regions of the basal forebrain. Stimulation at HT7 with the MAI alleviated the caffeine-induced sleep disturbance and the increase in locomotor activity. In addition, MAI treatment at HT7, compared with treatment at a location not corresponding to any traditional acupuncture point, reduced the caffeine-induced increase in c-Fos expression. CONCLUSION: These results indicate that the hypnotic effect of HT7 acupuncture stimulation on caffeine-induced insomnia was associated with suppression of neuronal activity in the basal forebrain.
Assuntos
Pontos de Acupuntura , Terapia por Acupuntura , Distúrbios do Início e da Manutenção do Sono/terapia , Animais , Cafeína/efeitos adversos , Humanos , Masculino , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Sono , Distúrbios do Início e da Manutenção do Sono/etiologia , Distúrbios do Início e da Manutenção do Sono/metabolismo , Distúrbios do Início e da Manutenção do Sono/fisiopatologiaRESUMO
Docetaxel, a chemotherapeutic agent used to treat breast cancer, produces a robust painful neuropathy that is aggravated by mechanical and thermal stimuli. This study was undertaken to investigate the analgesic effects of electrical stimulation on docetaxel-induced neuropathic pain in mice and to identify associated changes in ultrasound vocalizations. Peripheral neuropathy was induced with intraperitoneally injected docetaxel (5 mg/kg) on 3 times every 2 days in male ICR mice. Electrical wrist stimulation was administered and pain behavior signs were evaluated by von Frey filaments and thermal stimulation on the hind paw. Ultrasound vocalizations were measured using ultrasound microphones, after electrical stimulation. After mice developed docetaxel-induced neuropathic pain behavior, an electrical stimulation temporarily attenuated mechanical allodynia and thermal hyperalgesia. In formalin and NMDA test, pain-induced mice showed increases in 10-30 kHz ultrasound vocalizations, but not in 30-50 and 50-80 kHz vocalizations. Treatment with docetaxel selectively increased 10-30 kHz ultrasound vocalizations, whereas electrical stimulation caused a meaningful decrease. Moreover, electrical stimulation suppressed the docetaxel-enhanced phosphorylation of the NMDA receptor NR2B subunit in the spinal dorsal horn. These results of the analgesic effect of electrical stimulation in chemotherapy-induced neuropathy could potentially provide a new method to treat and manage peripheral neuropathy in patients with cancer.
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Antineoplásicos/toxicidade , Terapia por Estimulação Elétrica/métodos , Neuralgia/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/metabolismo , Vocalização Animal/fisiologia , Animais , Docetaxel/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neuralgia/induzido quimicamente , Neuralgia/terapia , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Medula Espinal/efeitos dos fármacos , Vocalização Animal/efeitos dos fármacosRESUMO
Cigarette smoke is a highly complex mixture of nicotine and non-nicotine constituents. Exposure to cigarette smoke enhances tobacco dependence by potentiating glutamatergic neurotransmission via stimulation of nicotinic acetylcholine receptors (nAChRs). We investigated the effects of nicotine and non-nicotine alkaloids in the cigarette smoke condensates extracted from two commercial cigarette brands in South Korea (KCSC A and KCSC B) on psychomotor behaviors and glutamate levels in the dorsal striatum. Repeated and challenge administration of KCSCs (nicotine content: 0.4 mg/kg, subcutaneous) increased psychomotor behaviors (ambulatory, rearing, and rotational activities) and time spent in psychoactive behavioral states compared to exposure to nicotine (0.4 mg/kg) alone. The increase in psychomotor behaviors lasted longer when exposed to repeated and challenge administration of KCSCs compared to nicotine alone. In parallel with sustained increase in psychomotor behaviors, repeated administration of KCSCs also caused long-lasting glutamate release in the dorsal striatum compared to nicotine alone. KCSC-induced changes in psychomotor behaviors and glutamate levels in the dorsal striatum were found to be strongly correlated. These findings suggest that non-nicotine alkaloids in commercial cigarette smoke synergistically act with nicotine on nAChRs, thereby upregulating glutamatergic response in the dorsal striatum, which contributes to the hypersensitization of psychomotor behaviors.
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BACKGROUND: Acupuncture has become a common complementary and alternative treatment approach for anxiety and depression. However, there is little research on the detailed mechanism of acupuncture therapy relieving depression. Previously, 17ß-estradiol (E2) was shown to prevent oxidative stress and endoplasmic reticulum (ER) stress in ovariectomized (OVX) rats. This study investigated whether stimulation of Sanyinjiao (SP6) using a mechanical acupuncture instrument can alleviate depression-like behavior caused by estrogen deficiency in OVX rats. Furthermore, we found that acupuncture reduced ER stress and oxidative stress-related proteins expression. METHODS: The OVX operation was performed on female SD rats that were separated into four groups: The E2 (2.5 µg/kg, i.p.) injection group (OVX + E2), the OVX group (OVX), and the OVX with acupuncture stimulation group (OVX + SP6). Non-acupoint stimulation group (OVX + NonAcu). The acupuncture point stimulation began three weeks after surgery. The depressive behavior was analyzed by the forced swim test and open field test. The 8-OHDG, BiP, Sigma receptor 1, pJNK, PDI, Ero1-Iα and Calnexin protein levels were evaluated by immunoreactivity in the amygdala. RESULTS: Acupuncture stimulation reduced depressive behavior and altered depression-related proteins. Stimulation of SP6 decreased the immobility time of the FST and altered the ER stress and oxidative stress marker proteins, such as 8-OHDG, BiP, pJNK, PDI, Ero1-Ia and Calnexin. CONCLUSION: Our results indicated that acupuncture at SP6 showed a significant antidepressant-like effect on an OVX-induced depression rat model by mitigation of ER stress and oxidative stress in amygdala.
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Menopause-related depression devastates women's quality of life after middle age. Previous research has shown that estrogen hormone therapy has serious adverse effects; thus, complementary and integrative therapies have been considered clinically. The present study investigates whether stimulation of an acupoint using a mechanical acupuncture instrument (MAI) can mitigate depression-like behavior caused by estrogen deficiency in ovariectomized (OVX) rats. The animals were divided into Sham OVX, OVX, OVX + Sameumgyo (SP6) and OVX + NonAcu (non-acupuncture point) groups. MAI stimulation significantly increased the total distance traveled in the open-field test and the number of open-arm entries in the elevated plus maze and decreased the duration of immobility in the forced swim test. In addition to this decrease in depression-like behavior, brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY) release increased in the hippocampus in response to MAI treatment, but estradiol levels did not recover. Furthermore, microinjection of the BDNF receptor antagonist ANA-12 (0.1 pmol/1 µl) into the hippocampus before MAI stimulation significantly suppressed the recovery of NPY levels. Taken together, these findings indicate that MAI stimulation at SP6 facilitates an estradiol-independent BDNF-NPY cascade, which may contribute to its antidepressant effects in OVX rats, an animal model of menopausal disorders.
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Pontos de Acupuntura , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/terapia , Menopausa/psicologia , Neuropeptídeo Y/metabolismo , Animais , Depressão/etiologia , Depressão/metabolismo , Depressão/psicologia , Modelos Animais de Doenças , Estradiol/metabolismo , Feminino , Hipocampo/metabolismo , Humanos , Menopausa/metabolismo , Ovariectomia/efeitos adversos , Ratos , Resultado do TratamentoRESUMO
Phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the striatum plays a crucial role in regulating the receptor-coupled signaling cascades leading to behavioral changes associated with psychostimulant exposure. The present study determined if activation of protein kinase G (PKG) contributes to the phosphorylation of AMPA receptor GluA1 subunit at the position of serine 831 (GluA1-S831) in the rat nucleus accumbens (NAc) after repeated cocaine administration. The results demonstrated that repeated intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once a day for seven consecutive days significantly increased the level of phosphorylated (p)GluA1-S831. This increase was decreased by the intra-NAc infusion of either the cyclic guanosine monophosphate (cGMP) analog, Rp-8-Br-PET-cGMPS (5 nmol/1 µL), or the PKG inhibitor, KT5823 (2 nmol/1 µL). Repeated cocaine administration increased PKG binding activity to GluA1. This increase in GluA1-S831 phosphorylation after repeated cocaine administration was decreased by the intra-NAc infusion of the synthetic peptide (Tat-tagged interfering peptide (Tat-GluA1-i)), that interferes with the binding of PKG to GluA1. Intra-NAc infusion of the interfering peptide also reduced the repeated cocaine-induced increase in locomotor activity. These findings suggest that activated PKG, after repeated exposure to cocaine, binds to AMPA receptor GluA1 and is required for the phosphorylation of S831, contributing to behavioral changes.
RESUMO
Nicotine, a nicotinic acetylcholine receptor agonist, produces the reinforcing effects of tobacco dependence by potentiating dopaminergic and glutamatergic neurotransmission. Non-nicotine alkaloids in tobacco also contribute to dependence by activating the cholinergic system. However, glutamatergic neurotransmission in the dorsal striatum associated with behavioral changes in response to cigarette smoking has not been investigated. In this study, the authors investigated alterations in glutamate levels in the rat dorsal striatum related to behavioral alterations after repeated administration of cigarette smoke condensate (CSC) using the real-time glutamate biosensing and an open-field behavioral assessment. Repeated administration of CSC including 0.4 mg nicotine (1.0 mL/kg/day, subcutaneous) for 14 days significantly increased extracellular glutamate concentrations more than repeated nicotine administration. In parallel with the hyperactivation of glutamate levels, repeated administration of CSC-evoked prolonged hypersensitization of psychomotor activity, including locomotor and rearing activities. These findings suggest that the CSC-induced psychomotor activities are closely associated with the elevation of glutamate concentrations in the rat dorsal striatum.