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1.
J Pharmacol Sci ; 148(3): 326-330, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35177212

RESUMO

Extracellular signal-regulated protein kinase 5 (ERK5) has various physiological functions. However, the physiological role of ERK5 in the treatment of mice with an illicit drug such as methamphetamine (METH) remains unknown. We revealed that mice treated with METH showed hyperactivity, and increased p-ERK5 and Iba1 (a microglia marker) levels in the striatum. Additionally, these changes were inhibited by pretreatment with the ERK5 inhibitor BIX02189. The results suggest that METH-induced hyperactivity is associated with the activation of microglia via p-ERK5 in the striatum. Thus, the ERK5 pathway components in the central nervous system are potential therapeutic targets for preventing METH addiction.


Assuntos
Compostos de Anilina/farmacologia , Corpo Estriado/citologia , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Indóis/farmacologia , Metantelina/efeitos adversos , Microglia/efeitos dos fármacos , Proteína Quinase 7 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 7 Ativada por Mitógeno/fisiologia , Compostos de Anilina/uso terapêutico , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Corpo Estriado/metabolismo , Indóis/uso terapêutico , Camundongos , Proteínas dos Microfilamentos/metabolismo , Microglia/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Agitação Psicomotora , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle
2.
Pharmacol Biochem Behav ; 213: 173337, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35063467

RESUMO

Manganese (Mn) is an essential micronutrient but is neurotoxic in excess. Environmental and genetic factors influence vulnerability to Mn toxicity, including sex, age, and the autosomal dominant mutation that causes Huntington disease (HD). To better understand the differential effects of Mn in wild-type (WT) versus YAC128 mice, we examined impacts of Mn exposure across different ages and sexes on disease-relevant behavioral tasks and dopamine dynamics. Young (3-week) and aged (12-month) WT and YAC128 mice received control (70 ppm) or high (2400 ppm) Mn diet for 8 weeks followed by a battery of behavioral tasks. In young female WT mice, high Mn diet induced hyperactivity across two independent behavioral tasks. Changes in the expression of tyrosine hydroxylase (TH) were consistent with the behavioral data in young females such that elevated TH in YAC128 on control diet was decreased by high Mn diet. Aged YAC128 mice showed the expected disease-relevant behavioral impairments in females and decreased TH expression, but we observed no significant effects of Mn diet in either genotype of the aged group. Fast-scan cyclic voltammetry recorded dopamine release and clearance in the nucleus accumbens of eight-month-old WT and YAC128 mice following acute Mn exposure (3×/1 week subcutaneous injections of 50 mg/kg MnCl[2]-tetrahydrate or saline). In WT mice, Mn exposure led to faster dopamine clearance that resembled saline treated YAC128 mice. Mn treatment increased dopamine release only in YAC128 mice, possibly indirectly correcting the faster dopamine clearance observed in saline treated YAC128 mice. The same exposure paradigm led to decreased dopamine and serotonin and metabolites (3-MT, HVA and 5-HIAA) in striatum and increased glutamate in YAC128 mice but not WT mice. These studies confirm an adverse effect of Mn in young, female WT animals and support a role for Mn exposure in stabilizing dopaminergic dysfunction and motivated behavior in early HD.


Assuntos
Dopamina/metabolismo , Doença de Huntington/metabolismo , Manganês/farmacologia , Atividade Motora/efeitos dos fármacos , Fatores Etários , Animais , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Feminino , Genótipo , Doença de Huntington/genética , Hipercinese/induzido quimicamente , Manganês/toxicidade , Camundongos , Núcleo Accumbens/metabolismo , Serotonina/metabolismo , Fatores Sexuais , Tirosina 3-Mono-Oxigenase/metabolismo
3.
J Clin Psychopharmacol ; 42(3): 238-246, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35489029

RESUMO

PURPOSE/BACKGROUND: Acute hyperkinetic movement disorders have been reported with the concomitant use of attention-deficit/hyperactivity disorder (ADHD) stimulants and antipsychotics in children and adolescents. We analyzed postmarketing reports of suspected acute hyperkinetic movement disorder associated with concomitant use of ADHD stimulants and antipsychotics. METHODS/PROCEDURES: We searched for postmarketing reports of acute hyperkinetic movement disorders associated with concomitant use of ADHD stimulants-antipsychotics in the US Food and Drug Administration Adverse Event Reporting System through December 6, 2019. PubMed and EMBASE were also searched for acute hyperkinetic movement reports with the concomitant use of ADHD stimulants-antipsychotics through January 13, 2020. FINDINGS/RESULTS: We identified 36 cases resulting in acute hyperkinetic movement disorder associated with the concomitant use of ADHD stimulants-antipsychotics, 19 of which were also identified in the medical literature. From an ADHD stimulant perspective, methylphenidate products accounted for the largest number of cases (n = 23 [64%]), followed by amphetamine products (n = 9 [25%]) and atomoxetine (n = 4 [11%]). From an antipsychotic perspective, all 36 cases were reported with second-generation antipsychotics, particularly risperidone (n = 20 [56%]). Most of the cases were reported in boys (n = 31 [86%]) aged 6 to 12 years (n = 27 [75%]). Approximately 53% of the cases reported a time to onset within 24 hours of the drug change. Acute dystonic reactions (n = 27 [75%]) were the most frequently reported movement disorder. IMPLICATIONS/CONCLUSIONS: As outlined in changes to the US prescribing information for all methylphenidate and risperidone products, health care professionals should be aware that changes to this combination may be associated with a pharmacodynamic drug-drug interaction resulting in acute hyperkinetic movement disorder.


Assuntos
Antipsicóticos , Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Adolescente , Anfetamina/uso terapêutico , Antipsicóticos/efeitos adversos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Criança , Interações Medicamentosas , Humanos , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Masculino , Metilfenidato/efeitos adversos , Risperidona/efeitos adversos
4.
Behav Brain Res ; 416: 113544, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34425181

RESUMO

Small-molecule modulators of calcineurin signaling have been proposed as potential therapeutics in Down syndrome and Alzheimer's disease. Models predict that in Down syndrome, suppressed calcineurin-NFAT signaling may be mitigated by proINDY, which activates NFAT, the nuclear factor of activated T-cells. Conversely, elevated calcineurin signaling in Alzheimer's disease may be suppressed with the calcineurin inhibitors cyclosporine and tacrolimus. Such small-molecule treatments may have both beneficial and adverse effects. The current study examines the effects of proINDY, cyclosporine and tacrolimus on behavior, using zebrafish larvae as a model system. To suppress calcineurin signaling, larvae were treated with cyclosporine and tacrolimus. We found that these calcineurin inhibitors induced hyperactivity, suppressed visually-guided behaviors, acoustic hyperexcitability and reduced habituation to acoustic stimuli. To activate calcineurin-NFAT signaling, larvae were treated with proINDY. ProINDY treatment reduced activity and stimulated visually-guided behaviors, opposite to the behavioral changes induced by calcineurin inhibitors. The opposing effects suggest that activity and visually-guided behaviors are regulated by the calcineurin-NFAT signaling pathway. A central role of calcineurin-NFAT signaling is further supported by co-treatments of calcineurin inhibitors and proINDY, which had therapeutic effects on activity and visually-guided behaviors. However, these co-treatments adversely increased excitability, suggesting that some behaviors are regulated by other calcineurin signaling pathways. Overall, the developed methodologies provide an efficient high-throughput platform for the evaluation of modulators of calcineurin signaling that restore neural function, while avoiding adverse side effects, in a complex neural system.


Assuntos
Encéfalo/metabolismo , Inibidores de Calcineurina/farmacologia , Calcineurina/farmacologia , Ciclosporina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra/metabolismo , Animais , Ciclosporina/antagonistas & inibidores , Hipercinese/induzido quimicamente , Fatores de Transcrição NFATC/metabolismo
5.
Commun Biol ; 4(1): 1054, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504272

RESUMO

A predominant trigger and driver of sporadic Alzheimer's disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences have remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind Aß1-42-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that Aß1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD.


Assuntos
Aminopiridinas/farmacologia , Peptídeos beta-Amiloides/farmacologia , Encéfalo/metabolismo , Glucose/metabolismo , Hipercinese/induzido quimicamente , NADPH Oxidase 2/antagonistas & inibidores , NADPH Oxidase 2/genética , Estresse Oxidativo , Sulfonamidas/farmacologia , Animais , Masculino , Camundongos , NADPH Oxidase 2/metabolismo
6.
Neuropharmacology ; 197: 108754, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34389398

RESUMO

Alzheimer's disease (AD) is a profoundly debilitating neurodegenerative disorder characterized most notably by progressive cognitive decline, but also agitation and behavioral disturbances that are extremely disruptive to patient and caregiver. Current pharmacological treatments for these symptoms have limited efficacy and significant side effects. We have recently reported the discovery of Compound 24, an M4 positive allosteric modulator (PAM) that is potent, highly selective, and devoid of cholinergic-like side effects in rats. In order to further evaluate the translatability of the effects of compound 24 in primates, here we describe the effect of Compound 24 on three behavioral and cognition assays in rhesus monkeys, the stimulant induced motor activity (SIMA) assay, the object retrieval detour task (ORD), and the visuo-spatial paired-associates learning (vsPAL) task. As far as we know, this is the first such characterization of an M4 PAM in non-human primate. Compound 24 and the clinical standard olanzapine attenuated amphetamine induced hyperactivity to a similar degree. In addition, Compound 24 demonstrated procognitive effects in scopolamine-impaired ORD and vsPAL, and these effects were of similar magnitude to donepezil. These findings suggest that M4 PAMs may be beneficial to diseases such as Alzheimer's disease and schizophrenia, which are marked by behavioral disturbances as well as deficits in cognitive function.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Comportamento Animal/efeitos dos fármacos , Colinérgicos/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Receptor Muscarínico M4/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Anfetamina/antagonistas & inibidores , Anfetamina/farmacologia , Animais , Aprendizagem por Associação/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central , Colinérgicos/farmacocinética , Transtornos Cognitivos/psicologia , Hipercinese/induzido quimicamente , Hipercinese/prevenção & controle , Macaca mulatta , Masculino , Atividade Motora/efeitos dos fármacos , Olanzapina/farmacologia , Orientação/efeitos dos fármacos
7.
Neurotoxicology ; 85: 209-221, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34097938

RESUMO

Bisphenol S (BPS), an analogue of the controversial bisphenol A (BPA) that is found in epoxy resins and plastics, is a potential endocrine-disrupting chemical that can mimic endogenous hormone signaling. However, little is known about the behavioral or immunologic effects of BPS. The purpose of this study was to examine the impact of diets in BPS-treated mice in relation to hyperglycemia, development of type 1 diabetes, immunomodulation, and behavioral changes. Adult male and female nonobese diabetic excluded flora (NODEF) mice were exposed to environmentally relevant doses of BPS (VH, 30, or 300 µg/kg BW) and fed either a soy-based diet, a phytoestrogen-free diet, or a Western diet. NODEF male mice fed a soy-based diet exhibited a decreased curiosity/desire to explore, and possibly increased anxiety-like behavior and decreased short-term memory when exposed to BPS (300 µg/kg BW). In addition, these mice had significant increases in non-fasting blood glucose levels along with increased insulin sensitivity, impaired glucose tolerance, resistance to fasting and proinflammation. Although BPS had little effect on the glucose parameters in NODEF male mice fed a Western diet, there were decreases in %CD24+CD5+ and %B220+CD40L-cell populations and increases in distance traveled during the novel object test, suggesting hyperactivity. NODEF females fed a phytoestrogen-free diet exhibited slight decreases in time spent immobile during the tail suspension test in both the 30 and 300 µg/kg BW dose groups along with increases in %CD4+CD8+ and %Mac3+CD45R+ cell populations, signifying increased hyperactivity and anxiety-like behavior. In conclusion, BPS-exposed NODEF mice exhibited sex and diet-related changes in hyperglycemia, behaviors and immune endpoints.


Assuntos
Dieta Ocidental/efeitos adversos , Hiperglicemia/metabolismo , Hipercinese/metabolismo , Fenóis/toxicidade , Alimentos de Soja/efeitos adversos , Sulfonas/toxicidade , Animais , Glicemia/metabolismo , Dieta Ocidental/psicologia , Disruptores Endócrinos/toxicidade , Feminino , Hiperglicemia/induzido quimicamente , Hiperglicemia/psicologia , Hipercinese/induzido quimicamente , Hipercinese/psicologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Fitoestrógenos/administração & dosagem , Fitoestrógenos/efeitos adversos
8.
Brain Res Bull ; 174: 141-152, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34119597

RESUMO

Schizophrenia is a mental illness characterized by episodes of psychosis, apathy, social withdrawal, and cognitive impairment. White matter lesions and glutamatergic hypofunction are reported to be the key pathogeneses underlying the multiple clinical symptoms of schizophrenia. Cuprizone (CPZ) is a copper chelator that selectively injures oligodendrocytes, and MK-801 is an antagonist of the N-methyl d-aspartate (NMDA) receptor. To better mimic the psychosis and complicated pathogenesis of schizophrenia, a novel possible mouse model was established by the combination of CPZ and MK-801. After exposure to CPZ for 5 weeks, the mice received a daily intraperitoneal injection of MK-801 for 2-weeks. Behavioral changes in the mouse model were evaluated using Y-maze, object recognition, and open field tests. Pathological changes were observed by transmission electron microscopy, oil red O staining, immunohistochemistry, and western blotting. The results showed that the novel mouse model induced by CPZ plus MK-801 exhibited severe spatial and recognition memory deficits, hyperactivity, and anxiety disorder. Moreover, the mice showed obvious demyelination and white matter damage and decreased expression levels of myelin basic protein (MBP) and 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) in the corpus callosum. Furthermore, the phosphorylation levels of Fyn and NMDA receptor 2B in the corpus callosum and NMDA receptor 1 in the cerebral cortex were noticeably decreased. Taken together, the novel mouse model induced by the combination of cuprizone and MK-801 showed comprehensive behavioral and neurobiological changes, which might make it a suitable animal model for schizophrenia.


Assuntos
Quelantes , Cuprizona , Maleato de Dizocilpina , Esquizofrenia/induzido quimicamente , Psicologia do Esquizofrênico , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Comportamento Animal , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/metabolismo , Hipercinese/induzido quimicamente , Hipercinese/psicologia , Injeções Intraperitoneais , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Reconhecimento Psicológico , Esquizofrenia/patologia , Memória Espacial/efeitos dos fármacos , Substância Branca/metabolismo , Substância Branca/patologia
9.
PLoS One ; 16(6): e0252900, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34111184

RESUMO

BACKGROUND: Khat is a plant that is used for its amphetamine-like stimulant properties. However, although khat is very popular in Eastern Africa, Arabian Peninsula, and the Middle East, there is still a lack of studies researching the possible neurobehavioral impairment derived from khat use. METHODS: A systematic review was conducted to identify studies that assessed the effects of khat use on neurobehavioral functions. MedLine, Scopus, Cochrane, Web of Science and Open Grey literature were searched for relevant publications from inception to December 2020. Search terms included (a) khat and (b) several cognitive domains. References from relevant publications and grey literature were also reviewed to identify additional citations for inclusion. RESULTS: A total of 142 articles were reviewed, 14 of which met the inclusion criteria (nine human and five rodent studies). Available human studies suggest that long term khat use is associated with significant deficits in several cognitive domains, including learning, motor speed/coordination, set-shifting/response inhibition functions, cognitive flexibility, short term/working memory, and conflict resolution. In addition, rodent studies indicated daily administration of khat extract resulted in dose-related impairments in behavior such as motor hyperactivity and decreased cognition, mainly learning and memory. CONCLUSIONS: The findings presented in this review indicates that long-term khat use may be contributing to an impairment of neurobehavioral functions. However, gaps in literature were detected that future studies could potentially address to better understand the health consequences of khat use.


Assuntos
Catha/efeitos adversos , Transtornos Cognitivos/induzido quimicamente , Hipercinese/induzido quimicamente , Transtornos da Memória/induzido quimicamente , Animais , Relação Dose-Resposta a Droga , Humanos , Negociação
10.
Eur J Pharmacol ; 904: 174148, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33961872

RESUMO

As drug addiction may result from pathological usurpations of learning and memory's neural mechanisms, we focused on the amphetamine-induced time-dependent neurochemical changes associated with neural plasticity. We used juvenile rats as the risk for drug abuse is higher during adolescence. Experiment 1 served to define the appropriate amphetamine dose and the neurochemical effects of a single administration. In experiment 2, rats received seven amphetamine or saline injections in the open-field test throughout a twelve-day period. We measured the mRNA levels of the brain-derived neurotrophic factor (BDNF), its tropomyosin receptor kinase B (TrkB), the cAMP response element-binding protein (CREB), the microRNA-132, the Rho GTPase-activating protein 32 (p250GAP), the corticotropin-releasing factor (CRF), and monoamines and amino-acids contents in the nucleus accumbens and the dorsal striatum 45, 90, and 180 min after the last injection. We found that amphetamine changed gene expression only at certain time points and in a dose and region-dependent manner. Repeated but not single administrations upregulated accumbal and striatal BDNF (180 min) and striatal pri-miR-132 (90 min) expression, while downregulated accumbal CREB levels (90 min). As only some drug users develop addiction, we compared brain parameters between low and high amphetamine responders. Prone subjects characterized by having reduced striatal 5-HT metabolism, higher accumbal BDNF and TrkB expression, and lower levels of CREB in the dorsal striatum and p250GAP in both regions. Thus, individual differences in drug-induced changes in neurotransmission and gene expression in nigrostriatal and mesolimbic dopaminergic pathways may underlie the plasticity adaptations associated with behavioral sensitization to amphetamine.


Assuntos
Anfetamina/farmacologia , Monoaminas Biogênicas/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/metabolismo , Anfetamina/administração & dosagem , Animais , Antecipação Psicológica/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Corpo Estriado/efeitos dos fármacos , Correlação de Dados , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Hipercinese/induzido quimicamente , Injeções Intraperitoneais , Masculino , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos Wistar , Fatores de Tempo
11.
Pharmacol Biochem Behav ; 202: 173108, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33450292

RESUMO

Ketamine, a dissociative anaesthetic, has been used in the treatment of major depressive disorder (MDD) as a rapid acting antidepressant drug. Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in MDD patients. Lithium is a well-known mood stabilizer and has been widely used for the treatment of mania. It is not fully understood which forebrain regions are involved in ketamine- and lithium-induced expression of c-Fos. Therefore, our aim was to investigate the effect of chronic lithium treatment on mania-like behavior and c-Fos expression in the mouse forebrain activated by a single administration of ketamine. In the open field test, our results showed that ketamine significantly increased the total distance and total cumulative duration of movement in mice, while chronic lithium could attenuate these effects of ketamine. In addition, acute ketamine induced higher c-Fos expression in the lateral septal nucleus, hypothalamus, amygdala, and hippocampus of mice in the treatment group compared to those in the control group. However, chronic lithium inhibited the significant increase in c-Fos-immunoreactive neurons following acute ketamine administration in the dentate gyrus of the hippocampus, field CA1 of the hippocampus, dorsal subiculum, ventral subiculum, ventral subiculum, central amygdaloid nucleus and basolateral amygdaloid nucleus. In summary, our research shows that pretreatment with lithium moderates the effects of acute ketamine administration on mania-like behavior and c-Fos expression in the forebrain. These findings could be helpful in better understanding the episodes of mania related to ketamine treatment for MDD and bipolar disorder.


Assuntos
Antidepressivos/efeitos adversos , Antimaníacos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Hipocampo/metabolismo , Ketamina/efeitos adversos , Compostos de Lítio/administração & dosagem , Mania/induzido quimicamente , Mania/tratamento farmacológico , Proteínas Proto-Oncogênicas c-fos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Antidepressivos/administração & dosagem , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Modelos Animais de Doenças , Hipercinese/induzido quimicamente , Ketamina/administração & dosagem , Masculino , Mania/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Resultado do Tratamento
12.
Behav Brain Res ; 400: 113045, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33309750

RESUMO

COR659 is a recently synthesized positive allosteric modulator (PAM) of the GABAB receptor. Similarly to all GABAB PAMs tested to date, COR659 has been reported to suppress different alcohol-related behaviors in rodents. The present study was designed to assess whether the anti-addictive properties of COR659 extend to drugs of abuse other than alcohol. Specifically, it investigated the effect of COR659 on cocaine-, amphetamine-, nicotine-, and morphine-induced locomotor hyperactivity in mice. To this aim, independent groups of CD1 mice were acutely pretreated with COR659 (0, 10, and 20 mg/kg; i.p.), then acutely treated with cocaine (0 and 10 mg/kg, s.c.), amphetamine (0 and 5 mg/kg; s.c.), nicotine (0 and 0.05 mg/kg; s.c.), or morphine (0 and 20 mg/kg; s.c.), and finally exposed for 60 min to a photocell-equipped motility cage. When given alone, both doses of COR659 were ineffective on spontaneous locomotor activity. Pretreatment with COR659 reduced, or even suppressed, the increase in motility counts induced by cocaine, amphetamine, nicotine, and morphine. Since locomotor hyperactivity is an attribute common to drugs of abuse, the results of the present study constitute the first line of evidence on the extension of the preclinical, anti-addictive profile of COR659 to cocaine, amphetamine, nicotine, and morphine.


Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Moduladores GABAérgicos/farmacologia , Hipercinese/induzido quimicamente , Hipercinese/prevenção & controle , Locomoção/efeitos dos fármacos , Morfina/farmacologia , Entorpecentes/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores de GABA-B , Anfetamina/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Moduladores GABAérgicos/administração & dosagem , Masculino , Camundongos , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem
13.
Nat Commun ; 11(1): 3996, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778725

RESUMO

Psychomotor stimulants increase dopamine levels in the striatum and promote locomotion; however, their effects on striatal pathway function in vivo remain unclear. One model that has been proposed to account for these motor effects suggests that stimulants drive hyperactivity via activation and inhibition of direct and indirect pathway striatal neurons, respectively. Although this hypothesis is consistent with the cellular actions of dopamine receptors and received support from optogenetic and chemogenetic studies, it has been rarely tested with in vivo recordings. Here, we test this model and observe that cocaine increases the activity of both pathways in the striatum of awake mice. These changes are linked to a dopamine-dependent cocaine-induced strengthening of upstream orbitofrontal cortex (OFC) inputs to the dorsomedial striatum (DMS) in vivo. Finally, depressing OFC-DMS pathway with a high frequency stimulation protocol in awake mice over-powers the cocaine-induced potentiation of OFC-DMS pathway and attenuates the expression of locomotor sensitization, directly linking OFC-DMS potentiation to cocaine-induced hyperactivity.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Hipercinese/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Animais , Comportamento Animal , Modelos Animais de Doenças , Dopamina , Feminino , Hipercinese/induzido quimicamente , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Optogenética
14.
Neuropeptides ; 82: 102059, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32600667

RESUMO

Bipolar disorder is a psychiatric pathology characterized by biphasic mood episodes of mania or hypomania and depression. The pharmacotherapy of bipolar disorder has significant adverse effects impairing treatment adherence and patient quality of life. The N/OFQ-NOP receptor system has been widely implicated with mood disorders. Clinical and preclinical findings suggest antidepressants actions for NOP antagonists. More recently, the administration of NOP agonists has shown to promote depressant states. The present study aimed to investigate the effects of non-peptide NOP ligands in methylphenidate-induced manic-like behavior in mice. The NOP agonist Ro 65-6570 (0.01-1 mg/kg, ip), at the higher dose, did not affect spontaneous locomotion per se, but prevented the methylphenidate (10 mg/kg, sc)-induced hyperlocomotion. The NOP partial agonist AT-090 (0.001-0.03 mg/kg, ip) and the NOP antagonist SB-612111 (1-10 mg/kg, ip) did not significantly affect the psychostimulant-induced hyperactivity. Experiments performed with mice lacking the NOP receptor (NOP(-/-)) demonstrated that the treatment with methylphenidate induced similar hyperlocomotion in NOP(-/-) and NOP(+/+) mice. In conclusion, these findings suggest a potential role for NOP agonists in the prevention of manic states, especially by counteracting the hyperactivity symptom of bipolar patients. However, more studies are necessary in order to evaluate these compounds in other features of bipolar disorder.


Assuntos
Antimaníacos/administração & dosagem , Transtorno Bipolar/fisiopatologia , Hipercinese/fisiopatologia , Imidazóis/administração & dosagem , Metilfenidato/administração & dosagem , Receptores Opioides/fisiologia , Compostos de Espiro/administração & dosagem , Animais , Feminino , Hipercinese/induzido quimicamente , Camundongos , Receptores Opioides/agonistas , Ácido Valproico/administração & dosagem
15.
Sci Rep ; 10(1): 9254, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32518276

RESUMO

Cebranopadol is known as a highly potent analgesic. Recent studies also demonstrated that administration of cebranopadol significantly decreased cocaine self-administration and significantly reduced cue-induced cocaine-seeking behaviors in rats. However, it was unclear whether these interesting behavioral observations are related to any potential effects of cebranopadol on cocaine pharmacokinetics or cocaine-induced hyperactivity. In principle, a promising therapeutic candidate for cocaine dependence treatment may alter the cocaine pharmacokinetics and/or attenuate cocaine-induced reward and hyperactivity and, thus, decrease cocaine self-administration and reduce cue-induced cocaine-seeking behaviors. In this study, we examined possible effects of cebranopadol on cocaine pharmacokinetics and cocaine-induced hyperactivity for the first time. According to our animal data in rats, cebranopadol did not significantly alter the pharmacokinetics of cocaine. According to our more extensive locomotor activity testing data, cebranopadol itself also dose-dependently induced hyperactivity in rats at doses higher than 50 µg/kg. Cebranopadol at a low dose of 25 µg/kg (p.o.) did not induce significant hyperactivity itself, but significantly potentiated cocaine-induced hyperactivity on Days 4 to 7 after the repeated daily dosing of the drug.


Assuntos
Cocaína/farmacocinética , Hipercinese/induzido quimicamente , Indóis/efeitos adversos , Compostos de Espiro/efeitos adversos , Analgésicos/efeitos adversos , Animais , Comportamento Animal/efeitos dos fármacos , Cocaína/toxicidade , Relação Dose-Resposta a Droga , Indóis/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Ratos Sprague-Dawley , Compostos de Espiro/farmacologia
16.
Brain Res ; 1740: 146873, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32387137

RESUMO

A single administration with METH (3 mg/kg) induced a hyperlocomotion in male ICR mice. Pretreatment of mice with pitolisant, a histamine H3 receptor antagonist (5 and 10 mg/kg), for 30 min showed a significant reduction of the hyperlocomotion induced by METH, as compared with vehicle (saline)-pretreated subjects. Pretreatment of mice with the histamine H3 receptor antagonists JNJ-10181457 (5 and 10 mg/kg) or conessine (20 mg/kg), also showed similar inhibitory effects on METH-induced hyperlocomotion, similar to pitolisant. No significant change in locomotion was observed in mice pretreated with pitolisant, JNJ-10181457, or conessine alone. The pitolisant (10 mg/kg) action on METH-induced hyperlocomotion was completely abolished by the histamine H1 receptor antagonist pyrilamine (10 mg/kg), but not by the peripherally acting histamine H1 receptor antagonist fexofenadine (20 mg/kg), the brain-penetrating histamine H2 receptor antagonist zolantidine (10 mg/kg), or the brain-penetrating histamine H4 receptor antagonist JNJ-7777120 (40 mg/kg). Pretreatment with a histamine H3 receptor agonist immepip (10 mg/kg) augmented METH--induced behavior, including hyperlocomotion and stereotyped biting, and combined pretreatment with pitolisant (10 mg/kg) significantly attenuated stereotyped biting. These observations suggest that pretreatment with histamine H3 receptor antagonists attenuate METH-induced hyperlocomotion via releasing histamine after blocking H3 receptors, which then bind to the post-synaptic histamine receptor H1 (but not H2 or H4). It is likely that activation of brain histamine systems may be a good strategy for the development of agents, which treat METH abuse and dependence.


Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Hipercinese/induzido quimicamente , Metanfetamina/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Hipercinese/tratamento farmacológico , Hipercinese/fisiopatologia , Injeções Intraperitoneais , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morfolinas/administração & dosagem , Piperidinas/administração & dosagem
17.
Sci Rep ; 10(1): 8278, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427942

RESUMO

Modulation of subthalamic nucleus (STN) firing patterns with injections of depolarizing currents into the STN is an important advance for the treatment of hypokinetic movement disorders, especially Parkinson's disease (PD). Chorea, ballism and dystonia are prototypical examples of hyperkinetic movement disorders. In our previous study, normal rats without nigro-striatal lesion were rendered hypokinetic with hyperpolarizing currents injected into the STN. Therefore, modulation of the firing pattern by injection of a hyperpolarizing current into the STN could be an effective treatment for hyperkinetic movement disorders. We investigated the effect of injecting a hyperpolarizing current into the STNs of two different types of hyperkinetic animal models and a patient with an otherwise uncontrollable hyperkinetic disorder. The two animal models included levodopa-induced hyperkinetic movement in parkinsonian rats (L-DOPA-induced dyskinesia model) and hyperkinesia induced by an intrastriatal injection of 3-nitropropionic acid (Huntington disease model), covering neurodegeneration-related as well as neurotoxin-induced derangement in the cortico-subcortical re-entrant loops. Delivering hyperpolarizing currents into the STN readily alleviated the hyperkinetic behaviors in the two animal models and in the clinical case, with an evident increase in subthalamic burst discharges in electrophysiological recordings. Application of a hyperpolarizing current into the STN via a Deep brain stimulation (DBS) electrode could be an effective general therapy for a wide spectrum of hyperkinetic movement disorders.


Assuntos
Estimulação Encefálica Profunda/métodos , Hipercinese/terapia , Levodopa/efeitos adversos , Nitrocompostos/efeitos adversos , Propionatos/efeitos adversos , Núcleo Subtalâmico/fisiologia , Animais , Polaridade Celular , Modelos Animais de Doenças , Humanos , Hipercinese/induzido quimicamente , Masculino , Ratos , Resultado do Tratamento
18.
Pharmacol Biochem Behav ; 195: 172951, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32439454

RESUMO

In rodents, prenatal nicotine exposure (PNE) has been associated with increased risk for development of cognitive and emotional disturbances, but the findings are somewhat conflicting. Lack of behavioral alterations following PNE could be due to the variety of methods available for nicotine delivery, exposure time and species used, with inbred strains being mostly employed. Such differences suggest the need to investigate the behavioral phenotype in each PNE model available if we are to find models with enhanced translational value. In this study, we assessed sex-dependent effects of PNE on ADHD-related behaviors and on the levels of mRNA coding for glutamate receptor subunits within the prefrontal cortex in the outbred NMRI mice exposed to nicotine via maternal drinking water during gestation. Cotinine levels were assessed in newborn pups. Behaviors related to anxiety, compulsivity, working memory, and locomotion were evaluated in both sexes of young adult offspring using the elevated zero maze, marble burying, spontaneous alternation behavior, and locomotor activity tests. Expression of mRNA coding for different glutamate receptors subunits within the prefrontal cortex (PFC) was measured using RT-qPCR. Cotinine levels in the serum of newborns confirmed fetal nicotine exposure. Both male and female offspring showed ADHD-like behaviors, such as deficit in the SAB test and hyperactivity. In addition, PNE male mice displayed anxiety- and compulsive-like behaviors, effects that were absent in female offspring. Finally, PNE reduced the mRNA expression of GluN1-, GluN2B-, and mGluR2-related genes within the PFC of male offspring, whereas it reduced the expression of mRNA coding for GluA2 subunit in female mice. PNE in NMRI mice induced sex-dependent behavioral changes, which parallels clinical findings following maternal cigarette smoke exposure. Alterations detected in PFC mRNA glutamate receptor proteins could contribute to the abnormal behavioral responses observed, but other signaling pathways or brain regions are likely involved in the behavioral susceptibility of PNE individuals.


Assuntos
Ansiedade/induzido quimicamente , Disfunção Cognitiva/induzido quimicamente , Expressão Gênica/efeitos dos fármacos , Hipercinese/induzido quimicamente , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Córtex Pré-Frontal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Receptores de Glutamato/genética , Animais , Ansiedade/sangue , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/sangue , Feminino , Hipercinese/sangue , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Nicotina/sangue , Agonistas Nicotínicos/sangue , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Receptores de Glutamato/metabolismo , Fatores Sexuais
19.
Artigo em Inglês | MEDLINE | ID: mdl-32121376

RESUMO

Fipronil is an insecticide widely used for veterinary and agricultural purposes. While its insecticidal properties mostly rely on its high affinity antagonistic activity on insect γ aminobutyric acid (GABA) receptors, fipronil and its main metabolite fipronil sulfone nevertheless display non-negligible affinity for mammalian GABAA receptor. As several environmental toxicants have been shown to raise the risk of developing various neurodegenerative disorders, the aim of this study was to evaluate whether long-term low dose administration of fipronil could lead to cognitive deficiencies. Our results indicate that long-term fipronil treatment leads to behavioral perturbations in mice, indicating an accumulative effect of sustained exposure to low dose of fipronil. Although no memory impairment was observed during the course of our study, we noticed a significant hyperlocomotion behavior after 43 weeks of weekly fipronil administration, which is consistent with its direct effect on the GABAergic system.


Assuntos
Hipercinese , Inseticidas , Pirazóis , Animais , Feminino , Hipercinese/induzido quimicamente , Inseticidas/toxicidade , Camundongos , Pirazóis/toxicidade , Receptores de GABA/efeitos dos fármacos , Ácido gama-Aminobutírico
20.
Brain Res ; 1733: 146721, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32045593

RESUMO

Bipolar Disorder is a disorder characterized by alternating episodes of depression, mania or hypomania, or even mixed episodes. The treatment consists on the use of mood stabilizers, which imply serious adverse effects. Therefore, it is necessary to identify new therapeutic targets to prevent or avoid new episodes. Evidence shows that individuals in manic episodes present a purinergic system dysfunction. In this scenario, inosine is a purine nucleoside known to act as an agonist of A1 and A2A adenosine receptors. Thus, we aimed to elucidate the preventive effect of inosine on locomotor activity, changes in purine levels, and adenosine receptors density in a ketamine-induced model of mania in rats. Inosine pretreatment (25 mg/kg, oral route) prevented the hyperlocomotion induced by ketamine (25 mg/kg, intraperitoneal route) in the open-field test; however, there was no difference in hippocampal density of A1 and A2A receptors, where ketamine, as well as inosine, were not able to promote changes in immunocontent of the adenosine receptors. Likewise, no effects of inosine pretreatments or ketamine treatment were observed for purine and metabolic residue levels evaluated. In this sense, we suggest further investigation of signaling pathways involving purinergic receptors, using pharmacological strategies to better elucidate the action mechanisms of inosine on bipolar disorder. Despite the limitations, inosine administration could be a promising candidate for bipolar disorder treatment, especially by attenuating maniac phase symptoms, once it was able to prevent the hyperlocomotion induced by ketamine in rats.


Assuntos
Hipercinese/induzido quimicamente , Hipercinese/prevenção & controle , Inosina/administração & dosagem , Ketamina/administração & dosagem , Locomoção/efeitos dos fármacos , Mania/induzido quimicamente , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipercinese/metabolismo , Masculino , Mania/metabolismo , Ratos Wistar , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo
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