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1.
Int J Mol Sci ; 24(9)2023 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-37175643

RESUMEN

Excessive inhibition of the external globus pallidus (GPe) by striatal GABAergic neurons is considered a central mechanism contributing to motor symptoms of Parkinson's disease (PD). While electrophysiological findings support this view, behavioral studies assessing the beneficial effects of global GPe activations are scarce and the reported results are controversial. We used an optogenetic approach and the standard unilateral 6-hydroxydopamine nigrostriatal dopamine (DA) lesion model of PD to explore the effects of GPe photostimulation on motor deficits in mice. Global optogenetic GPe inhibition was used in normal mice to verify whether it reproduced the typical motor impairment induced by DA lesions. GPe activation improved ipsilateral circling, contralateral forelimb akinesia, locomotor hypoactivity, and bradykinesia in 6-OHDA-lesioned mice at ineffective photostimulation parameters (532 nm, 5 Hz, 3 mW) in normal mice. GPe photoinhibition (450 nm, 12 mW) had no effect on locomotor activity and forelimb use in normal mice. Bilateral photoinhibition (450 nm, 6 mW/side) reduced directed exploration and improved working memory performances indicating that recruitment of GPe in physiological conditions may depend on the behavioral task involved. Collectively, these findings shed new light on the functional role of GPe and suggest that it is a promising target for neuromodulatory restoration of motor deficits in PD.


Asunto(s)
Enfermedad de Parkinson , Ratones , Animales , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/patología , Globo Pálido/patología , Oxidopamina , Optogenética , Cuerpo Estriado , Dopamina/fisiología , Hipocinesia/inducido químicamente , Hipocinesia/terapia , Hipocinesia/patología
2.
J Clin Psychiatry ; 84(1)2023 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-36724110

RESUMEN

Patients who require antipsychotic drug treatment are at increased risk of fractures, including osteoporosis-related fragility fractures, for reasons related to demographics, illness-related factors, and treatment-related factors. As examples, patients with dementia may be vulnerable to falls due to cognitive and psychomotor impairment, patients with schizophrenia may be vulnerable to injury related to physical restlessness or physical aggression, and patients receiving antipsychotics may suffer falls related to sedation, psychomotor impairment, bradykinesia, or postural hypotension. Antipsychotics may also increase the risk of fracture through long-term hyperprolactinemia and resultant osteoporosis. A meta-analysis of 36 observational studies conducted in mostly elderly samples found that antipsychotic exposure was associated with an increased risk of hip fracture as well as increased risk of any fracture; the findings were consistent in almost all subgroup analyses. An observational study that controlled for confounding by indication and illness severity found that fragility fractures in patients with schizophrenia were associated with higher daily doses, higher cumulative doses, longer duration of treatment, and prolactin-raising rather than prolactin-sparing antipsychotics; in patients receiving prolactin-raising antipsychotics, the concurrent use of aripiprazole appeared protective. The absolute risks of fracture are unknown and could vary depending on patient age, patient sex, indication for antipsychotic use, nature of the antipsychotic (and associated risk of sedation, psychomotor impairment, bradykinesia, and postural hypotension), daily dose prescribed, duration of antipsychotic exposure, baseline risk of fracture, and other risk factors. Patients should therefore be individually evaluated for risk factors for falls and fractures related to sociodemographic, clinical, and treatment-related risk factors. Patients identified to be at risk should be advised about risk-mitigating strategies. If prolactin-raising antipsychotics are required in the long term, prolactin levels should be monitored and prolactin-lowering strategies should be considered. Osteoporosis should be investigated and managed, if identified, to prevent fragility fractures.


Asunto(s)
Antipsicóticos , Demencia , Hiperprolactinemia , Hipotensión Ortostática , Osteoporosis , Esquizofrenia , Humanos , Anciano , Antipsicóticos/efectos adversos , Prolactina , Esquizofrenia/complicaciones , Hipocinesia/inducido químicamente , Hipocinesia/complicaciones , Hipocinesia/tratamiento farmacológico , Hipotensión Ortostática/inducido químicamente , Hipotensión Ortostática/complicaciones , Hipotensión Ortostática/tratamiento farmacológico , Hiperprolactinemia/inducido químicamente , Hiperprolactinemia/complicaciones , Hiperprolactinemia/tratamiento farmacológico , Osteoporosis/inducido químicamente , Osteoporosis/complicaciones , Osteoporosis/tratamiento farmacológico , Factores de Riesgo , Demencia/complicaciones , Estudios Observacionales como Asunto
3.
J Exp Biol ; 225(6)2022 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-35320357

RESUMEN

The subjugation strategy employed by the jewel wasp is unique in that it manipulates the behavior of its host, the American cockroach, rather than inducing outright paralysis. Upon envenomation directly into the central complex (CX), a command center in the brain for motor behavior, the stung cockroach initially engages in intense grooming behavior, then falls into a lethargic sleep-like state referred to as hypokinesia. Behavioral changes evoked by the sting are due at least in part to the presence of the neurotransmitter dopamine in the venom. In insects, dopamine receptors are classified as two families, the D1-like and the D2-like receptors. However, specific roles played by dopamine receptor subtypes in venom-induced behavioral manipulation by the jewel wasp remain largely unknown. In the present study, we used a pharmacological approach to investigate roles of D1-like and D2-like receptors in behaviors exhibited by stung cockroaches, focusing on grooming. Specifically, we assessed behavioral outcomes of focal CX injections of dopamine receptor agonists and antagonists. Both specific and non-specific compounds were used. Our results strongly implicate D1-like dopamine receptors in venom-induced grooming. Regarding induction of hypokinesia, our findings demonstrate that dopamine signaling is necessary for induction of long-lasting hypokinesia caused by brain envenomation.


Asunto(s)
Cucarachas , Avispas , Animales , Conducta Animal , Cucarachas/fisiología , Dopamina/farmacología , Agonistas de Dopamina/farmacología , Humanos , Hipocinesia/inducido químicamente , Instinto , Receptores Dopaminérgicos , Receptores de Dopamina D1 , Venenos de Avispas/efectos adversos , Avispas/fisiología
4.
Behav Brain Res ; 425: 113827, 2022 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-35248650

RESUMEN

Our aims were to assess the effect of melatonin on fluphenazine-induced hypokinesia during the light (ZT 9.5-10.5) and dark (ZT 17.5-18.5) phases in mice lacking endogenous pineal melatonin (C57BL/6 mouse), and to investigate the effects of the manipulation of environmental lighting in mice with a targeted deletion of the MT1 melatonin receptor. In both knockout (C57KO MT1) and wild type (C57WT) mice, fluphenazine (1 mg/kg) induced hypokinesia during the light phase (C57WT: M=105, SEM=31.2 s, n = 31; C57 MT1KO:M=118, SEM = 32.6 s, n = 29). During the light phase melatonin (10 mg/kg, sc) significantly reduced hypokinesia in both genotypes (C57WT: M=33.1, SEM=8.4 s; C57 MT1KO: M=33.3, SEM=13.0 s). In the dark, fluphenazine did not induce a substantial hypokinesia in either C57WT or C57 MT1KO mice. Manipulating the lightning environment during testing, experiments conducted during the light phase in a dark environment served to abolish the hypokinetic effect of fluphenazine in all groups regardless of melatonin treatment. Conversely, experiments conducted during the dark phase in a light environment showed mice to have hypokinetic effects by fluphenazine treatment in both C57WT (M=98.4, SEM=20.2 s) and C57 MT1KO (M=40.4 SEM=9.5 s) groups. These data suggest that fluphenazine-induced hypokinesia is more pronounced under light than dark conditions, and that melatonin is only able to counteract hypokinesia during the light phase. Importantly, our data suggest that the effect of melatonin on hypokinesia was not solely mediated by the MT1 melatonin receptor in the C57BL/6 mouse, leaving the possible activation of MT2 receptor as the mechanism of action which is regulated by the light/dark environment.


Asunto(s)
Melatonina , Glándula Pineal , Animales , Ritmo Circadiano , Flufenazina/efectos adversos , Hipocinesia/inducido químicamente , Melatonina/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Glándula Pineal/metabolismo , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT2/genética
5.
Sr Care Pharm ; 36(1): 34-41, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33384032

RESUMEN

OBJECTIVE: To report pharmacogenomics post-related bradykinesia secondary to phenoconversion in an elderly post-bilateral lung transplant patient.SUMMARY: The patient was a 68-year-old double lung transplant patient taking the immunosuppressant and CYP3A4/5 substrate tacrolimus concomitantly with 2 CYP3A4/5 inhibitor medications, fluconazole and diltiazem. This drug combination post-dosing resulted in debilitating bradykinesia 1-2 hours after dosing, increasing the risk of falls and possible increased mortality and morbidity risk.CONCLUSION: Taking tacrolimus in combination with CYP3A4/5 inhibitors may increase neurologic adverse effects resulting in increased fall and associated increased mortality and morbidity risk.


Asunto(s)
Hipocinesia/inducido químicamente , Inmunosupresores/efectos adversos , Trasplante de Pulmón , Tacrolimus/efectos adversos , Anciano , Inhibidores del Citocromo P-450 CYP3A , Humanos , Trasplante de Pulmón/efectos adversos
6.
Bull Exp Biol Med ; 169(4): 431-434, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32889565

RESUMEN

We studied the effect of single and repeated intranasal administration of antibodies to glutamate in experimental parkinsonian syndrome induced by injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6J mice. Intranasal administration of anti-glutamate antibodies to mice in parallel with administration of MPTP over 10 days alleviated parkinsonian symptoms (oligokinesia and rigidity). In the serum of mice injected with antibodies to glutamate and/or MPTP, the titers of autoantibodies to glutamate and dopamine were higher than in control animals receiving saline. Single intranasal administration of anti-glutamate antibodies to mice with established parkinsonian syndrome did not affect the severity of parkinsonian symptoms.


Asunto(s)
Anticuerpos/farmacología , Antiparkinsonianos/farmacología , Dopamina/inmunología , Ácido Glutámico/inmunología , Hipocinesia/tratamiento farmacológico , Trastornos Parkinsonianos/tratamiento farmacológico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/administración & dosificación , Administración Intranasal , Animales , Anticuerpos/química , Anticuerpos/aislamiento & purificación , Antiparkinsonianos/química , Antiparkinsonianos/aislamiento & purificación , Autoanticuerpos/biosíntesis , Dopamina/química , Ácido Glutámico/química , Caballos , Hipocinesia/inducido químicamente , Hipocinesia/inmunología , Hipocinesia/fisiopatología , Inmunoconjugados/administración & dosificación , Inmunoconjugados/química , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/inmunología , Trastornos Parkinsonianos/fisiopatología , Conejos , gammaglobulinas/química , gammaglobulinas/inmunología
7.
Behav Brain Res ; 379: 112313, 2020 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-31715211

RESUMEN

It has been well established that the striatal dopaminergic system is compromised with aging, namely D2 receptor function. Also well documented is the age related decline of the neurohormone, melatonin, in both humans and nonhuman animals. What has not been well studied is the possible interaction between the D2 receptor system and the age related decline in melatonin with its unmistakable pattern of synthesis and release exclusively during the dark phase. We tested the effect of the D2 antagonist, haloperidol (1.0 mg/kg ip), in adolescent (2 mo old) and adult rats (10 mo old) in the light (ZT3) and dark phases (ZT 15) in rats kept in a 12 L/12D cycle and the effect of exogenous melatonin (15 mg/kg ip/day x 4 days for a total of 60 mg/kg) on D2 antagonism. Using the bar test, measuring the extrapyramidal side-effect of hypokinesia, we report haloperidol to work differentially depending on both age and phase. Adult rats experienced the effect of the D2 antagonist in both the light and dark phases, while younger rats did not show hypokinetic affects in the dark. By manipulated lighting, we were able to restore the effect of haloperidol in younger rats in the dark phase. We also found ameliorating effects of melatonin lessening time on the bar after treatment with haloperidol, however, this effect was only found in older rats. These data demonstrate the importance of the light/dark cycle and age in the susceptibility of extrapyramidal effects with use of drugs that target D2 receptor function.


Asunto(s)
Conducta Animal/efectos de los fármacos , Depresores del Sistema Nervioso Central/farmacología , Antagonistas de los Receptores de Dopamina D2/farmacología , Haloperidol/farmacología , Hipocinesia/inducido químicamente , Melatonina/farmacología , Fotoperiodo , Factores de Edad , Animales , Depresores del Sistema Nervioso Central/administración & dosificación , Modelos Animales de Enfermedad , Antagonistas de los Receptores de Dopamina D2/administración & dosificación , Haloperidol/administración & dosificación , Melatonina/administración & dosificación , Ratas , Ratas Sprague-Dawley
8.
Free Radic Biol Med ; 135: 274-282, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30862545

RESUMEN

Mitochondrial dysfunction named complex I syndrome was observed in striatum mitochondria of rotenone treated rats (2 mg rotenone/kg, i. p., for 30 or 60 days) in an animal model of Parkinson disease. After 60 days of rotenone treatment, the animals showed: (a) 6-fold increased bradykinesia and 60% decreased locomotor activity; (b) 35-34% decreases in striatum O2 uptake and in state 3 mitochondrial respiration with malate-glutamate as substrate; (c) 43-57% diminished striatum complex I activity with 60-71% decreased striatum mitochondrial NOS activity, determined both as biochemical activity and as functional activity (by the NO inhibition of active respiration); (d) 34-40% increased rates of mitochondrial O2•- and H2O2 productions and 36-46% increased contents of the products of phospholipid peroxidation and of protein oxidation; and (e) 24% decreased striatum mitochondrial content, likely associated to decreased NO-dependent mitochondrial biogenesis. Intermediate values were observed after 30 days of rotenone treatment. Frontal cortex tissue and mitochondria showed similar but less marked changes. Rotenone-treated rats showed mitochondrial complex I syndrome associated with cellular oxidative stress in the dopaminergic brain areas of striatum and frontal cortex, a fact that describes the high sensitivity of mitochondrial complex I to inactivation by oxidative reactions.


Asunto(s)
Complejo I de Transporte de Electrón/metabolismo , Mitocondrias/metabolismo , Oxígeno/metabolismo , Enfermedad de Parkinson/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Complejo I de Transporte de Electrón/deficiencia , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Sustancia Gris/efectos de los fármacos , Sustancia Gris/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Hipocinesia/inducido químicamente , Hipocinesia/metabolismo , Hipocinesia/patología , Peroxidación de Lípido/efectos de los fármacos , Locomoción/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Ratas , Rotenona/farmacología
9.
Environ Sci Pollut Res Int ; 25(22): 21937-21948, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29797195

RESUMEN

Methylmercury (MeHg) is a hazardous environmental pollutant, affecting Amazon basin communities by anthropogenic activities. The exact safe level of MeHg exposure is unclear, despite the efforts of health international societies to avoid mercury (Hg) poisoning. Central nervous system is severely impacted by Hg intoxication, reflecting on motor impairment. In addition, alcohol has been associated to an overall brain damage. According to lifestyle of Amazon riverside communities, alcohol intake occurs frequently. Thus, we investigated if continuous MeHg exposure at low doses during adolescence displays motor deficits (experiment 1). In the experiment 2, we examine if the co-intoxication (i.e. MeHg plus ethanol exposure) during adolescence intensify motor damage. In the experiment 1, Wistar adolescent rats (31 days old) received chronic exposure to low dose (CELD) of MeHg (40 µg/kg/day) for 35 days. For the experiment 2, five sessions of alcohol binge drinking paradigm (3ON-4OFF; 3.0 g/kg/day) were employed associated to MeHg intoxication. Motor behaviour was evaluated by the open field, pole test, beam walking and rotarod paradigms. CELDS of MeHg display motor function damage, related to hypoactivity, bradykinesia-like behaviour, coordination deficits and motor learning impairment. Co-intoxication of MeHg plus ethanol reduced cerebellar Hg content, however also resulted in motor behavioural impairment, as well as additive effects on bradykinesia and fine motor evaluation.


Asunto(s)
Intoxicación Alcohólica/fisiopatología , Compuestos de Metilmercurio/toxicidad , Actividad Motora/efectos de los fármacos , Adolescente , Animales , Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Contaminantes Ambientales/toxicidad , Etanol/administración & dosificación , Etanol/toxicidad , Femenino , Humanos , Hipocinesia/inducido químicamente , Mercurio/administración & dosificación , Mercurio/farmacocinética , Compuestos de Metilmercurio/administración & dosificación , Ratas Wistar , Pruebas de Toxicidad Crónica
10.
Neurotoxicology ; 64: 152-158, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28965701

RESUMEN

BACKGROUND: Excessive exposure to manganese (Mn) may cause parkinsonian-like motor and tremor symptoms and adverse cognitive effects, including problems with executive functioning (EF), resembling those found in later-stage Parkinson's disease (PD). Studies seeking to differentiate PD patients into subgroups with associated cognitive and functional outcomes using motor and tremor symptoms identified tremor-dominant (TD) and non-tremor dominant (NTD) subtypes. It is unclear whether differing patterns of pathophysiology and symptoms exist in Mn neurotoxicity, as they do in PD. METHODS: Residents of East Liverpool (n=83) and Marietta, OH (n=99) exposed to chronic (>10years) environmental Mn through industrial pollution were administered neuropsychological measures and a physician-rated scale of movement-disorder symptoms. Two-step cluster analysis was used to group residents based on tremor symptoms, bradykinesia/rigidity symptoms, gait disturbance, and executive function. Cluster membership was validated using modeled air-Mn exposure and a computerized tremor measure. RESULTS: Elevated tremor and motor symptoms and executive dysfunction were observed, and TD and NTD symptom clusters were identified. Two additional clusters were also identified: Executive Dysfunction and Normal Functioning. The NTD residents, with elevated levels of gait disturbance and other movement disorder symptoms, did not evidence EF impairment, as predicted. Instead, residents with EF impairment formed their own cluster, and were relatively free of movement disorder symptoms. CONCLUSIONS: Results resemble reports in the PD literature with TD and NTD clusters identified, but executive dysfunction did not cluster with NTD symptoms. PD and Mn exposure likely have differing pathophysiology and developmental courses, and therefore different symptom patterns, even when similar symptoms are present.


Asunto(s)
Contaminantes Atmosféricos/efectos adversos , Disfunción Cognitiva/inducido químicamente , Exposición a Riesgos Ambientales , Manganeso/efectos adversos , Enfermedad de Parkinson Secundaria/diagnóstico , Temblor/inducido químicamente , Anciano , Femenino , Trastornos Neurológicos de la Marcha/inducido químicamente , Humanos , Hipocinesia/inducido químicamente , Masculino , Pruebas Neuropsicológicas , Ohio
11.
Mov Disord ; 32(10): 1474-1478, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28895186

RESUMEN

BACKGROUND: Placebo effects represent a major drawback in clinical trials, and their magnitude hampers the development of new treatments. Previous research showed that prior exposure to active treatments increases the placebo response for muscle rigidity in Parkinson's disease. METHODS: We investigated the effects of prior exposure to apomorphine on the placebo response of another cardinal symptom of Parkinson's disease, bradykinesia, by a movement time analyzer. RESULTS: We found no placebo response if the placebo was given for the first time, whereas the placebo response was substantial after prior pharmacological conditioning with apomorphine. CONCLUSIONS: These findings indicate that prior exposure to drugs is a critical factor in the occurrence and magnitude of placebo effects. These learning effects should be carefully assessed in clinical trials in which patients receive the active treatment first and then are randomized. Indeed, this sequence may generate high placebo responders. © 2017 International Parkinson and Movement Disorder Society.


Asunto(s)
Hipocinesia/terapia , Efecto Placebo , Anciano , Apomorfina/efectos adversos , Dopaminérgicos/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Hipocinesia/inducido químicamente , Levodopa/efectos adversos , Masculino , Persona de Mediana Edad , Movimiento/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico
12.
BMJ Case Rep ; 20172017 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-28801325

RESUMEN

Aluminium phosphide (ALP) is a common cause of suicidal poisoning in India where it is easily available and commonly known as 'rice tablet'. In rural areas of India, it is still used to protect rice and stored grains from rodents and pests. 1 There is no specific antidote for phosphide poisoning and treatment involves meticulous supportive care. Ingestion can lead to severe cardiac suppression and cardiogenic shock. For patients poisoned with ALP who continue to have refractory shock with persistent myocardial suppression despite the use of adrenergic inotropic agents, the addition of digoxin may be beneficial. We present a case where digoxin was utilised with beneficial patient outcomes.


Asunto(s)
Acidosis Láctica/inducido químicamente , Compuestos de Aluminio/envenenamiento , Cardiotónicos/uso terapéutico , Digoxina/uso terapéutico , Hipocinesia/inducido químicamente , Plaguicidas/envenenamiento , Fosfinas/envenenamiento , Choque Cardiogénico/inducido químicamente , Acidosis Láctica/fisiopatología , Acidosis Láctica/terapia , Fluidoterapia , Lavado Gástrico , Humanos , Hipocinesia/fisiopatología , Hipocinesia/terapia , India , Masculino , Choque Cardiogénico/fisiopatología , Choque Cardiogénico/terapia , Resultado del Tratamiento , Adulto Joven
13.
Riv Psichiatr ; 52(4): 172-173, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28845867

RESUMEN

The present report describes extrapyramidal side effects (EPS) appearing after 32 months of exclusive treatment with clozapine at low dosages. This case evidences that long-term treatment with clozapine may be associated with EPS and suggests that, even if clozapine is considered the medication with the fewest EPS and it is often prescribed as an effective treatment for them, its use does not fully eliminate the risk of neurological side effects.


Asunto(s)
Antipsicóticos/efectos adversos , Enfermedades de los Ganglios Basales/inducido químicamente , Clozapina/efectos adversos , Adulto , Antipsicóticos/administración & dosificación , Clozapina/administración & dosificación , Sustitución de Medicamentos , Humanos , Hipocinesia/inducido químicamente , Masculino , Hipertonía Muscular/inducido químicamente , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/tratamiento farmacológico , Risperidona/efectos adversos , Tioridazina/administración & dosificación , Temblor/inducido químicamente
15.
Int J Mol Sci ; 18(7)2017 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-28671605

RESUMEN

Dysfunction of the N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathogenesis of schizophrenia. Although agonists for the glycine-binding sites of NMDA receptors have potential as new medication for schizophrenia, their modulation of antipsychotic-induced extrapyramidal side effects (EPS) has not yet been clarified. We herein evaluated the effects of glycine-binding site stimulants of NMDA receptors on antipsychotic-induced EPS in mice and rats. d-cycloserine (DCS) and d-serine significantly improved haloperidol (HAL)-induced bradykinesia in mice, whereas glycine showed no effects. Sodium benzoate, a d-amino acid oxidase inhibitor, also attenuated HAL-induced bradykinesia. Improvements in HAL-induced bradykinesia by DCS were antagonized by the NMDA antagonist dizocilpine or nitric oxide synthase inhibitor L-NG-Nitro-l-arginine methyl ester. In addition, DCS significantly reduced HAL-induced Fos expression in the dorsolateral striatum without affecting that in the nucleus accumbens. Furthermore, a microinjection of DCS into the substantia nigra pars compacta significantly inhibited HAL-induced EPS concomitant with elevations in dopamine release in the striatum. The present results demonstrated for the first time that stimulating the glycine-binding sites of NMDA receptors alleviates antipsychotic-induced EPS by activating the nigrostriatal dopaminergic pathway, suggesting that glycine-binding site stimulants are beneficial not only for efficacy, but also for side-effect management.


Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Glicina/metabolismo , Trastornos Motores/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sustancia Negra/metabolismo , Animales , Sitios de Unión , Cuerpo Estriado/efectos de los fármacos , Cicloserina/farmacología , Maleato de Dizocilpina/farmacología , Haloperidol , Hipocinesia/inducido químicamente , Masculino , Ratones , Microdiálisis , Microinyecciones , NG-Nitroarginina Metil Éster/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistas , Sustancia Negra/efectos de los fármacos
18.
J Neurosci ; 36(35): 9161-72, 2016 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-27581457

RESUMEN

UNLABELLED: Over the last decade, striatal cholinergic interneurons (ChIs) have reemerged as key actors in the pathophysiology of basal-ganglia-related movement disorders. However, the mechanisms involved are still unclear. In this study, we address the role of ChI activity in the expression of parkinsonian-like motor deficits in a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion model using optogenetic and pharmacological approaches. Dorsal striatal photoinhibition of ChIs in lesioned ChAT(cre/cre) mice expressing halorhodopsin in ChIs reduces akinesia, bradykinesia, and sensorimotor neglect. Muscarinic acetylcholine receptor (mAChR) blockade by scopolamine produces similar anti-parkinsonian effects. To decipher which of the mAChR subtypes provides these beneficial effects, systemic and intrastriatal administration of the selective M1 and M4 mAChR antagonists telenzepine and tropicamide, respectively, were tested in the same model of Parkinson's disease. The two compounds alleviate 6-OHDA lesion-induced motor deficits. Telenzepine produces its beneficial effects by blocking postsynaptic M1 mAChRs expressed on medium spiny neurons (MSNs) at the origin of the indirect striatopallidal and direct striatonigral pathways. The anti-parkinsonian effects of tropicamide were almost completely abolished in mutant lesioned mice that lack M4 mAChRs specifically in dopamine D1-receptor-expressing neurons, suggesting that postsynaptic M4 mAChRs expressed on direct MSNs mediate the antiakinetic action of tropicamide. The present results show that altered cholinergic transmission via M1 and M4 mAChRs of the dorsal striatum plays a pivotal role in the occurrence of motor symptoms in Parkinson's disease. SIGNIFICANCE STATEMENT: The striatum, where dopaminergic and cholinergic systems interact, is the pivotal structure of basal ganglia involved in pathophysiological changes underlying Parkinson's disease. Here, using optogenetic and pharmacological approaches, we investigated the involvement of striatal cholinergic interneurons (ChIs) and muscarinic receptor subtypes (mAChRs) in the occurrence of a wide range of motor deficits such as akinesia, bradykinesia, motor coordination, and sensorimotor neglect after unilateral nigrostriatal 6-hydroxydopamine lesion in mice. Our results show that photoinhibition of ChIs in the dorsal striatum and pharmacological blockade of muscarinic receptors, specifically postsynaptic M1 and M4 mAChRs, alleviate lesion-induced motor deficits. The present study points to these receptor subtypes as potential targets for the symptomatic treatment of parkinsonian-like motor symptoms.


Asunto(s)
Neuronas Colinérgicas/fisiología , Cuerpo Estriado/patología , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M4/metabolismo , Adrenérgicos/toxicidad , Anfetamina/farmacología , Análisis de Varianza , Animales , Colina O-Acetiltransferasa/genética , Colina O-Acetiltransferasa/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Lateralidad Funcional , Genotipo , Hipocinesia/inducido químicamente , Levodopa/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/genética , Optogenética , Oxidopamina/toxicidad , Enfermedad de Parkinson/etiología , Transducción Genética
19.
Acta Cir Bras ; 31(2): 133-7, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26959623

RESUMEN

PURPOSE: To investigate the role of adenosine A2A receptors on 6-OHDA-induced motor disorder in rat. METHODS: In order to induce experimental model of Parkinson's disease, 6-hydoxydopamine (8 µg/rat) was injected unilaterally into the SNc. After three weeks as a recovery period, 6-OHDA-induced bradykinesia and balance disturbances were assessed by using beam traversal test 10, 30 and 60 minutes after intraperitoneal injections of the drugs (caffeine, SCH58261). RESULTS: The results showed that 6-OHDA (8 µg/rat, Intra-SNc) induced motor disorders of Parkinson's disease and increased elapsed time in the beam test (p<0.001). Injection of caffeine (30 mg/kg, i.p.) and SCH58261 (2 mg/kg, i.p.) attenuated elapsed time on beam (p<0.01 and p<0.001). We showed that acute administration of caffeine and SCH 58261 can improve the 6-OHDA-induced bradykinesia and motor disturbance. CONCLUSION: Adenosine A2AR antagonists improve 6-OHDA-motor deficit and this effect seems to be mediated by the inhibition of A2A presynaptic receptors in substantia nigra pars compacta.


Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Cafeína/farmacología , Oxidopamina/efectos adversos , Enfermedad de Parkinson Secundaria/inducido químicamente , Antagonistas de Receptores Purinérgicos P1/farmacología , Animales , Modelos Animales de Enfermedad , Hipocinesia/inducido químicamente , Masculino , Actividad Motora/efectos de los fármacos , Trastornos Motores/inducido químicamente , Ratas Wistar , Estudios de Tiempo y Movimiento
20.
Pharmacol Rep ; 68(3): 608-15, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26977821

RESUMEN

BACKGROUND: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are indolealkylamine (IAA) drugs often abused together. Our recent studies have revealed the significant effects of co-administered harmaline, a monoamine oxidase inhibitor (MAOI), on 5-MeO-DMT pharmacokinetics and thermoregulation. This study was to delineate the impact of harmaline and 5-MeO-DMT on home-cage activity in mouse models, as well as the contribution of serotonin (5-HT) receptors. METHODS: Home-cage activities of individual animals were monitored automatically in the home cages following implantation of telemetry transmitters and administration of various doses of IAA drugs and 5-HT receptor antagonists. Area under the effect curve (AUEC) of mouse activity values were calculated by trapezoidal rule. RESULTS: High dose of harmaline (15mg/kg, ip) alone caused an early-phase (0-45min) hypoactivity in mice that was fully attenuated by 5-HT1A receptor antagonist WAY-100635, whereas a late-phase (45-180min) hyperactivity that was reduced by 5-HT2A receptor antagonist MDL-100907. 5-MeO-DMT (10 and 20mg/kg, ip) alone induced biphasic effects, an early-phase (0-45min) hypoactivity that was completely attenuated by WAY-100635, and a late-phase (45-180min) hyperactivity that was fully suppressed by MDL-100907. Interestingly, co-administration of MAOI harmaline (2-15mg/kg) with a subthreshold dose of 5-MeO-DMT (2mg/kg) induced excessive hyperactivities at late phase (45-180min) that could be abolished by either WAY-100635 or MDL-100907. CONCLUSIONS: Co-administration of MAOI with 5-MeO-DMT provokes excessive late-phase hyperactivity, which involves the activation of both 5-HT1A and 5-HT2A receptors.


Asunto(s)
Harmalina/farmacología , Hipercinesia/inducido químicamente , Hipocinesia/inducido químicamente , Metoxidimetiltriptaminas/farmacología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Fluorobencenos , Harmalina/antagonistas & inhibidores , Masculino , Metoxidimetiltriptaminas/antagonistas & inhibidores , Ratones , Inhibidores de la Monoaminooxidasa/farmacología , Actividad Motora/efectos de los fármacos , Piperazinas/farmacología , Piperidinas , Piridinas/farmacología
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