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1.
Bratisl Lek Listy ; 121(3): 225-229, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115981

RESUMO

AIM: Nicotine at high concentrations induces apoptosis in trophoblastic cells through induction of cell cytotoxicity and Reactive Oxygen Species (ROS). Methamphetamine in low dose has pharmaceutical properties. It seems that this components in low dose can protect the trophoblastic cells from nicotine-induced cell death. METHOD: Trophoblastic (JEG-3) cells grown in DMEM culture medium. MTT assay test detected the cell viability and Lactate Dehydrogenase test measured the cells cytotoxicity. Griess reaction was used for NO production analysis. Cell migration traced by wounding technique. Human Cytokine Array Focused 13-plex was also used for analysis of IL-1α, IL-1ß, IL-6, INFγ, and TNFα pre-inflammatory cytokines. RESULTS: Methamphetamine, in very low dose (pM), increased the cell viability and NO production, and decreased cell cytotoxicity, IL-1α, IL-1ß, IL-6, INFγ, and TNFα pre-inflammatory cytokines of JEG-3 cell which were exposed to high dose of nicotine, respectively. Cell migration was enhanced by low dose of methamphetamine in JEG-3 cells. CONCLUSION: Methamphetamine in very low dose suppressed the JEG-3 cell death induced by high dose of nicotine (Fig. 5, Ref. 48) Keywords: methamphetamine, nicotine, cell death, NO.


Assuntos
Dopaminérgicos , Inflamação , Metanfetamina , Trofoblastos , Linhagem Celular Tumoral , Sobrevivência Celular , Dopaminérgicos/farmacologia , Humanos , Inflamação/tratamento farmacológico , Metanfetamina/farmacologia , Nicotina/toxicidade , Trofoblastos/efeitos dos fármacos
2.
Asian Pac J Cancer Prev ; 20(9): 2763-2774, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31554375

RESUMO

Objective: Interaction of methamphetamine and sigma (σ) receptors lead to up-regulation and activation of these receptors. The σ receptors induced apoptosis in some parts of the brain by increasing calcium, dopamine, ROS, mitochondrial pores and caspase activity. Ibudilast is a phosphodiesterase inhibitor and anti-inflammatory drug, which can decrease the inflammatory cytokines. Also, it has a neuroprotective effect. It seems that ibudilast can reduce the methamphetamine-induced cell death due to inhibition of σ receptors. Materials and Methods: There were seven treatments including; control: culture medium, Treatment 1: 1mM methamphetamine, Treatment 2: 1mM methamphetamine and 1nM ibudilast, Treatment 3: 1mM methamphetamine and 10nM ibudilast, Treatment 4: 1mM methamphetamine and 100nM ibudilast, Treatment 5: 1mM methamphetamine and 1uM ibudilast, Treatment 6: 1mM methamphetamine and 10uM ibudilast, and Treatment 7: 1mM methamphetamine and 100uM ibudilast. Finally, for inhibition of PKA, CREB, IP3 receptor, NMDA receptor, Sigma receptor antagonist, sigma receptor agonist, cells were preincubated with adding H89 dihydrochloride, 666-15, Heparin, Ketamine, BMY 14802, and Pentazocine. MTT and LDH tests were performed for cell viability and cytotoxicity measurement, respectively. In continuing, the caspase activity colorimetric assay kit used for caspase 3 activity diagnosis. Rhodamine-123 performed to detection of mitochondrial membrane potential. TUNEL test used to DNA fragmentation and apoptosis, Fura-2 used to Measurement of (Ca2+) ic and (Ca2+) m, and fluorescence microscope used to Measurement of antioxidant enzyme activities. Results: Ibudilast increased the cell viability and the rhodamine-123 absorbance in methamphetamin-treated PC12 cells. It reduced cell cytotoxicity, caspase 3 activity, ic and m Ca2+ concentration, (OH) generation and DNA fragmentation in all concentrations of 1 nM t0 100 µM (p<0.05) by the optimal concentration of 100 µM, between our tested treatments. Conclusion: Ibudilast as a phosphodiesterase inhibitor can reduce the methamphetamine-induced cell death due to inhibition of σ receptors through cAMP production.


Assuntos
Apoptose/efeitos dos fármacos , Metanfetamina/farmacologia , Mitocôndrias/patologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Broncodilatadores/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Combinação de Medicamentos , Mitocôndrias/efeitos dos fármacos , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo
3.
Pharmacol Biochem Behav ; 185: 172759, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31415776

RESUMO

Susceptibility to interference can be a result of memory retrieval and reconsolidation. Given the fact that addiction develops through the neural mechanisms of learning and memory, it would not be surprising that a consolidated drug reward memory may also be susceptible to interference following retrieval/reconsolidation. Due to the critical role of sleep in memory consolidation, sleep deprivation (SD) has been shown to impair memory. Therefore, the major objective of this study was to investigate the effect of rapid eye movement (REM) sleep deprivation (RSD) on the retrieval and reconsolidation of methamphetamine (METH) reward memory in male rats. The animals were trained to acquire METH-induced CPP (2 mg/kg, i.p.). METH reward memory was then reactivated/retrieved in the drug-paired chamber during a drug-free (memory reactivation) session. A period of 48-h RSD paradigm using the multiple platform technique resulted in persistent deficits in the retrieval of METH reward memory. Nevertheless, the same protocol of RSD, which was conducted immediately after the memory reactivation, did not affect the reconsolidation of METH reward memory. Additionally, the RSD episode induced a temporary potentiation of METH-induced hyperlocomotion. Our findings would seem to suggest that sleep is involved in the retrieval, but not reconsolidation, of METH reward memory. The results may also demonstrate that RSD mimics the effects of METH on locomotor activity. The results of this study, therefore, support the idea that sleep is involved in the processing of METH reward memory which can be considered for further investigations to manage the relapse associated with drug-related memory.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Memória/efeitos dos fármacos , Metanfetamina/farmacologia , Recompensa , Privação do Sono/psicologia , Sono REM/fisiologia , Animais , Comportamento Aditivo , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Comportamento de Procura de Droga , Locomoção/efeitos dos fármacos , Masculino , Metanfetamina/administração & dosagem , Ratos , Ratos Wistar , Recidiva , Solução Salina/administração & dosagem , Solução Salina/farmacologia , Privação do Sono/fisiopatologia
4.
Mol Pharmacol ; 96(4): 493-504, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31409621

RESUMO

Methamphetamine (MA) is highly addictive and neurotoxic, causing cell death in humans and in rodent models. MA, along with many of its analogs, is an agonist at the G protein-coupled trace amine-associated receptor 1 (TAAR1). TAAR1 activation protects against MA-induced degeneration of dopaminergic neurons, suggesting that TAAR1 plays a role in regulating MA-induced neurotoxicity. However, the mechanisms involved in TAAR1's role in neurotoxicity and cell death have not been described in detail. In this study, we investigated the apoptosis pathway in Taar1 wild-type (WT) and knockout (KO) mice and in cells expressing the recombinant receptor. Bcl-2, an antiapoptotic protein, was upregulated ∼3-fold in the midbrain area (substantial nigra and ventral tegmental area) in Taar1 KO compared with WT mice, and MA significantly increased Bcl-2 expression in WT mice but decreased Bcl-2 expression in KO mice. The proapoptotic protein Bax did not differ across genotype or in response to MA. Bcl-2 expression was significantly upregulated by the TAAR1 agonist RO5166017 ((S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine) in cells expressing the recombinant mouse TAAR1. Additionally, activation of TAAR1 by RO5166017 increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and protein kinase B (AKT), but only inhibition of ERK1/2 phosphorylation prevented TAAR1-induced increases in Bcl-2 levels, indicating that TAAR1 activation increases Bcl-2 through an ERK1/2-dependent pathway. All changes to ERK1/2 pathway intermediates were blocked by the TAAR1 antagonist, N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl) benzamide. These findings suggest that TAAR1 activation protects against MA-induced cell apoptosis and TAAR1 may play a role in cell death in neurodegenerative diseases. SIGNIFICANCE STATEMENT: Methamphetamine stimulates TAAR1, a G protein-coupled receptor. The role and mechanisms for TAAR1 in methamphetamine-induced neurotoxicity are not known. Here, we report that, in genetic mouse models and cells expressing the recombinant receptor, TAAR1 activates the ERK1/2 pathway but not the AKT pathway to upregulate the antiapoptotic protein Bcl-2, which protects cells from drug-induced toxicity.


Assuntos
Metanfetamina/efeitos adversos , Neurônios/citologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Acoplados a Proteínas-G/genética , Animais , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mesencéfalo/metabolismo , Metanfetamina/farmacologia , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxazóis/farmacologia , Fenetilaminas/farmacologia , Fosforilação/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/metabolismo , Regulação para Cima
5.
Curr HIV Res ; 17(2): 126-133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31269883

RESUMO

BACKGROUND: Methamphetamine abuse and human immunodeficiency virus (HIV) are common comorbidities. HIV-associated proteins, such as the regulatory protein TAT, may contribute to brain reward dysfunction, inducing an altered sensitivity to methamphetamine reward and/or withdrawal in this population. OBJECTIVE: These studies examined the combined effects of TAT protein expression and, chronic and binge methamphetamine regimens on brain reward function. METHODS: Transgenic mice with inducible brain expression of the TAT protein were exposed to either saline, a chronic, or a binge methamphetamine regimen. TAT expression was induced via doxycycline treatment during the last week of methamphetamine exposure. Brain reward function was assessed daily throughout the regimens, using the intracranial self-stimulation procedure, and after a subsequent acute methamphetamine challenge. RESULTS: Both methamphetamine regimens induced withdrawal-related decreases in reward function. TAT expression substantially, but not significantly increased the withdrawal associated with exposure to the binge regimen compared to the chronic regimen, but did not alter the response to acute methamphetamine challenge. TAT expression also led to persistent changes in adenosine 2B receptor expression in the caudate putamen, regardless of methamphetamine exposure. These results suggest that TAT expression may differentially affect brain reward function, dependent on the pattern of methamphetamine exposure. CONCLUSION: The subtle effects observed in these studies highlight that longer-term TAT expression, or its induction at earlier stages of methamphetamine exposure, may be more consequential at inducing behavioral and neurochemical effects.


Assuntos
Encéfalo/efeitos dos fármacos , Metanfetamina/farmacologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Animais , Encéfalo/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Receptores Purinérgicos P1/genética , Recompensa , Regulação para Cima/efeitos dos fármacos , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
6.
EBioMedicine ; 45: 432-446, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31255657

RESUMO

BACKGROUND: Betaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. We aimed to test the role of betaine in schizophrenia pathophysiology, and to evaluate its potential as a novel psychotherapeutic. METHODS: Using Chdh (a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses. FINDINGS: The Chdh-deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations in the brain. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine (PCP) treatments. Betaine also showed a prophylactic effect on behavioral abnormality induced by PCP. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with "betaine deficit-oxidative stress pathology". We revealed the decrease of betaine levels in glyoxylase 1 (GLO1)-deficient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, a CHDH variant, rs35518479, was identified as a cis-expression quantitative trait locus (QTL) for CHDH expression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy. INTERPRETATION: The present study revealed the role of betaine in psychiatric pathophysiology and underscores the potential benefit of betaine in a subset of schizophrenia. FUND: This study was supported by the Strategic Research Program for Brain Sciences from AMED (Japan Agency for Medical Research and Development) under Grant Numbers JP18dm0107083 and JP19dm0107083 (TY), JP18dm0107129 (MM), JP18dm0107086 (YK), JP18dm0107107 (HY), JP18dm0107104 (AK) and JP19dm0107119 (KH), by the Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT under Grant Numbers JP18H05435 (TY), JP18H05433 (AH.-T), JP18H05428 (AH.-T and TY), and JP16H06277 (HY), and by JSPS KAKENHI under Grant Number JP17H01574 (TY). In addition, this study was supported by the Collaborative Research Project of Brain Research Institute, Niigata University under Grant Numbers 2018-2809 (YK) and RIKEN Epigenetics Presidential Fund (100214-201801063606-340120) (TY).


Assuntos
Betaína/farmacologia , Colina Desidrogenase/genética , Psicotrópicos/farmacologia , Esquizofrenia/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Metilação de DNA/efeitos dos fármacos , Suplementos Nutricionais , Modelos Animais de Doenças , Genótipo , Humanos , Japão , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Metanfetamina/farmacologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Locos de Características Quantitativas , Esquizofrenia/genética , Esquizofrenia/fisiopatologia
7.
Neurochem Res ; 44(9): 2081-2091, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31338719

RESUMO

Methamphetamine (meth) use is often comorbid with anxiety disorders, with both conditions predominant during adolescence. Conditioned fear extinction is the most widely used model to study the fear learning and regulation that are relevant for anxiety disorders. The present study investigates how meth binge injections or meth self-administration affect subsequent fear conditioning, extinction and retrieval in adult and adolescent rats. In experiment 1, postnatal day 35 (P35-adolescent) and P70 (adult) rats were intraperitoneally injected with increasing doses of meth across 9 days. At P50 or P85, they underwent fear conditioning followed by extinction and test. In experiments 2a-c, P35 or P70 rats self-administered meth for 11 days then received fear conditioning at P50 or P85, followed by extinction and test. We observed that meth binge exposure caused a significant disruption of extinction retrieval in adult but not adolescent rats. Interestingly, meth self-administration in adolescence or adulthood disrupted acquisition of conditioned freezing in adulthood. Meth self-administration in adolescence did not affect conditioned freezing in adolescence. These results suggest that intraperitoneal injections of high doses of meth and meth self-administration have dissociated effects on fear conditioning and extinction during adulthood, while adolescent fear conditioning and extinction are unaffected.


Assuntos
Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Memória/efeitos dos fármacos , Metanfetamina/farmacologia , Animais , Injeções Intraperitoneais , Masculino , Metanfetamina/administração & dosagem , Ratos Sprague-Dawley , Autoadministração
8.
PLoS One ; 14(6): e0217880, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31194769

RESUMO

Protein tyrosine phosphatase receptor type Z (PTPRZ) is preferentially expressed in the central nervous system as two transmembrane receptor isoforms PTPRZ-A/B and one secretory isoform PTPRZ-S. Ptprz-knockout mice lacking the expression of all three isoforms show behavioral, learning, and neurological abnormalities, including increased exploratory activities to novelty, deficits in spatial and contextual learning, and reduced responses to methamphetamine, relative to wild-type mice. To investigate whether PTPRZ isoforms play distinct physiological roles, we herein performed behavioral studies on two knock-in mouse lines: One expresses the catalytically inactive Cys-1930 to Ser (CS) mutants of PTPRZ-A/B, while the other generated in the present study expresses catalytically active mutants of PTPRZ-A/B lacking the negative regulatory PTP-D2 domain and C-terminal PDZ-binding motif (ΔD2) instead of wild-type PTPRZ-A/-B. In contrast to Ptprz-knockout mice, neither increased responses to novelty in the open field nor memory impairments in the inhibitory-avoidance task were observed in Ptprz-CS or Ptprz-ΔD2 mice. However, the effects of methamphetamine on locomotor activity were significantly weaker in Ptprz-KO mice and CS mutant mice than in wild-type mice, but were normal in ΔD2 mutant mice. Furthermore, microdialysis experiments revealed that methamphetamine-evoked dopamine release in the nucleus accumbens was reduced in Ptprz-KO mice and CS mutant mice. These results suggest that the extracellular region of PTPRZ, including the secretory isoform, is crucial for behavioral responses to novelty and the formation of aversive memories, whereas the PTPase activities of PTPRZ receptor isoforms are involved in regulating the dopaminergic system.


Assuntos
Comportamento Animal , Mutação com Perda de Função , Núcleo Accumbens/metabolismo , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Substituição de Aminoácidos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Catálise , Dopamina/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Feminino , Técnicas de Introdução de Genes , Locomoção/efeitos dos fármacos , Masculino , Metanfetamina/farmacologia , Camundongos , Camundongos Knockout , Núcleo Accumbens/efeitos dos fármacos , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/química , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo
9.
Psychopharmacology (Berl) ; 236(11): 3281-3289, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31197434

RESUMO

RATIONALE: Juvenile social isolation (SI) and neglect is associated with a wide range of psychiatric disorders. While dysfunction of the corticolimbic pathway is considered to link various abnormal behaviors in SI models of schizophrenia, the enduring effects of early social deprivation on physiological properties of medium spiny neurons (MSNs) in nucleus accumbens (NAc) are not well understood. OBJECTIVES: This study investigated the impacts of juvenile SI on locomotor activity to methamphetamine (METH) and neurophysiological characteristics of MSNs in the core of NAc. METHODS: Socially isolated C57BL/6 mice experienced single housing for 4 weeks on postnatal day (PND) 21. The locomotor response to METH (1.0 mg/kg) was observed in both socially isolated and group-housed mice at PND 56. The effects of juvenile SI on the excitatory synaptic events in MSNs and the intrinsic excitability of MSNs in NAc core were investigated in other batches during PND 63-70. RESULTS: Socially isolated mice showed locomotor hypersensitivity to METH, although the expression of locomotor sensitization to METH in socially isolated mice was not different from group-housed mice. The recordings from MSNs of SI-reared mice exhibited higher frequency and smaller amplitude of miniature/spontaneous excitatory postsynaptic current than those from group-reared mice. Moreover, SI resulted in increased intrinsic excitability of MSNs in adult mice. CONCLUSIONS: These results demonstrate neuronal hyperactivity in the NAc of socially isolated mice, which could contribute to locomotor hypersensitivity to METH. Furthermore, the findings indicate a biological link between early negative life events and the vulnerability to psychostimulant-induced psychosis in adulthood.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Neurônios/efeitos dos fármacos , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Isolamento Social/psicologia , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Metanfetamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Neurônios/fisiologia , Núcleo Accumbens/fisiologia , Gravidez
10.
Psychopharmacology (Berl) ; 236(8): 2413-2423, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31165207

RESUMO

RATIONALE: Methamphetamine (MA) use is steadily increasing and thus constitutes a major public health concern. Women seem to be particularly vulnerable to developing MA use disorder, as they initiate use at a younger age and transition more quickly to problematic use. Initial drug responses may predict subsequent use, but little information exists on potential gender differences in the acute effects of MA prior to dependence. OBJECTIVE: We examined gender differences in the acute effects of MA on subjective mood and reward-related behavior in healthy, non-dependent humans. METHODS: Men (n = 44) and women (n = 29) completed 4 sessions in which they received placebo or MA under double-blind conditions twice each. During peak drug effect, participants completed the monetary incentive delay task to assess reaction times to cues signaling potential monetary losses or gains, in an effort to determine if MA would potentiate reward-motivated behavior. Cardiovascular and subjective drug effects were assessed throughout sessions. RESULTS: Overall, participants responded more quickly to cues predicting incentivized trials, particularly large-magnitude incentives, than to cues predicting no incentive. MA produced faster reaction times in women, but not in men. MA produced typical stimulant-like subjective and cardiovascular effects in all participants, but subjective ratings of vigor and (reduced) sedation were greater in women than in men. CONCLUSIONS: Women appear to be more sensitive to the psychomotor-related behavioral and subjective effects of MA. These findings provide initial insight into gender differences in acute effects of MA that may contribute to gender differences in problematic MA use.


Assuntos
Afeto/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Metanfetamina/farmacologia , Tempo de Reação/efeitos dos fármacos , Recompensa , Caracteres Sexuais , Adolescente , Adulto , Afeto/fisiologia , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Sinais (Psicologia) , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Motivação/efeitos dos fármacos , Motivação/fisiologia , Tempo de Reação/fisiologia , Adulto Jovem
11.
Bratisl Lek Listy ; 120(5): 336-343, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31113195

RESUMO

OBJECTIVE: Methamphetamine in low doses can increase vigilance and power and at high doses has destructive effects that cause toxicity and death of various cell lines and affect the central nervous system. Morphine has also protective properties, which were observed in low concentrations, for nerve cells and also seem to have the ability to reduce cell death in neural cell lines. MATERIALS AND METHODS: In this study, we used PC12 and U87 cell lines, which grew in DMEM culture media. Assays used in this study are listed below: MTT test for cell viability detection, LDH test for cytotoxicity measurement, caspase activity colorimetric assay kit (Bio-techne) for caspase 3 activity diagnosis, Rhodamine 123 for Detection of mitochondrial membrane potential. TUNNEL test for DNA fragmentation, fura-2 for Measurement of (Ca2+) ic and (Ca2+) m. fluorescence microscope for measurement of antioxidant enzyme activities. RESULTS: morphine increased cell viability and the rhodamine-123 absorbance. It reduced cell cytotoxicity, caspase 3 activity, ic (et) m Ca2+ concentration, (.OH) generation, and DNA fragmentation in all concentrations of 1 pM t0 100 nM (p < 0.05) by optimal concentration of 1 pM. CONCLUSION: morphine as a pain mediator can reduce the methamphetamine-induced cell death, may be due to its anti-inflammatory properties (Fig. 7, Ref. 52).


Assuntos
Morte Celular , Metanfetamina , Morfina , Espécies Reativas de Oxigênio , Animais , Apoptose , Caspase 3/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular , Metanfetamina/farmacologia , Morfina/farmacologia , Ratos
12.
Psychopharmacology (Berl) ; 236(11): 3147-3158, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31139878

RESUMO

RATIONALE: Previous research indicates that the selective sigma-1 receptor ligand PD144418 and the selective sigma-2 ligands YUN-252 can inhibit cocaine-induced hyperactivity. The effects of these ligands on other stimulants, such as methamphetamine, have not been reported. OBJECTIVES: The present study examined the effects of PD144418 and YUN-252 pretreatment on methamphetamine-induced hyperactivity after acute treatment. METHODS: Mice (n = 8-14/group) were injected with PD144418 (3.16, 10, or 31.6 µmol/kg), YUN-252 (0.316, 3.16, 31.6 µmol/kg), or saline. After 15 min, mice injected with 2.69 µmol/kg methamphetamine or saline vehicle, where distance traveled during a 60-min period was recorded. Additionally, the effect of PD144418 on the initiation and expression of methamphetamine sensitization was determined by treating mice (n = 8-14/group) with PD144418, methamphetamine or saline repeatedly over a 5-day period, and testing said mice with a challenge dose after a 7-day withdrawal period. RESULTS: Results indicate that both PD144418 and YUN-252, in a dose-dependent manner, attenuated hyperactivity induced by an acute methamphetamine injection. Specifically, 10 µmol/kg or 31.6 µmol/kg of PD144418 and 31 µmol/kg of YUN-252 suppressed methamphetamine-induced hyperactivity. In regard to methamphetamine sensitization, while 10 µmol/kg PD144418 prevented the initiation of methamphetamine sensitization, it did not have an effect on the expression. CONCLUSIONS: Overall, the current results suggest an intriguing potential for this novel sigma receptor ligand as a treatment for the addictive properties of methamphetamine. Future analysis of this novel sigma receptor ligand in assays directly measuring reinforcement properties will be critical.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Isoxazóis/metabolismo , Locomoção/efeitos dos fármacos , Metanfetamina/farmacologia , Piridinas/metabolismo , Receptores sigma/metabolismo , Animais , Estimulantes do Sistema Nervoso Central/antagonistas & inibidores , Isoxazóis/farmacologia , Ligantes , Locomoção/fisiologia , Masculino , Camundongos , Piridinas/farmacologia , Receptores sigma/antagonistas & inibidores
13.
Nihon Yakurigaku Zasshi ; 153(5): 224-230, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31092755

RESUMO

Decision-making is a key activity process that influences many aspects of daily living and both mental and physical health. In general, healthy participants reveal rational choice, but patients with neuropsychiatric disorders reveal irrational and risky choice in decision-making. Addiction is one of typical diseases revealed risky decision-making, addicts select risky action and options that confer short-term rewards at the cost of long-term disadvantages. Thus, irrational and risky decision-making is recognized as a core problem in patients with neuropsychiatric disorders, and a better understanding of the mechanisms underlying altered decision-making would provide insights into potential therapeutic approaches for these diseases. However, the neural pathway and substrates underlying these deficits are particularly unknown. Recently, we found that insular cortex is one of key regions for risky decision-making in an animal model of methamphetamine addiction, by using the designer receptor exclusively activated by designer drug (DREADD) technology, and that GABAergic dysfunction in insular cortex is involved in evaluating the subjective value of reward and reward prediction error. These brain dysfunctions would be related to risk taking behavior in addiction. In this review, we introduced the possible neural pathway related to risky decision-making and behavioral changes in choice strategy using adeno associated virus (AAV).


Assuntos
Córtex Cerebral/fisiologia , Tomada de Decisões , Metanfetamina/farmacologia , Assunção de Riscos , Animais , Dependovirus , Neurônios GABAérgicos/citologia , Humanos , Recompensa
14.
Drug Alcohol Depend ; 199: 50-58, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30986635

RESUMO

BACKGROUND: The development of novel synthetic psychoactive substances continues to accelerate. There are little or no data on the pharmacological mechanisms, behavioral effects, or abuse liability of many of the newer compounds, despite increasing reports of severe adverse effects in recreational users. METHODS: The current study investigated the discriminative stimulus and locomotor stimulant effects of a group of synthetic cathinone analogs: N-ethylpentylone, dimethylone, dibutylone, clephedrone, 3',4'-tetramethylene-α-pyrrolidinovalerophenone (TH-PVP). Locomotor activity was assessed in an open-field assay using Swiss-Webster mice. Discriminative stimulus effects were assessed in Sprague-Dawley rats trained to discriminate either cocaine, methamphetamine or MDMA from vehicle. RESULTS: N-Ethylpentylone, dimethylone, dibutylone and clephedrone increased locomotor activity. Maximal effects were similar among the test compounds. Relative potencies were: methamphetamine > N-ethylpentylone > clephedrone > dimethylone > MDMA > cocaine > dibutylone. TH-PVP dose-dependently depressed locomotor activity. N-Ethylpentylone, dimethylone, dibutylone and clephedrone substituted fully for the discriminative stimulus effects of methamphetamine. N-Ethylpentylone, dibutylone and clephedrone fully substituted for cocaine, whereas dimethylone produced a maximum of 67% drug-appropriate responding. Dimethylone, dibutylone and clephedrone fully substituted for MDMA, whereas N-ethylpentylone produced only 50% drug-appropriate responding. TH-PVP produced a maximum of 38% methamphetamine-appropriate responding, 50% cocaine-appropriate responding, and less than 1% MDMA-appropriate responding. CONCLUSIONS: These data provide initial evidence that the novel psychoactive substances N-ethylpentylone, dimethylone, dibutylone, and clephedrone demonstrate potential for abuse as psychostimulants and/or club drugs, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of methamphetamine, cocaine and/or MDMA. TH-PVP has minimal activity in the assays tested and may have little or no abuse liability.


Assuntos
Alcaloides/farmacologia , Aprendizagem por Discriminação/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Medicamentos Sintéticos/farmacologia , Alcaloides/química , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Aprendizagem por Discriminação/fisiologia , Relação Dose-Resposta a Droga , Locomoção/fisiologia , Masculino , Metanfetamina/farmacologia , Camundongos , Ratos , Ratos Sprague-Dawley
15.
Psychopharmacology (Berl) ; 236(3): 1015-1029, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30980094

RESUMO

RATIONALE: The underlying pharmacological mechanisms of mephedrone, especially as related to interactions with different neurotransmitter systems, are a critical area of study as mephedrone continues to be abused. OBJECTIVE: Direct-acting 5-HT2A/2C receptor agonists and antagonists and D1-3 receptor antagonists were examined in two groups of rats trained to discriminate mephedrone. A high dose of mephedrone was trained to extend previous results with traditional monoamine transporter inhibitors and substrate releasers. A very low dose of mephedrone was trained to preferentially capture serotonergic activity and to minimize the influence of rate-decreasing effects on substitution patterns. Selective 5-HT2A/2C and D1-3 receptor antagonists were examined in both groups. METHODS: Male Sprague-Dawley rats were trained to discriminate either a low dose of 0.5 mg/kg mephedrone (N = 24) or a high dose of 3.2 mg/kg mephedrone (N = 11) from saline. RESULTS: In the low training-dose group, mephedrone, MDMA, methamphetamine, d-amphetamine, cocaine, and enantiomers of mephedrone substituted for mephedrone; mCPP partially substituted overall for mephedrone; and DOI, WAY163909, and morphine failed to substitute for mephedrone. In the high training-dose group, only mephedrone and MDMA substituted for mephedrone. Sulpiride produced a small antagonism of the low training dose of mephedrone while SCH23390, SB242084, and ketanserin altered response rates. CONCLUSIONS: A lower training dose of mephedrone produces a discriminative stimulus fully mimicked by MDMA, methamphetamine, cocaine, and d-amphetamine, whereas a higher training dose of mephedrone requires a discriminative stimulus that was only mimicked by MDMA. Dopaminergic or serotoninergic antagonists failed to produce significant blockade of mephedrone at either training dose.


Assuntos
Alcaloides/farmacologia , Condicionamento Operante/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Metanfetamina/análogos & derivados , Antagonistas da Serotonina/farmacologia , Animais , Benzazepinas/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Condicionamento Operante/fisiologia , Dextroanfetamina/farmacologia , Aprendizagem por Discriminação/fisiologia , Relação Dose-Resposta a Droga , Ketanserina/farmacologia , Masculino , Metanfetamina/farmacologia , Psicotrópicos/farmacologia , Ratos , Ratos Sprague-Dawley
16.
J Pharmacol Exp Ther ; 369(2): 244-258, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30867225

RESUMO

The molecular mechanism and treatment of methamphetamine (METH) use disorder remain unclear. The current study aimed to investigate the role of central angiotensin II receptor (ATR) in drug taking and seeking behavior associated with METH use disorder. The effect of an ATR type 1 (AT1R) antagonist, candesartan cilexetil, on the reinforcing and motivational effects of METH was first assessed using the animal model of METH self-administration (SA) and reinstatement. The levels of dopamine D2 receptor (D2R) and AT1R were subsequently examined. Furthermore, the present study determined the expression of microRNAs (miRNAs) by comparing METH SA, METH-yoked, and Saline-yoked groups. The target miRNAs were further overexpressed in the nucleus accumbens (NAc) via a lentivirus vector to investigate the effects of target miRNAs on METH SA maintained under a fixed ratio 1, progressive ratio, and cue/drug reinstatement of METH SA. The potential role of the AT1R-PLCß-CREB signaling pathway was finally investigated. The results suggest that AT1R blockade effectively reduced METH SA and reinstatement, in conjunction with the counter-regulation of D2R and AT1R. A total of 17 miRNAs targeting Ang II in NAc were found to be associated with the voluntary intake of METH. Furthermore, overexpression of specific miR-219a-5p targeting AT1R-regulated METH SA and reinstatement. The AT1R-PLCß-CREB signaling pathway was found to be associated with the effect of AT1R on the drug-taking and drug-seeking behavior involving METH use disorder.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Metanfetamina/antagonistas & inibidores , Receptores de Angiotensina/metabolismo , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiologia , Sinais (Psicologia) , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Metanfetamina/farmacologia , MicroRNAs/genética , Células PC12 , Fosfolipase C beta/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores de Dopamina D2/metabolismo , Autoadministração , Tetrazóis/farmacologia
17.
Neurotox Res ; 36(1): 132-143, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30879275

RESUMO

Designer drug mixtures popularized as "bath salts" often contain the synthetic cathinones 3,4 methylenedioxypyrovalerone (MDPV), mephedrone, and methylone in various combinations. However, most preclinical investigations have only assessed the effects of individual bath salt constituents, and little is known about whether co-exposure to MDPV, mephedrone, and methylone produces significant neuropharmacological interactions. This study evaluated and compared how MDPV, mephedrone, and methylone influence discrete brain tissue dopamine (DA) levels and motor stimulant responses in mice when administered alone and as a ternary mixture. Male adolescent Swiss-Webster mice received intraperitoneal injections of saline or 1 or 10 mg/kg doses of MDPV, mephedrone, or methylone, or a cocktail of all three cathinones at doses of 1, 3.3, or 10 mg/kg each. The effect of each treatment on DA and DA metabolite levels in mesolimbic and nigrostriatal brain tissue was quantified 15 min after a single exposure using HPLC-ECD. Additionally, locomotor activity was recorded in mice after acute (day 1) and chronic intermittent (day 7) dosing. MDPV, mephedrone, and methylone produced dose-related increases in mesolimbic and nigrostriatal DA levels that were significantly enhanced following their co-administration. In addition, mice treated with the cathinone cocktail displayed decreased locomotor activity on day 1 that was exacerbated by day 7 and not observed with any of the drugs alone. Our findings demonstrate a significant enhanced effect of MDPV, mephedrone, and methylone on both DA, and these effects on DA result in significant alterations in locomotor activity.


Assuntos
Benzodioxóis/farmacologia , Encéfalo/efeitos dos fármacos , Dopaminérgicos/farmacologia , Dopamina/metabolismo , Metanfetamina/análogos & derivados , Pirrolidinas/farmacologia , Animais , Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Drogas Desenhadas/farmacologia , Dopamina/análise , Relação Dose-Resposta a Droga , Lobo Límbico/efeitos dos fármacos , Lobo Límbico/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Metanfetamina/farmacologia , Camundongos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo
18.
Psychopharmacology (Berl) ; 236(7): 2243-2258, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30919007

RESUMO

RATIONALE: Methamphetamine (MA) is an abused psychostimulant that causes cognitive deficits after chronic use. Neostriatal dopamine receptors play a role in MA monoamine neurotoxicity. Blocking dopamine receptors prior to MA exposure in adult rats attenuates monoamine reductions and reactive gliosis. OBJECTIVES: We tested whether blocking dopamine receptors protects against cognitive deficits. METHODS: First, we determined the effects of MA alone versus MA in combination with the dopamine receptor D1 antagonist SCH-23390 or the dopamine receptor D2 antagonist sulpiride on cFos expression and monoamines at the age when rats in the cognitive experiment were to begin testing and monoamines in rats after cognitive testing. RESULTS: SCH-23390 infused into the neostriatum prior to systemic administration of MA attenuated MA-induced cFos activation while sulpiride induced cFos activation. Two weeks after MA, rats had dopamine and serotonin reductions that were attenuated by each antagonist. Other rats treated the same way, were tested for egocentric learning and memory in the Cincinnati water maze, for navigational strategy in a star water maze, and spatial learning and memory in a Morris water maze. Pre-treatment with SCH-23390 or sulpiride attenuated the effects of MA on egocentric and spatial learning and memory. MA-treated rats showed a shift from an egocentric to a disorganized strategy in the star maze that was less disorganized in groups receiving MA and an antagonist. Post-behavior monoamine reductions remained but were attenuated by the antagonists but not identically to what was seen in rats not behaviorally tested. CONCLUSIONS: The results show for the first time that dopamine receptors are mediators of MA-induced cognitive deficits.


Assuntos
Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Metanfetamina/toxicidade , Receptores de Dopamina D1/antagonistas & inibidores , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidade , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/uso terapêutico , Antagonistas dos Receptores de Dopamina D2/farmacologia , Egocentrismo , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Metanfetamina/farmacologia , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo
19.
Neuroscience ; 406: 278-289, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30885640

RESUMO

Methamphetamine (MA), neurotoxic drug of abuse, causes cell death in vitro and in vivo via several mechanisms such as mitochondrial dysfunction. In this study we evaluated the effect of MA on cell viability and mitochondrial biogenesis in primary midbrain culture. Primary mesencephalon cells prepared from E14.5 rat embryo were treated with 0.2-5 mM MA concentrations for 24, 48, and 72 h. Morphological changes of the cells were observed under light microscope. Cell viability and cell death following MA were assessed using MTT assay and immunocytochemistry. Gene expressions of mitochondrial biogenesis-involved factors (PGC1α, NRF1 and TFAM), and neuronal and glial markers were measured by qPCR. Low to moderate MA concentrations elevated cell viability in all time points, while higher concentrations and longer incubation times (48 and 72 h) decreased it. Sphered cell bodies and neurites degeneration were observed following exposure to high MA concentrations. MA at 5 mM concentration decreased the number of ß3-tubulin-, TH-, GFAP- and Iba1-positive cells, and their corresponding mRNA levels; however, 1 mM MA reduced α-synuclein mRNA. Unexpectedly, gene expression of PGC1α, NRF1 and TFAM was increased in response to 5 mM MA, with no changes following 1 mM MA. The results indicated that MA effect on cell viability occurs in a dose-dependent manner. While moderate concentrations increased cell viability, the higher ones reduced it and caused cell death. Mitochondrial biogenesis activation, as a compensatory mechanism, did not prevent neuronal and glial cell death following high MA concentration.


Assuntos
Mesencéfalo/efeitos dos fármacos , Metanfetamina/farmacologia , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Feminino , Mesencéfalo/metabolismo , Mitocôndrias/metabolismo , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Neurônios/metabolismo , Síndromes Neurotóxicas/tratamento farmacológico , Biogênese de Organelas , Ratos Wistar , alfa-Sinucleína/efeitos dos fármacos , alfa-Sinucleína/metabolismo
20.
Behav Brain Res ; 364: 233-244, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-30731099

RESUMO

BACKGROUND: At present, the harm of new-type drug, methamphetamine (METH), has gradually exceeded that of the traditional opioid drugs, and METH abuse has become a serious public health and social problem. In our previous study, complement factor H (CFH) was found to be upregulated in the sera of METH-addicted patients and rats and in certain brain regions in the rats. METHODS: We used ELISA and immunofluorescence to confirm the changes in CFH in the serum and hippocampus of a METH behavioral sensitization mouse model, and C1q expression was also detected by immunofluorescence in the hippocampus. We aimed to elucidate the involvement of CFH and C1q in the mechanism of METH addiction. We also detected the distribution of various small molecules by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) in select brain regions: the nucleus accumbens, the hippocampus and the ventral tegmental area. RESULTS: The expression of CFH was upregulated in the serum and hippocampus of METH behavioral sensitization model mice, consistent with our previous research on conditioned place preference rats. In contrast, C1q decreased dramatically in the mossy fibers of the hippocampus. The results of small-molecule imaging by MALDI-MSI showed that the levels of K+, antioxidants, neurotransmitters, and ATP metabolism-related molecules were altered in different regions. CONCLUSIONS: These results indicate the involvement of the complement system in the mechanism of METH addiction and validate the presence of oxidative stress, energy metabolism changes during addiction. This suggests the utility of further investigation into the above aspects.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Comportamento Animal/efeitos dos fármacos , Fator H do Complemento/metabolismo , Animais , Comportamento Aditivo/metabolismo , Encéfalo/metabolismo , Complemento C1q/metabolismo , Fator H do Complemento/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/metabolismo , Aprendizagem/efeitos dos fármacos , Masculino , Metanfetamina/efeitos adversos , Metanfetamina/metabolismo , Metanfetamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Imagem Molecular/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
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