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1.
Eur J Pharmacol ; 981: 176866, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39089461

RESUMO

RATIONALE: The rewarding effect of Methamphetamine (METH) is commonly believed to play an important role in METH use disorder. The altered expression of dopamine D1 receptor (D1R) has been suggested to be essential to the rewarding effect of METH. Notably, D1R could interact with histamine H3 receptors (H3R) by forming a H3R-D1R heteromer (H3R-D1R). OBJECTIVES: This study was designed to specifically investigate the involvement of H3R-D1R in the rewarding effect of METH. METHODS: C57BL/6 mice were treated with intraperitoneal injections of a selective H3R antagonist (Thioperamide, THIO; 20 mg/kg), an H1R antagonist (Pyrilamine, PYRI; 10 mg/kg), or microinjections of cytomegalovirus (CMV)-transmembrane domain 5 (TM5) into the nucleus accumbens (NAc). The animal model of Conditioned Place Preference (CPP) was applied to determine the impact of H3R-D1R on the rewarding effect of METH. RESULTS: METH resulted in a significant preference for the drug-associated chamber, in conjunction with increased H3R and decreased D1R expression in both NAc and the ventral tegmental area (VTA). THIO significantly attenuated the rewarding effect of METH, accompanied by decreased H3R and increased D1R expression. In contrast, pyrilamine failed to produce the similar effects. Moreover, the inhibitory effect of THIO on METH-induced CPP was reversed by SKF38393, a D1R agonist. Furthermore, SCH23390, a D1R antagonist, counteracted the ameliorative effect of SKF38393 on THIO. Co-immunoprecipitation (CO-IP) experiments further demonstrated the specific interaction between H3R and D1R in METH CPP mice. The rewarding effect of METH was also significantly blocked by the interruption of CMV-transmembrane domain 5 (TM5), but not CMV-transmembrane domain 7 (TM7) in NAc. CONCLUSION: These results suggest that modulating the activity of H3R-D1R complex holds promise for regulating METH use disorder and serves as a potential drug target for its treatment.


Assuntos
Metanfetamina , Camundongos Endogâmicos C57BL , Receptores de Dopamina D1 , Receptores Histamínicos H3 , Animais , Metanfetamina/farmacologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Masculino , Camundongos , Receptores Histamínicos H3/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Recompensa , Multimerização Proteica/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos
2.
Brain Behav Immun ; 120: 167-180, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38834156

RESUMO

It is widely believed that the activation of the central dopamine (DA) system is crucial to the rewarding effects of methamphetamine (METH) and to the behavioral outcomes of METH use disorder. It was reported that METH exposure induced gasdermin D (GSDMD)-dependent pyroptosis in rats. The membrane pore formation caused by METH-induced pyroptosis may also contribute to the overflow of DA into the extracellular space and subsequently increase the DA levels in the brain. The present study firstly investigated whether the membrane pore information induced by GSDMD-dependent pyroptosis was associated with the increased DA levels in the ventral tegmental area (VAT) and nucleus accumbens (NAc) of rats self-administering METH and SY-SH5Y cells treated by METH. Subsequently, the effect of pore formation blockade or genetic inhibition of GSDMD on the reinforcing and motivational effect of METH was determined in rats, using the animal model of METH self-administration (SA). METH exposure significantly increased the activity of NLRP1/Cas-1/GSDMD pathway and the presence of pyroptosis, accompanied by the significantly increased DA levels in VTA and NAc. Moreover, intraperitoneal injections of disulfiram (DSF) or microinjection of rAAV-shGSDMD into VTA/NAc significantly reduced the reinforcing and motivational effect of METH, accompanied by the decreased level of DA in VTA and NAc. The results provided novel evidence that METH-induced pyroptosis could increase DA release in VTA and NAc via the NLRP1/Cas-1/GSDMD pathway. Additionally, membrane pores or GSDMD blockade could significantly reduce the reinforcing and motivational effect of METH. In conclusion, blocking GSDMD and membrane pore formation could be a promising potential target for the development of agents to treat METH use disorder.


Assuntos
Dopamina , Metanfetamina , Núcleo Accumbens , Proteínas de Ligação a Fosfato , Piroptose , Autoadministração , Área Tegmentar Ventral , Animais , Metanfetamina/farmacologia , Metanfetamina/administração & dosagem , Piroptose/efeitos dos fármacos , Masculino , Proteínas de Ligação a Fosfato/metabolismo , Ratos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Dopamina/metabolismo , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ratos Sprague-Dawley , Humanos , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Gasderminas
3.
Neurosci Lett ; 823: 137630, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38215873

RESUMO

OBJECTIVE: Methamphetamine (METH) exposure commonly causes cognitive impairment. An angiotensin II receptor/neprilysin inhibitor (ARNI), LCZ696 has been demonstrated to inhibit inflammation, oxidative stress and apoptosis. The present study was designed to examine the effect of LCZ696 on METH-induced cognitive impairment and the underlying mechanism. METHODS: Following daily treatment of either saline or METH (5 mg/kg) for 5 consecutive days, the cognitive function was tested using the Y-maze and the Novel Object Recognition (NOR) in Experiment 1. In Experiment 2, mice were initially treated with saline or LCZ696 (60 mg/kg) for 9 consecutive days, followed by LCZ696, METH or saline for 5 days. Cognitive testing was carried out as Experiment 1. In Experiment 3, SH-SY5Y cells were treated with either METH (2.5 Mm) or ddH2O for 12 h. The apoptosis and reactive oxygen species (ROS) level of SH-SY5Y were examined. In Experiment 4, SH-SY5Y cells were pretreated with either ddH2O or LCZ696 (70um) for 30 min, followed by ddH2O or METH treatment for 12 h. Nrf2 and HO-1 protein expression was examined in the ventral tegemental area (VTA) of all the animals and SH-SY5Y cells. RESULTS: LCZ696 significantly improved METH-induced cognitive impairment, in conjunction with decreased apoptosis and ROS levels in VTA of METH-treated mice and SH-SY5Y cells. METH significantly decreased Nrf2 and HO-1 protein expression in VTA of mice and SH-SY5Y cells, which was reversed by LCZ696 treatment. CONCLUSION: LCZ696 yields a neuroprotective effect against METH-induced cognitive dysfunction via the Nrf2/HO-1 signaling pathway.


Assuntos
Aminobutiratos , Compostos de Bifenilo , Disfunção Cognitiva , Metanfetamina , Neuroblastoma , Fármacos Neuroprotetores , Valsartana , Animais , Humanos , Metanfetamina/toxicidade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2 , Linhagem Celular Tumoral , Neuroblastoma/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Apoptose , Combinação de Medicamentos
4.
Addict Biol ; 28(8): e13307, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37500489

RESUMO

Methamphetamine (METH) use disorder is a chronic, relapsing disorder and involves frequent failures of self-control of drug seeking and taking. Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenolic compounds of green tea, which has shown great therapeutic effectiveness in neurological disorders. However, it is still unknown whether and how EGCG affects METH seeking behaviour. Here, we show nanostructured EGCG/ascorbic acid nanoparticles (EGCG/AA NPs) dose-dependently reduced METH self-administration (SA) under fixed-ratio 1 (FR1) and progressive ratio (PR) reinforcement schedules in mice and shifted METH dose-response curves downward. Furthermore, EGCG/AA NPs decreased drug- and cue-induced METH seeking. In addition, we found that METH SA led to a decrease in inhibitory postsynaptic currents (IPSCs) and increase in the AMPAR/NMDAR ratio and excitation/inhibition (E/I) ratio in ex vivo midbrain slices from ventral tegmental area (VTA) dopamine neurons. EGCG/AA NPs enhanced Gamma-aminobutyric acid (GABA)ergic inhibition and normalized the E/I ratio. EGCG restored the balance between excitation and inhibition in VTA dopamine neurons, which may contribute to the attenuation of METH SA. These findings indicate that EGCG is a promising pharmacotherapy for METH use disorder.


Assuntos
Catequina , Metanfetamina , Camundongos , Animais , Metanfetamina/farmacologia , Catequina/farmacologia , Esquema de Reforço , Ácido Ascórbico , Autoadministração , Comportamento de Procura de Droga
5.
Life Sci Alliance ; 6(3)2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36669783

RESUMO

For the past decade, the prevalence and mortality of methamphetamine (METH) use have doubled, suggesting that METH use could be the next substance use crisis worldwide. Ingested METH is transformed into other products in the liver, a major metabolic organ. Studies have revealed that METH causes deleterious inflammatory response, oxidative stress, and extensive DNA damage. These pathological damages are driving factors of hepatocellular carcinoma (HCC). Nonetheless, the potential role of METH in HCC and the underlying mechanisms remain unknown. Herein, we found a higher HCC incidence in METH abusers. METH promoted cellular proliferation, migration, and invasion in two human-derived HCC cells. Consistently, METH uptake promoted HCC progression in a xenograft mouse model. Mechanistically, METH exposure induced ROS production, which activated the Ras/MEK/ERK signaling pathway. Clearance of ROS by NAC suppressed METH-induced activation of Ras/ERK1/2 pathways, leading to arrest of HCC xenograft formation in nude mice. To the best of our knowledge, this is the first study to substantiate that METH promotes HCC progression and inhibition of ROS may reverse this process.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Metanfetamina , Humanos , Camundongos , Animais , Carcinoma Hepatocelular/patologia , Metanfetamina/farmacologia , Neoplasias Hepáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , Camundongos Nus
6.
Pharmacol Biochem Behav ; 222: 173512, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36572112

RESUMO

OBJECTIVE: Methamphetamine (METH) exposure is commonly believed to result in cognitive impairment. Histamine H3 receptor (H3R) antagonists reportedly have potential applications for treating cognitive impairment accompanied by various neuropsychiatric disorders. The present study aimed to investigate the effect of H3R blockade by Thioperamide (THIO) on METH-induced cognitive impairment and the underlying mechanism. METHODS: In Experiment 1, C57BL/6 mice received daily injections of saline or 5 mg/kg METH for 5 consecutive days. The Novel Object Recognition (NOR) and Morris water maze (MWM) tasks were used to assess cognitive functions of mice. H3R protein expression and apoptosis were subsequently measured in the hippocampus. In Experiment 2, HT22 cells were first treated with ddH2O or 3 mM METH. The cell survival rate and H3R protein level were subsequently assessed. In Experiment 3, the animals were first treated with saline or 20 mg/kg THIO for 7 days, followed by co-administration of either saline or 5 mg/kg METH for an additional 5 days. The remaining experiments were carried out in the same manner as Experiment 1. In Experiment 4, HT22 cells were pretreated with either ddH2O or 5 mM THIO for 2 h, followed by ddH2O or 3 mM METH treatment for an additional 12 h. The remaining experiments were carried out in the same manner as Experiment 2. In Experiment 5, the changes in MEK1/2, p-MEK1/2, ERK1/2 and p-ERK1/2 protein levels were examined in the hippocampus of all mice from Experiment 3 and HT22 cells from Experiment 4. RESULTS: METH-treated mice showed significantly worsened NOR and MWM performance, along with markably hippocampal apoptosis. A significantly lower cell survival rate was observed in METH-treated HT22 cells. Increased levels of H3R protein were found in both METH-treated mice and HT22 cells. THIO significantly improved METH-induced cognitive impairment in mice and toxicity in HT22 cells. METH significantly increased the level of p-MEK1/2 and p-ERK1/2 proteins in the hippocampus of mice and HT22 cells, which was reversed by THIO pretreatment. CONCLUSION: Our findings reveal that H3R blockade by THIO yields a neuroprotective effect against METH-induced cognitive impairment in mice and toxicity in HT22 cells via the raf-MEK-ERK signaling pathway.


Assuntos
Disfunção Cognitiva , Metanfetamina , Fármacos Neuroprotetores , Receptores Histamínicos H3 , Animais , Camundongos , Fármacos Neuroprotetores/farmacologia , Receptores Histamínicos H3/metabolismo , Transtornos da Memória/induzido quimicamente , Camundongos Endogâmicos C57BL , Histamina
7.
Brain Sci ; 12(8)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36009120

RESUMO

The NLRP inflammasome is a multi-protein complex which mainly consists of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain. Its activation is linked to microglial-mediated neuroinflammation and partial neuronal degeneration. Many neuropsychiatric illnesses have increased inflammatory responses as both a primary cause and a defining feature. The NLRP inflammasome inhibition delays the progression and alleviates the deteriorating effects of neuroinflammation on several neuropsychiatric disorders. Evidence on the central effects of the NLRP inflammasome potentially provides the scientific base of a promising drug target for the treatment of neuropsychiatric disorders. This review elucidates the classification, composition, and functions of the NLRP inflammasomes. It also explores the underlying mechanisms of NLRP inflammasome activation and its divergent role in neuropsychiatric disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, depression, drug use disorders, and anxiety. Furthermore, we explore the treatment potential of the NLRP inflammasome inhibitors against these disorders.

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