RESUMEN
Dopamine (DA) D2 receptors (D2Rs) have 2 isoforms, a long form (D2L) and a short form (D2S). D2L is predominantly postsynaptic in the striatal medium spiny neurons and cholinergic interneurons. D2S is principally presynaptic autoreceptors in the nigrostriatal DA neurons. Recently, we demonstrated that L-3,4-dihydroxyphenylalanine (L-DOPA) augments D2L function through the coupling between D2L and GPR143, a receptor of L-DOPA that was originally identified as the gene product of ocular albinism 1. Here we show that GPR143 modifies the functions of D2L and D2S in an opposite manner. Haloperidol-induced catalepsy was attenuated in DA neuron-specific Gpr143 gene-deficient (Dat-cre;Gpr143flox/y) mice, compared with wild-type (Wt) mice. Haloperidol increased in vivo DA release from the dorsolateral striatum, and this increase was augmented in Gpr143-/y mice compared with Wt mice. A D2R agonist quinpirole-induced increase in the phosphorylation of GSK3ß(pGSK3ß(S9)) was enhanced in Chinese hamster ovary (CHO) cells coexpressing D2L and GPR143 compared with cells expressing D2L alone, while it was suppressed in cells coexpressing D2S and GPR143 compared with D2S alone, suggesting that GPR143 differentially modifies D2R functions depending on its isoforms of D2L and D2S.
Asunto(s)
Cricetulus , Dopamina , Haloperidol , Receptores de Dopamina D2 , Animales , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/genética , Haloperidol/farmacología , Células CHO , Dopamina/metabolismo , Cuerpo Estriado/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/genética , Ratones , Levodopa/farmacología , Catalepsia/inducido químicamente , Catalepsia/genética , Catalepsia/metabolismo , Ratones Endogámicos C57BL , Fosforilación , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiología , Quinpirol/farmacología , Neuronas Dopaminérgicas/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismoRESUMEN
Over the years, mounting evidences have suggested a strong association between chronic chlorpromazine therapy, a popular first-generation antipsychotic drug, and psycho-neuroendocrine changes. In this study, we aim to examine whether treatment with taurine and coenzyme Q10 (COQ-10), compounds with steroidogenic-gonadotropin hormone-enhancing properties, can attenuate the negative impacts of chlorpromazine on steroidogenic, gonadotropin, thyroid and HPA-axis hormones, dopamine levels, catalepsy behavior and neuronal cells of the hypothalamus and pituitary gland in the preventive and reversal treatments in male Wister rats. In the drug treatment alone or preventive protocol, rats received oral administration of saline (10 mL/kg), taurine (150 mg/kg/day), COQ-10 (10 mg/kg/day), or both (taurine + COQ-10/day) alone for 56 consecutive days, or in combination with oral chlorpromazine (30 mg/kg/day) treatment from days 29 to 56. In the reversal protocol, the animals received chlorpromazine or saline for 56 days prior to taurine, COQ-10, or the combination from days 29 to 56. Thereafter, serum prolactin, steroidogenic (testosterone, estrogen, progesterone), gonadotropin (luteinizing hormone, LH, follicle-stimulating hormone, FSH), thyroid (thyrotropin-stimulating hormone, tetraiodothyronine, triiodothyronine) hormones, corticosterone, brain dopamine levels and cataleptic behavior were investigated. The histopathological features of the hypothalamus and pituitary gland were also evaluated. Taurine, COQ-10, or their combination prevented and reversed chlorpromazine-induced hyperprolactinemia, decrease in FSH, LH, testosterone, progesterone and dopamine concentrations, as well as the increase in estrogen levels. Taurine and COQ-10 reduced the changes in thyroid hormones, corticosterone release, histological distortions of the hypothalamus and the pituitary gland of chlorpromazine-treated rats. Taurine and COQ-10 attenuated chlorpromazine-induced catalepsy. The study showed that taurine and COQ-10 prevented and reversed chlorpromazine-induced changes in reproductive, thyroid hormones, dopamine level, corticosterone release, neurodegenerations, and cataleptic behavior in rats.
Asunto(s)
Antipsicóticos/efectos adversos , Catalepsia/tratamiento farmacológico , Clorpromazina/efectos adversos , Fármacos Neuroprotectores/uso terapéutico , Taurina/uso terapéutico , Ubiquinona/análogos & derivados , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Catalepsia/inducido químicamente , Catalepsia/metabolismo , Catalepsia/patología , Dopamina/metabolismo , Sinergismo Farmacológico , Quimioterapia Combinada , Hormonas/sangre , Masculino , Fármacos Neuroprotectores/farmacología , Ratas Wistar , Taurina/farmacología , Ubiquinona/farmacología , Ubiquinona/uso terapéuticoRESUMEN
Considerable evidence indicates that adenosine and dopamine systems interact in the regulation of basal ganglia function. Nonselective adenosine antagonists such as the methylxanthine caffeine as well as selective adenosine A2A antagonists have been shown to produce antiparkinsonian and antidepressant effects in animal models. The present studies were conducted to assess if another methylxantine, theophylline, can reverse motor and motivational impairments induced by dopamine antagonism in rats. RESULTS: Theophylline (3.75-30.0 mg/kg, IP) reversed tremulous jaw movements (TJMs), catalepsy, and locomotor suppression induced by the dopamine D2 antagonist pimozide. It also reversed TJMs induced by the muscarinic receptor agonist pilocarpine, which is a well-known tremorogenic agent. Parallel studies assessed the ability of theophylline (5.0-20.0 mg/kg, IP) to reverse the changes in effort-related choice behavior induced by the dopamine D1 antagonist ecopipam (0.2 mg/kg, IP) and the D2 antagonist haloperidol (0.1 mg/kg, IP). Rats were tested on two different operant choice tasks which assess the tendency to work for a preferred reinforcer by lever pressing (for palatable pellets or a high 5% sucrose solution) vs. approaching and consuming a less preferred reinforcer (freely available lab chow or a less concentrated 0.3% sucrose solution). Theophylline restored food and sucrose-reinforced lever pressing in animals treated with the D2 antagonist. However, it was unable to reverse the effects of the D1 antagonist. Overall, the effects of theophylline resembled those previously reported for adenosine A2A antagonists, and suggest that theophylline could be clinically useful for the treatment of motor and motivational symptoms in humans.
Asunto(s)
Conducta de Elección/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Actividad Motora/efectos de los fármacos , Antagonistas de Receptores Purinérgicos P1/farmacología , Teofilina/farmacología , Temblor/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Benzazepinas/farmacología , Catalepsia/tratamiento farmacológico , Catalepsia/metabolismo , Condicionamiento Operante/efectos de los fármacos , Haloperidol/farmacología , Humanos , Masculino , Motivación/efectos de los fármacos , Agonistas Muscarínicos/farmacología , Pilocarpina/farmacología , Pimozida/farmacología , Ratas , Ratas Sprague-Dawley , Sacarosa/farmacología , Temblor/tratamiento farmacológicoRESUMEN
Δ9-tetrahydrocannabinol (THC), the major psychoactive ingredient of Cannabis sativa, exerts its actions through the endocannabinoid system by stimulation of the cannabinoid type 1 (CB1) receptor. The widespread distribution of this receptor in different neuronal cell types and the plethora of functions that is modulated by the endocannabinoid system explain the versatility of the effects of THC. However, the cell types involved in the different THC effects are still not fully known. Conditional CB1 receptor knock-out mice were previously used to identify CB1 receptor subpopulations that are "necessary" for the tetrad effects of a high dose of THC: hypothermia, hypolocomotion, catalepsy and analgesia. Here, we used mouse models for conditional CB1 receptor "rescue" in dorsal telencephalic glutamatergic and forebrain GABAergic neurons to determine which CB1 receptor subpopulations are "sufficient" for these tetrad effects. Glutamatergic CB1 receptor was not only necessary but also sufficient for THC-induced hypothermia and hypolocomotion. Analgesic and cataleptic effects of THC are largely independent of glutamatergic and GABAergic CB1 receptors, since no sufficiency was found, in agreement with the previously reported lack of necessity. We also revealed a novel aspect of GABAergic CB1 receptor signaling. In animals with CB1 receptors exclusively in forebrain GABAergic neurons, THC stimulated rather than reduced locomotion. This cell-type selective and hitherto unsuspected hyperlocomotive effect may be occluded in wild-types and conditional knockouts and only be exposed when CB1 signaling is absent in all other cell types, thus underlining the importance of investigating both necessary and sufficient functions to unequivocally unravel cell-type specific actions.
Asunto(s)
Agonistas de Receptores de Cannabinoides/farmacología , Dronabinol/farmacología , Receptor Cannabinoide CB1/agonistas , Receptores de GABA , Receptores de Glutamato , Analgesia/métodos , Animales , Agonistas de Receptores de Cannabinoides/metabolismo , Catalepsia/inducido químicamente , Catalepsia/metabolismo , Dronabinol/metabolismo , Agonistas de Aminoácidos Excitadores/metabolismo , Agonistas de Aminoácidos Excitadores/farmacología , Agonistas del GABA/metabolismo , Agonistas del GABA/farmacología , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Ratones Noqueados , Receptor Cannabinoide CB1/metabolismo , Receptores de GABA/metabolismo , Receptores de Glutamato/metabolismoRESUMEN
Hydrogen peroxide is the preeminent chemical weapon that organisms use for combat. Individual cells rely on conserved defenses to prevent and repair peroxide-induced damage, but whether similar defenses might be coordinated across cells in animals remains poorly understood. Here, we identify a neuronal circuit in the nematode Caenorhabditis elegans that processes information perceived by two sensory neurons to control the induction of hydrogen peroxide defenses in the organism. We found that catalases produced by Escherichia coli, the nematode's food source, can deplete hydrogen peroxide from the local environment and thereby protect the nematodes. In the presence of E. coli, the nematode's neurons signal via TGFß-insulin/IGF1 relay to target tissues to repress expression of catalases and other hydrogen peroxide defenses. This adaptive strategy is the first example of a multicellular organism modulating its defenses when it expects to freeload from the protection provided by molecularly orthologous defenses from another species.
Cells of all kinds often wage chemical warfare against each other. Hydrogen peroxide is often the weapon of choice on the microscopic battlefield, where it is used to incapacitate opponents or to defend against attackers. For example, some plants produce hydrogen peroxide in response to infection to fight off disease-causing microbes. Individual cells have also evolved defenses to prevent or repair 'injuries' caused by hydrogen peroxide. These are similar across many different species. They include enzymes called catalases, which break down hydrogen peroxide, and others to repair damage. However, scientists still do not fully understand how animals and other multicellular organisms might coordinate these defenses across their cells. Caenorhabditis elegans is a microscopic species of worm that lives in rotting fruits. It often encounters the threat of cellular warfare: many types of bacteria in its environment generate hydrogen peroxide, and some can make enough to kill the worms outright. Like other organisms, C. elegans also produces catalases to defend itself against hydrogen peroxide attacks. However, it must activate its defenses at the right time; if it did so when they were not needed, this would result in a detrimental energy 'cost' to the worm. Although C. elegans is a small organism containing only a defined number of cells, exactly why and how it switches its chemical defenses on or off remains unknown. Schiffer et al. therefore set out to determine how C. elegans controls these defenses, focusing on the role of the brain in detecting and processing information from its environment. Experiments looking at the brains of genetically manipulated worms revealed a circuit of sensory nerve cells whose job is to tell the rest of the worm's tissues that they no longer need to produce defense enzymes. Crucially, the circuit became active when the worms sensed E. coli bacteria nearby. Bacteria in the same family as E. coli are normally found in in the same habitat as C. elegans and these bacteria are also known to make enzymes of their own to eliminate hydrogen peroxide around them. These results indicate that C. elegans can effectively decide, based on the activity of its circuit, when to use its own defenses and when to 'freeload' off those of neighboring bacteria. This work is an important step towards understanding how sensory circuits in the brain can control hydrogen peroxide defenses in multicellular organisms. In the future, it could help researchers work out how more complex animals, like humans, coordinate their cellular defenses, and therefore potentially yield new strategies for improving health and longevity.
Asunto(s)
Caenorhabditis elegans/fisiología , Células Receptoras Sensoriales/fisiología , Animales , Proteínas de Caenorhabditis elegans/metabolismo , Catalepsia/metabolismo , Escherichia coli , Peróxido de Hidrógeno/metabolismo , Factor I del Crecimiento Similar a la Insulina/fisiología , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Aging represents the largest risk factor for developing Parkinson's disease (PD); another salient feature of this disorder is a decreased brain levels of somatostatin. Recently, in aged Wistar rats, we simulated the central somatostatinergic deficiency by intracerebroventricular injections of a somatostatin antagonist, cyclosomatostatin (cSST). The treated animals displayed catalepsy, a state that resembles the extrapyramidal signs of Parkinson's disease; young animals were insensitive to cSST. The neuroanatomical substrates responsible for the increased cataleptogenic activity of cSST in aged animals, are currently unknown. To study this issue, we assessed the cSST effect on brain c-Fos-protein expression in aged and young rats; thirty three brain regions were examined. cSST was employed at the dose cataleptogenic for aged animals and non-cataleptogenic for young ones. c-Fos expression patterns in the 'cataleptic' and 'non-cataleptic' animals were very similar, with the only distinction being a decrease in the c-Fos expression in the aged lateral entorhinal cortex (LEntCx). This decrease was not observed when the cSST-induced cataleptic response was inhibited by administration of diphenhydramine and nicotine. Thus, the development of catalepsy in the aged Wistar rats appeared to be associated with a hypoactivation of the LEntCx; possibly, there exists a mechanistic link between the LEntCx hypoactivation and increased susceptibility of aged rats to catalepsy. Apparently, these findings may provide novel insight into the link between mechanisms of parkinsonian motor disorders and aging.
Asunto(s)
Envejecimiento/metabolismo , Catalepsia/inducido químicamente , Catalepsia/metabolismo , Corteza Entorrinal/metabolismo , Péptidos Cíclicos/toxicidad , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Envejecimiento/efectos de los fármacos , Animales , Corteza Entorrinal/efectos de los fármacos , Expresión Génica , Masculino , Proteínas Proto-Oncogénicas c-fos/genética , Ratas , Ratas WistarRESUMEN
OBJECTIVE: To investigate the effect of desferrioxamine (DFO) and dextromethorphan (DXM) combination in animal model of Parkinson's disease (PD). METHODS: The PD was induced in rats through intracerebroventricular administration of 6-hydroxydopamine (6-OHDA) using stereotaxic apparatus. The animals were subjected to behavioural assessments and neurobiochemicals estimation followed by immunohistochemistry staining of neuron specific enolase (NSE) in striatum. KEY FINDINGS: Desferrioxamine and DXM combination has significantly reversed the catalepsy behaviour and elevated the antioxidant enzymes (SOD, CAT, GSH) and dopamine levels. Interestingly, the level of glutamate, nitric oxide, cytokines (IL-1ß, TNF-α) and NSE expressions were found to be decreased in striatum region of 6-OHDA-administered rats. The combination of DFO and DXM has shown synergism in most of the parameters studied, when compared to per se treatment. CONCLUSIONS: The reversal of catalepsy behaviour represents the protective effect of above combination on dopamine neurons in striatum from 6-OHDA toxicity. The mechanism of DFO and DXM combination might be attributed through attenuation of glutamate-induced excitotoxicity in neurons through ameliorating the reactive oxygen species and pro-inflammatory cytokines release. Treatment with DFO and DXM combination could control the multiple events in the pathogenesis of PD.
Asunto(s)
Catalepsia/tratamiento farmacológico , Cuerpo Estriado/efectos de los fármacos , Deferoxamina/farmacología , Dextrometorfano/farmacología , Ácido Glutámico/metabolismo , Hidroxidopaminas/farmacología , Animales , Antioxidantes/farmacología , Catalepsia/metabolismo , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Combinación de Medicamentos , Sinergismo Farmacológico , Masculino , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Ratas , Ratas WistarRESUMEN
Medicinal plants, as new drugs, are considered for treatment of insomnia, anxiety, depression, confusion, nausea, and vomiting symptoms. The current study aimed to evaluate the neuroprotective and antiemetic effects of Albizia. julibrissin Durazz. flower extract in the chickens. Emesis was induced by copper sulfate and ipecac (60 and 600 mg/kg, orally, respectively) and the methanolic extract (50, 100, and 200 mg/kg) were injected intraperitoneally (i.p.). Mitochondrial function, lipid peroxidation (LPO), protein carbonyl (PC) content, and catalase activity as biomarkers of oxidative damage were evaluated in the brain mitochondria. All doses of extract showed significant (p < 0.001) antiemetic activity against induced emesis by copper sulfate and ipecac. Brain mitochondria function (by 50, 100, and 200 mg/kg of extract) were increased 48%, 85%, and 90% against emesis induced by ipecac and 32%, 18%, and 24% against emesis induced by copper sulfate, respectively. LPO and PC contents were significantly decreased after the administration of extract in emesis induced by copper sulfate and ipecac. A significant decrease (p < 0.01) of CAT activity was observed in the extract (200 mg/kg) group in emesis induced by copper sulfate in chickens brain mitochondria. The present study suggests that the extract had antiemetic effects against emesis induced by copper sulfate and ipecac in young chickens via peripheral and central mechanisms. Neuroprotective effect of the extract could be due to the increase in bioactive compounds, plasma antioxidants, or direct free radical scavenging that could prevent lipid and protein alteration and impede the formation of oxidative damage.
Asunto(s)
Albizzia/química , Antieméticos/farmacología , Encéfalo/efectos de los fármacos , Flores/química , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Vómitos/tratamiento farmacológico , Animales , Biomarcadores/metabolismo , Catalepsia/metabolismo , Pollos , Sulfato de Cobre/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Flavonoides/análisis , Ipeca/farmacología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Fenoles/análisis , Extractos Vegetales/química , Vómitos/inducido químicamenteRESUMEN
The realisation of manned space exploration requires the development of Bioregenerative Life Support Systems (BLSS). In such self-sufficient closed habitats, higher plants have a fundamental role in air regeneration, water recovery, food production and waste recycling. In the space environment, ionising radiation represents one of the main constraints to plant growth. In this study, we explore whether low doses of heavy ions, namely Ca 25 Gy, delivered at the seed stage, may induce positive outcomes on growth and functional traits in plants of Solanum lycopersicum L. 'Microtom'. After irradiation of seed, plant growth was monitored during the whole plant life cycle, from germination to fruit ripening. Morphological parameters, photosynthetic efficiency, leaf anatomical functional traits and antioxidant production in leaves and fruits were analysed. Our data demonstrate that irradiation of seeds with 25 Gy Ca ions does not prevent achievement of the seed-to-seed cycle in 'Microtom', and induces a more compact plant size compared to the control. Plants germinated from irradiated seeds show better photochemical efficiency than controls, likely due to the higher amount of D1 protein and photosynthetic pigment content. Leaves of these plants also had smaller cells with a lower number of chloroplasts. The dose of 25 Gy Ca ions is also responsible for positive outcomes in fruits: although developing a lower number of berries, plants germinated from irradiated seeds produce larger berries, richer in carotenoids, ascorbic acid and anthocyanins than controls. These specific traits may be useful for 'Microtom' cultivation in BLSS in space, in so far as the crew members could benefit from fresh food richer in functional compounds that can be directly produced on board.
Asunto(s)
Frutas/efectos de la radiación , Sistemas de Manutención de la Vida , Fotosíntesis/efectos de la radiación , Hojas de la Planta/efectos de la radiación , Solanum lycopersicum/efectos de la radiación , Antioxidantes/metabolismo , Ácido Ascórbico/metabolismo , Western Blotting , Catalepsia/metabolismo , Clorofila A/metabolismo , Germinación/efectos de la radiación , Iones Pesados , Solanum lycopersicum/anatomía & histología , Solanum lycopersicum/crecimiento & desarrollo , Solanum lycopersicum/metabolismo , Hojas de la Planta/anatomía & histología , Hojas de la Planta/metabolismo , Proteínas de Plantas/metabolismo , Semillas/efectos de la radiación , Superóxido Dismutasa/metabolismoRESUMEN
Given the fact that oxidative stress response induced by training/detraining has still not been clarified and may be influenced by gender, the aim of our investigation was to compare the effects of swimming training and detraining on oxidative and antioxidative parameters in rats, with a special focus on sex differences. Wistar albino rats (n = 64) were divided into 4 groups: control, trained group, groups exposed to 2 and 4 weeks of detraining. Each group included two subgroups: males and females. After sacrificing, hearts were isolated and retrogradely perfused according to Langendorff technique. Levels of superoxide anion radical, hydrogen peroxide, nitrites and thiobarbituric acid reactive substances were measured in plasma and coronary venous effluent, while reduced glutathione, activities of superoxide dismutase and catalase were measured in erythrocytes. Our results indicate that swimming training doesn't promote oxidative damage, nor act protectively within the heart. However, 2 and 4 weeks of detraining led to a partial lost in exercise-induced adaptation. It seems that moderate-intensity physical exercise of sufficient duration leads to beneficial adaptations, which may be partially lost during detraining period. Positive antioxidative effects of training remained longer in males. Findings of present study may help in elucidation of training and detraining effects on modulation of redox homeostasis, especially from aspect of gender differences.
Asunto(s)
Condicionamiento Físico Animal , Caracteres Sexuales , Animales , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Catalepsia/metabolismo , Femenino , Glutatión/metabolismo , Peróxido de Hidrógeno/metabolismo , Masculino , Miocardio/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Ratas , Ratas Wistar , Superóxidos/metabolismo , Natación , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
The effects of chronic 5-HT1A receptor activation on the behavior, functional activity of 5-HT1A receptors, and expression of key genes of the brain 5-HT system were studied in mice of the catalepsy-prone CBA strain and the catalepsy-resistant C57BL/6 strain. Chronic treatment with 8-Hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) led to a significant decrease in the hypothermic response to acute administration of 8-OH-DPAT in CBA and C57BL/6 mice, which indicates the desensiti-zation of 5-HT1A receptors in both strains. Pretreatment with the 5-HT7 receptor agonist SB 269970 did not affect the hypothermic response to the acute administration of 8-OH-DPAT, which suggests an independent functional response of 5-HT1A receptors. The treatment did not induce any changes in the behavior in the open field paradigm in CBA mice, but significantly increased the total path, the time spent in the center, and the number of rearings in C57BL/6 mice, which indicates the enhancement of locomotor and exploratory activity in C57BL/6 mice. The chronic activation of 5-HT1A receptor downregulated 5-HT1A gene expression, as well as the expression of the gene that encodes tryptophan hydroxylase 2, a key enzyme of 5-HT biosynthesis, in the midbrain and the expression of the gene that encodes the 5-HT2A receptor in the frontal cortex of CBA, but not C57BL/6 mice. The obtained data provide a new evidence on the receptor-gene cross talk in the brain 5-HT system that may underlie the loss of pharmacological efficacy of 5-HT1A receptor agonists. In turn, the loss of the behavioral response and compensatory alterations in key genes of the brain 5-HT system in CBA mice suggests that catalepsy-prone and -resistant genotypes demonstrate different sensibility to the effects of drugs.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Catalepsia , Predisposición Genética a la Enfermedad , Receptor de Serotonina 5-HT1A , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Animales , Catalepsia/inducido químicamente , Catalepsia/genética , Catalepsia/metabolismo , Ratones , Ratones Endogámicos CBA , Ratones Mutantes , Receptor de Serotonina 5-HT1A/genética , Receptor de Serotonina 5-HT1A/metabolismoRESUMEN
BACKGROUND: Stigmasterol, a naturally occurring phytoestrogen has been reported to possess many pharmacological activities. The aim of the present study was to screen the effect of stigmasterol against ketamine-induced mice model of psychosis. METHODS: The behavioural studies included an assessment of locomotor activity, stereotypic behaviours, immobility duration, step down latency and effects on catalepsy. Biochemical estimations involved the estimations of GABA, dopamine, GSH, MDA, TNF-α, total protein content and AChE activity. Histopathological changes and effect on androgenic parameters were also evaluated. RESULTS: Stigmasterol treated animals showed significant decrease in locomotor activity, stereotypic behaviours, immobility duration and increased step down latency. Biochemical estimations revealed increased GABA, GSH levels and decreased dopamine, MDA, TNF-α levels and AChE activity. These findings were confirmed by histopathological changes in the cortex part of the brain. Further, stigmasterol was not found to cause catalepsy and any adverse effect on the reproductive system. CONCLUSION: This study concluded that stigmasterol could ameliorate ketamine-induced behavioral, biochemical and histopathological alterations in mice showing its potential effects in the management of psychotic symptoms.
Asunto(s)
Antipsicóticos/farmacología , Sustancias Protectoras/farmacología , Trastornos Psicóticos/tratamiento farmacológico , Estigmasterol/farmacología , Acetilcolina/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Catalepsia/tratamiento farmacológico , Catalepsia/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Glutatión/metabolismo , Ketamina/farmacología , Masculino , Malondialdehído/metabolismo , Ratones , Actividad Motora/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Trastornos Psicóticos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Background Parkinson's disease (PD) is a neurodegenerative disorder of the central nervous system (CNS). However, there is no known drug to stop/slow down this neurodegeneration. Varenicline is an anti-smoking drug and has the potential to prevent neurodegeneration. Thus, the present study was designed to evaluate the effect of varenicline in animal models of PD. Methods Levodopa and haloperidol were administered in doses of 30 and 1 mg/kg, intraperitoneally (i.p.), respectively. Group 1 was administered haloperidol; groups 2, 3 and 4 were administered haloperidol along with varenicline in doses of 0.5, 1.5 and 2.5 mg/kg, i.p., respectively and group 5 was administered levodopa along with haloperidol. Varenicline was administered daily, 30 min prior to the administration of haloperidol. Varenicline was administered for the first 8 days, and then from the 9th day until the 15th day. Behavioral assessment (rotarod and catalepsy tests) was performed on days 9 and 15. Assessment of striatal dopamine levels and histopathology were also performed. Results In the haloperidol-treated groups, significant decrease in latency to fall off (on rotarod) and increase in catalepsy duration (in catalepsy test) were observed as compared to the control group. In the levodopa-treated group, significant increase in latency to fall off the rotarod and significant decrease in catalepsy duration were observed as compared to the haloperidol-treated groups. Further, on day 9, varenicline (2.5 mg/kg) significantly increased the latency to fall off the rotarod, while varenicline (0.5 and 1.5 mg/kg) did not cause any significant change in latency to fall off the rotarod as compared to the haloperidol-treated group. On day 15, significant increase in latency to fall off the rotarod was observed in varenicline (at all doses) as compared to the haloperidol-treated group. In the catalepsy test, the varenicline-treated (at all doses) groups showed significant decrease in duration of catalepsy on day 9 and day 15 as compared to the haloperidol-treated group. Significant decrease in striatal dopamine levels was observed among the haloperidol-treated groups as compared to the control group. Further, varenicline-treated (at all doses) and levodopa-treated groups showed significant increase in striatal dopamine levels when compared with the haloperidol-treated group. In histology, varenicline (0.5 mg/kg) showed moderate decrease in neurons, while varenicline (1.5 and 2.5 mg/kg) showed mild decrease in neurons. However, the levodopa-treated group did not show any significant decrease in neurons. Thus, varenicline has shown promising results and has provided novel strategy for the treatment of PD.
Asunto(s)
Haloperidol/farmacología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , Vareniclina/farmacología , Animales , Catalepsia/tratamiento farmacológico , Catalepsia/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Femenino , Levodopa/farmacología , Masculino , Ratones , Neuronas/efectos de los fármacos , Trastornos Parkinsonianos/metabolismoRESUMEN
Manganese (Mn) is required for many essential biological processes as well as in the development and functioning of the brain. Extensive accumulation of Mn in the brain may cause central nervous system dysfunction known as manganism, a motor disorder associated with cognitive and neuropsychiatric deficits similar to parkinsonism. Vinpocetine, a synthetic derivative of the alkaloid vincamine, is used to improve the cognitive function in cerebrovascular diseases. It possesses antioxidant and antiinflammatory properties. The present work was designed to explore the potential neuroprotective mechanisms exerted by vinpocetine in the Mn-induced neurotoxicity in rats. Rats were allocated into four groups. First group was given saline. The other three groups were given MnCl2; two of them were treated with either L-dopa, the gold standard antiparkinsonian drug, or vinpocetine. Rats receiving MnCl2 exhibited lengthened catalepsy duration in the grid and bar tests, motor impairment in the open-field test and short-term memory deficit in the Y-maze test. Additionally, histological examination revealed structural alterations and degeneration in different brain regions. Besides, striatal monoamines and mitochondrial complex I contents were declined, apoptotic biomarker caspase-3 expression and acetylcholinesterase activity were elevated. Moreover, oxidative stress and inflammation were detected in the striata. L-dopa or vinpocetine exerted protective effects against MnCl2-induced neurotoxicity. It could be hypothesized that modulation of monoamines, upregulation of mitochondrial complex I, antioxidant, antiinflammatory, and antiapoptotic activities are significant mechanisms underlying the neuroprotective effect of vinpocetine in the Mn-induced neurotoxicity model in rats.
Asunto(s)
Manganeso/toxicidad , Fármacos Neuroprotectores/uso terapéutico , Síndromes de Neurotoxicidad/tratamiento farmacológico , Alcaloides de la Vinca/uso terapéutico , Animales , Monoaminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Caspasa 3/metabolismo , Catalepsia/tratamiento farmacológico , Catalepsia/metabolismo , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Síndromes de Neurotoxicidad/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Alcaloides de la Vinca/farmacologíaRESUMEN
Paradoxical kinesia is a sudden transient ability of akinetic patients to perform motor tasks they are otherwise unable to perform. This phenomenon is known to depend on the patient's emotional state and external stimuli. Paradoxical kinesia can be induced by appetitive 50-kHz ultrasonic vocalizations (USV) in rats displaying catalepsy following systemic haloperidol. We investigated the role of the inferior colliculus (IC) in paradoxical kinesia induced by 50-kHz USV, since the IC modulates haloperidol-induced catalepsy. We focused on glutamatergic and GABAergic neurotransmission, with male rats receiving intracollicular NMDA or the GABA receptor agonist diazepam 10â¯min before systemic haloperidol. Catalepsy time was assessed by means of the bar test, during which rats were exposed to playback of 50-kHz USV, white noise, and background noise. Our results show that playback of 50-kHz USV induced paradoxical kinesia by reducing haloperidol-induced catalepsy in rats which had received saline intracollicular microinjection. This paradoxical kinesia effect of 50-kHz USV playback on haloperidol-induced catalepsy was prevented by intracollicular NMDA administration. Although intracollicular diazepam microinjection potentiated haloperidol-induced catalepsy, it did not affect the response to 50-kHz USV playback. Together, NMDA receptor agonist suppressed the effectiveness of 50-kHz USV playback, whereas diazepam did not. These findings suggest that the IC is a key structure involved in paradoxical kinesia, with relevant processes being glutamatergic rather than GABAergic. Our approach thus appears useful for uncovering neural mechanisms of paradoxical kinesia and it might help identifying novel therapeutic targets for Parkinson's disease.
Asunto(s)
Conducta Apetitiva/fisiología , Catalepsia/metabolismo , Ácido Glutámico/metabolismo , Colículos Inferiores/metabolismo , Vocalización Animal/fisiología , Animales , Conducta Apetitiva/efectos de los fármacos , Diazepam/farmacología , Modelos Animales de Enfermedad , Moduladores del GABA/farmacología , Haloperidol , Colículos Inferiores/efectos de los fármacos , Masculino , N-Metilaspartato/metabolismo , N-Metilaspartato/farmacología , Neurotransmisores/farmacología , Ratas Wistar , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/metabolismo , Ultrasonido , Vocalización Animal/efectos de los fármacosRESUMEN
The cyclooxygenase-2/prostanoid pathway (COX-2) serves as a potential therapeutic target in various pathological conditions. Thus, the modulatory effect of celecoxib (CXB), a COX-2 inhibitor, in atrazine-induced toxicity was investigated. Five groups (nâ¯=â¯6 rats per group) of adult male Wistar rats received corn oil (2â¯ml/kg), atrazine (ATZ, 300â¯mg/kg) and CXB (5.7â¯mg/kg) respectively and their combinations via the oral route. Results obtained showed reduced (pâ¯<â¯0.05) sperm motility (25.8%) and counts (27.6%), testosterone (29.9%), luteinizing (33%) and follicle stimulating hormones (78.7%) plus elevated total cholesterol (112.3%), triglyceride (115.7%), malondialdehyde levels respectively in ATZ-treated rats. Similarly, ATZ administration causes reduced locomotion (33.6%), spontaneous motor activity (46.6%) and catalepsy effects (157.3%) respectively. However, CXB divided doses moderately reverse reproductive abnormalities, modulate neurobehavioural deficits and slightly preserved COX-2 elevation following ATZ intoxication. Furthermore, histopathology of testis shows improvement in treated rats. Overall, our data suggest chemopreventive actions via pharmacological inhibition of COX-2 activity during ATZ toxicity.
Asunto(s)
Atrazina/toxicidad , Celecoxib/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Herbicidas/toxicidad , Enfermedades del Sistema Nervioso/prevención & control , Animales , Conducta Animal/efectos de los fármacos , Catalepsia/inducido químicamente , Catalepsia/metabolismo , Catalepsia/patología , Catalepsia/prevención & control , Celecoxib/farmacología , Quimioprevención , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Hormona Folículo Estimulante/sangre , Metabolismo de los Lípidos/efectos de los fármacos , Locomoción/efectos de los fármacos , Hormona Luteinizante/sangre , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Enfermedades del Sistema Nervioso/inducido químicamente , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patología , Ratas Wistar , Reproducción/efectos de los fármacos , Recuento de Espermatozoides , Motilidad Espermática/efectos de los fármacos , Testículo/efectos de los fármacos , Testículo/metabolismo , Testículo/patología , Testosterona/sangreRESUMEN
The GPR55 receptor is expressed abundantly in the brain, especially in the striatum, suggesting it might fulfill a role in motor function. Indeed, motor behavior is impaired in mice lacking GPR55, which also display dampened inflammatory responses. Abnormal-cannabidiol (Abn-CBD), a synthetic cannabidiol (CBD) isomer, is a GPR55 agonist that may serve as a therapeutic agent in the treatment of inflammatory diseases. In this study, we explored whether modulating GPR55 could also represent a therapeutic approach for the treatment of Parkinson's disease (PD). The distribution of GPR55 mRNA was first analyzed by in situ hybridization, localizing GPR55 transcripts to neurons in brain nuclei related to movement control, striatum, globus pallidus, subthalamic nucleus, substantia nigra and cortex. Striatal expression of GPR55 was downregulated in parkinsonian conditions. When Abn-CBD and CBD (5 mg/kg) were chronically administered to mice treated over 5 weeks with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp), Abn-CBD but not CBD prevented MPTPp induced motor impairment. Although Abn-CBD protected dopaminergic cell bodies, it failed to prevent degeneration of the terminals or preserve dopamine levels in the striatum. Both compounds induced morphological changes in microglia that were compatible with an anti-inflammatory phenotype that did not correlate with a neuroprotective activity. The symptomatic relief of Abn-CBD was further studied in the haloperidol-induced catalepsy mouse model. Abn-CBD had an anti-cataleptic effect that was reversed by CBD and PSB1216, a newly synthesized GPR55 antagonist, and indeed, two other GPR55 agonists also displayed anti-cataleptic effects (CID1792197 and CID2440433). These results demonstrate for the first time that activation of GPR55 might be beneficial in combating PD.
Asunto(s)
Antiparkinsonianos/farmacología , Agonistas de Receptores de Cannabinoides/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/metabolismo , Receptores de Cannabinoides/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Ganglios Basales/efectos de los fármacos , Ganglios Basales/metabolismo , Ganglios Basales/patología , Proteínas de Unión al Calcio/metabolismo , Cannabidiol/análogos & derivados , Cannabidiol/farmacología , Catalepsia/tratamiento farmacológico , Catalepsia/metabolismo , Catalepsia/patología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Dopamina/metabolismo , Haloperidol , Ácido Homovanílico/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Trastornos Parkinsonianos/patología , ARN Mensajero/metabolismoRESUMEN
The effects of antipsychotic drugs (APDs) on the adolescent brain are poorly understood despite a dramatic increase in prescription of these drugs in adolescents over the past twenty years. Neuronal systems continue to be remodeled during adolescence. Therefore, when given in adolescence, antipsychotic drugs (APDs) have the potential to affect this remodeling. In this study we investigated the effects of chronic 22-day risperidone treatment (1.3mg/kg/day) in both adolescent and adult rats. We examined short- and long-term changes in behaviour (catalepsy, locomotion and conditioned avoidance response (CAR)), and dopaminergic and serotonergic neurochemistry in the striatum and the nucleus accumbens. Here, we report that, both during chronic treatment and after a lengthy drug-free interval, risperidone induced a sensitised cataleptic response regardless of the age of exposure. Selectively in adolescents, risperidone-induced catalepsy was inversely correlated with striatal dopamine turnover immediately after chronic treatment. After a drug-free interval, a significant proportion of rats with prior adolescent risperidone treatment also failed to acquire CAR to a defined criterion. Our data provide evidence that the same chronic risperidone treatment regimen can induce contrasting short- and long-term neural outcomes in the adolescent and adult brains.
Asunto(s)
Antipsicóticos/efectos adversos , Catalepsia/inducido químicamente , Risperidona/efectos adversos , Factores de Edad , Animales , Antipsicóticos/administración & dosificación , Monoaminas Biogénicas/análisis , Monoaminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Encéfalo/fisiopatología , Catalepsia/sangre , Catalepsia/metabolismo , Catalepsia/fisiopatología , Corticosterona/sangre , Dopamina/metabolismo , Locomoción/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Risperidona/administración & dosificaciónRESUMEN
Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing.
Asunto(s)
Amígdala del Cerebelo , Catalepsia , Núcleo Dorsal del Rafe , Neuronas Serotoninérgicas/metabolismo , Transducción de Señal , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/patología , Amígdala del Cerebelo/fisiopatología , Animales , Catalepsia/genética , Catalepsia/metabolismo , Catalepsia/patología , Catalepsia/fisiopatología , Núcleo Dorsal del Rafe/metabolismo , Núcleo Dorsal del Rafe/patología , Núcleo Dorsal del Rafe/fisiopatología , Movimientos Oculares , Masculino , Ratones , Ratones Noqueados , Neuronas Serotoninérgicas/patología , Serotonina/metabolismoRESUMEN
Previous studies showed that the repeated administration with a low dose of reserpine (RES) induces a gradual appearance of motor signs and cognitive deficits compatible with parkinsonism in rodents. Environmental stimulation has neuroprotective effects in animal models of neurodegenerative damage, including acutely induced parkinsonism. We investigated the effects of exposure to an enriched environment (EE) on motor, cognitive and neuronal (levels of tyrosine hydroxylase, TH and brain derived neurotrophic factor, BDNF) deficits induced by a progressive model of Parkinson's disease (PD) in mice. Male mice were repeatedly treated with vehicle or 0.1mg/kg of RES (s.c) and kept under two housing conditions: standard environment (SE) and EE. In animals kept in SE, the treatment with RES induced deficits in motor function (catalepsy test, open field and oral movements), in novel object recognition (NOR) and plus-maze discriminative avoidance tasks. The environmental stimulation facilitated the recovery of motor deficits assessed by the catalepsy test after the end of treatment. Additionally, exposure to EE prevented the memory deficit in the NOR task. Treatment with RES induced a reduction in the number of TH positive cells in SNpc and VTA, which recovered 30days after the end of treatment. Finally, RES reduced the levels of BDNF in the striatum and the exposure to the EE prevented this effect. These results suggest that plastic brain changes induced by EE promote beneficial effects on the progression of neuronal impairment related to PD.