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1.
Behav Brain Res ; 378: 112315, 2020 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-31654662

RESUMEN

Schizophrenia is a major psychiatric disorder associated with positive and negative symptoms and cognitive impairments. In this study, we used animal models of behavior to evaluate the antipsychotic activity of ASP2905, a potent and selective inhibitor of the potassium channel Kv12.2 encoded by the Kcnh3/BEC1 gene. ASP2905 inhibited hyperlocomotion induced by methamphetamine and by phencyclidine. In contrast, ASP2905 did not affect spontaneous locomotion, suggesting that ASP2905 selectively inhibits abnormal behaviors induced by stimulants. Chronic infusion of ASP2905 significantly ameliorated phencyclidine-induced prolongation of immobility time in mice subjected to the forced swimming test. These findings suggest that ASP2905 potentially mitigates symptoms of schizophrenia, such as apathy. The antipsychotic clozapine also reversed phencyclidine-induced prolonged immobility, while risperidone and haloperidol had no effect. Assessment of the effects of ASP2905 on latent learning deficits in mice treated with phencyclidine as neonates subjected to the water-finding task showed that ASP2905 significantly ameliorated phencyclidine-induced prolongation of finding latency, which reflects latent learning performance. These findings suggest that ASP2905 potentially mitigates cognitive impairments caused by schizophrenia, such as attention deficits. In contrast, administration of clozapine did not ameliorate phencyclidine-induced prolongation of finding latency. Therefore, ASP2905 may alleviate the broad spectrum of symptoms of schizophrenia, including positive and negative symptoms and cognitive impairments, which is in contrast to currently available antipsychotics, which are generally only partially effective for ameliorating these symptoms.


Asunto(s)
Antipsicóticos/farmacología , Disfunción Cognitiva/tratamiento farmacológico , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Hipercinesia/tratamiento farmacológico , Aprendizaje/efectos de los fármacos , Locomoción/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Pirimidinas/farmacología , Esquizofrenia/tratamiento farmacológico , Triazinas/farmacología , Animales , Antipsicóticos/administración & dosificación , Conducta Animal/efectos de los fármacos , Disfunción Cognitiva/etiología , Modelos Animales de Enfermedad , Hipercinesia/inducido químicamente , Masculino , Memoria a Corto Plazo , Ratones , Bloqueadores de los Canales de Potasio/administración & dosificación , Pirimidinas/administración & dosificación , Esquizofrenia/inducido químicamente , Esquizofrenia/complicaciones , Triazinas/administración & dosificación
2.
PLoS One ; 13(11): e0207750, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30462746

RESUMEN

N-(4-fluorophenyl)-N'-phenyl-N"-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine [ASP2905] is a potent and selective inhibitor of the potassium voltage-gated channel subfamily H member 3 (KCNH3) that was originally identified in our laboratory. KCNH3 is concentrated in the forebrain, and its overexpression in mice leads to cognitive deficits. In contrast, Kcnh3 knockout mice exhibit enhanced performance in cognitive tasks such as attention. These data suggest that KCNH3 plays important roles in cognition. Here we investigated the neurochemical and neurophysiological profiles of ASP2905 as well as its effects on cognitive function, focusing on attention. ASP2905 (0.0313 and 0.0625 mg/kg, po) improved the latent learning ability of mice, which reflects attention. Microdialysis assays in rats revealed that ASP2905 increased the efflux of dopamine and acetylcholine in the medial prefrontal cortex (0.03, 0.1 mg/kg, po; 0.1, 1 mg/kg, po, respectively). The activities of these neurotransmitters are closely associated with attention. We used a multiple-trial passive avoidance task to investigate the effects of ASP2905 on inattention and impulsivity in juvenile stroke-prone spontaneously hypertensive rats. ASP2905 (0.1 and 0.3 mg/kg, po) significantly prolonged cumulative latency as effectively as methylphenidate (0.1 and 0.3 mg/kg, sc), which is the gold standard for treating ADHD. Further, ASP2905, amphetamine, and methylphenidate significantly increased the alpha-band power of rats, suggesting that ASP2905 increases arousal, which is a pharmacologically important activity for treating ADHD. In contrast, atomoxetine and guanfacine did not significantly affect power. Together, these findings suggest that ASP2905, which acts through a novel mechanism, is as effective for treating ADHD as currently available drugs such as methylphenidate.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/farmacología , Pirimidinas/farmacología , Triazinas/farmacología , Animales , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/patología , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Reacción de Prevención/efectos de los fármacos , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Masculino , Ratones , Bloqueadores de los Canales de Potasio/uso terapéutico , Pirimidinas/uso terapéutico , Ratas , Triazinas/uso terapéutico
3.
Eur J Pharmacol ; 810: 26-35, 2017 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-28552344

RESUMEN

KCNH3 (BEC1) is a member of the ether-à-go-go (KCNH) family of voltage-gated K+ channels. The aim of this study was to determine the pharmacological profiles in vitro and in vivo of a KCNH3 inhibitor N-(4-fluorophenyl)-N'-phenyl-N''-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine (ASP2905). We analyzed the effects of ASP2905 on channel activity in vitro and its neuropharmacological properties in young and aged rats as well as in mice. ASP2905 potently inhibited potassium currents in CHO cells expressing KCNH3 (IC50 = 9.0nM). In contrast, ASP2905 (≤ 10µM) minimally bound with low affinities to 55 transmembrane proteins. ASP2905 (0.1µM, 1µM) decreased the frequency of spontaneous inhibitory postsynaptic currents in cultured rat hippocampal neurons. In mice, ASP2905 reversed the disruption of spontaneous alternation behavior induced by MK-801 and scopolamine (minimum effective dose of ASP2905: 0.0625mg/kg, po). ASP2905 ameliorated the cognitive deficits of aged rats in step-through passive avoidance (0.0313 and 0.0625mg/kg, po) and Morris water-maze tasks (0.01mg/kg, po) and effectively penetrated the brain. The mean plasma and brain concentrations of ASP2905 reached their maxima (Cmax = 0.399ng/ml and 1.77ng/g, respectively) 1h after a single oral administration and then decreased (t1/2 = 1.5-1.6h) (brain plasma ratio = 2.7-4.9). The present study suggests that ASP2905 is a selective, orally administered inhibitor of KCNH3, which can enhance cognitive performance.


Asunto(s)
Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/farmacología , Pirimidinas/farmacología , Triazinas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Células CHO , Cognición/efectos de los fármacos , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Neuroquímica , Ratas
4.
Eur Neuropsychopharmacol ; 24(10): 1698-708, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25108314

RESUMEN

We recently identified ASP5736, (N-(diaminomethylene)-1-(3,5-difluoropyridin-4-yl)-4-fluoroisoquinoline-7-carboxamide (2E)-but-2-enedioate), a novel antagonist of 5-HT5A receptor, and here describe the in vitro and in vivo characterization of this compound. ASP5736 exhibited a high affinity for the human 5-HT5A receptor (Ki = 3.6 ± 0.66 nM) and antagonized 5-carboxamidotryptamine (5-CT)-induced Ca(2+) influx in human cells stably expressing the 5-HT5A receptor with approximately 200-fold selectivity over other receptors, including other 5-HT receptor subtypes, enzymes, and channels except human 5-HT2c receptor (Ki = 286.8 nM) and 5-HT7 receptor (Ki = 122.9 nM). Further, ASP5736 dose-dependently antagonized the 5-CT-induced decrease in cAMP levels in HEK293 cells stably expressing the 5-HT5A receptor. We then evaluated the effects of ASP5736 on cognitive impairments in several animal models of schizophrenia. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both ameliorated by ASP5736. In addition, ASP5736 also attenuated MK-801- and methamphetamine (MAP)-induced hyperactivity in mice without causing sedation, catalepsy, or plasma prolactin increase. The addition of olanzapine did not affect ASP5736-induced cognitive enhancement, and neither the sedative nor cataleptogenic effects of olanzapine were worsened by ASP5736. These results collectively suggest that ASP5736 is a novel and potent 5-HT5A receptor antagonist that not only ameliorates positive-like symptoms but also cognitive impairments in animal models of schizophrenia, without adverse effects. Present studies also indicate that ASP5736 holds potential to satisfy currently unmet medical needs for the treatment of schizophrenia by either mono-therapy or co-administered with commercially available antipsychotics.


Asunto(s)
Antipsicóticos/farmacología , Guanidinas/farmacología , Isoquinolinas/farmacología , Esquizofrenia/tratamiento farmacológico , Antagonistas de la Serotonina/farmacología , Animales , Antipsicóticos/química , Antipsicóticos/farmacocinética , Calcio/metabolismo , Catalepsia/tratamiento farmacológico , Catalepsia/fisiopatología , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/fisiopatología , AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Guanidinas/química , Guanidinas/farmacocinética , Células HEK293 , Humanos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Receptor de Serotonina 5-HT2C/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Esquizofrenia/fisiopatología , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacocinética
5.
Neuropharmacology ; 79: 412-9, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24373902

RESUMEN

γ-Secretase is the enzyme responsible for the intramembranous proteolysis of various substrates, such as amyloid precursor protein (APP) and Notch. Amyloid-ß peptide 42 (Aß42) is produced through the sequential proteolytic cleavage of APP by ß- and γ-secretase and causes the synaptic dysfunction associated with memory impairment in Alzheimer's disease. Here, we identified a novel cyclohexylamine-derived γ-secretase modulator, {(1R*,2S*,3R*)-3-[(cyclohexylmethyl)(3,3-dimethylbutyl)amino]-2-[4-(trifluoromethyl)phenyl]cyclohexyl}acetic acid (AS2715348), that may inhibit this pathological response. AS2715348 was seen to reduce both cell-free and cellular production of Aß42 without increasing levels of APP ß-carboxyl terminal fragment or inhibiting Notch signaling. Additionally, the compound increased Aß38 production, suggesting a shift of the cleavage site in APP. The inhibitory potency of AS2715348 on endogenous Aß42 production was similar across human, mouse, and rat cells. Oral administration with AS2715348 at 1 mg/kg and greater significantly reduced brain Aß42 levels in rats, and no Notch-related toxicity was observed after 28-day treatment at 100 mg/kg. Further, AS2715348 significantly ameliorated cognitive deficits in APP-transgenic Tg2576 mice. Finally, AS2715348 significantly reduced brain Aß42 levels in cynomolgus monkeys. These findings collectively show the promise for AS2715348 as a potential disease-modifying drug for Alzheimer's disease.


Asunto(s)
Acetatos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Encéfalo/efectos de los fármacos , Ciclohexilaminas/farmacología , Fármacos Neuroprotectores/farmacología , Acetatos/efectos adversos , Acetatos/farmacocinética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/metabolismo , Línea Celular Tumoral , Cognición/efectos de los fármacos , Ciclohexilaminas/efectos adversos , Ciclohexilaminas/farmacocinética , Modelos Animales de Enfermedad , Femenino , Humanos , Macaca fascicularis , Masculino , Ratones , Ratones Transgénicos , Estructura Molecular , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/farmacocinética , Nootrópicos/efectos adversos , Nootrópicos/química , Nootrópicos/farmacología , Fragmentos de Péptidos/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Notch/metabolismo
6.
J Neurochem ; 125(3): 465-72, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23240999

RESUMEN

Given that amyloid-ß 42 (Aß42) is believed to be a culprit in Alzheimer's disease (AD), reducing Aß42 production should be a potential therapeutic approach. γ-Secretase modulators (GSMs) cause selective reduction of Aß42 or both reduction of Aß42 and Aß40 without affecting total Aß through shifting the γ-cleavage position in amyloid precursor protein. We recently reported on GSM-2, one of the second-generation GSMs, that selectively reduced brain Aß42 level and significantly ameliorated cognitive deficits in plaque-free 5.5-month-old Tg2576 AD model mice. Here, we investigated the effects of GSM-2 on 10-, 14-, and 18-month-old mice which had age-dependent increase in amyloid plaques. Eight-day treatment with GSM-2 significantly ameliorated cognitive deficits measured by Y-maze task in the mice of any age. However, GSM-2 reduced brain soluble Aß42 only in 10-month-old mice. In contrast, GSM-2 markedly reduced newly synthesized soluble Aß42 in both 10- and 18-month-old mice with similar efficacy when measured using the stable isotope-labeling technique, suggesting that nascent Aß42 plays a more significant role than plaque-associated soluble Aß42 in the cognitive deterioration of Tg2576 mice. These findings further indicate the potential utility of approach to reducing Aß42 synthesis in AD therapeutic regimens.


Asunto(s)
Enfermedad de Alzheimer/complicaciones , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Trastornos del Conocimiento/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Fragmentos de Péptidos/metabolismo , Acetatos/farmacología , Acetatos/uso terapéutico , Factores de Edad , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/inmunología , Precursor de Proteína beta-Amiloide/genética , Animales , Anticuerpos/uso terapéutico , Cromatografía Liquida , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/química , Ensayo de Inmunoadsorción Enzimática , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Espectrometría de Masas , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/genética , Fragmentos de Péptidos/inmunología , Piperidinas/farmacología , Piperidinas/uso terapéutico
7.
Eur J Pharmacol ; 685(1-3): 59-69, 2012 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-22542656

RESUMEN

Hypofunction of brain N-methyl-d-aspartate (NMDA) receptors has been implicated in psychiatric disorders such as schizophrenia and Alzheimer's disease. Inhibition of glycine transporter-1 (GlyT1) is expected to increase glycine, a co-agonist of the NMDA receptor and, consequently, to facilitate NMDA receptor function. We have identified ASP2535 (4-[3-isopropyl-5-(6-phenyl-3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole) as a novel GlyT1 inhibitor, and here describe our in vitro and in vivo characterization of this compound. ASP2535 potently inhibited rat GlyT1 (IC(50)=92 nM) with 50-fold selectivity over rat glycine transporter-2 (GlyT2). It showed minimal affinity for many other receptors except for µ-opioid receptors (IC(50)=1.83 µM). Oral administration of ASP2535 dose-dependently inhibited ex vivo [(3)H]-glycine uptake in mouse cortical homogenate, suggesting good brain permeability. This profile was confirmed by pharmacokinetic analysis. We then evaluated the effect of ASP2535 on animal models of cognitive impairment in schizophrenia and Alzheimer's disease. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both attenuated by ASP2535 (0.3-3mg/kg, p.o. and 0.3-1mg/kg, p.o., respectively). ASP2535 (1-3mg/kg, p.o.) also improved the PCP-induced deficit in prepulse inhibition in rats. Moreover, the working memory deficit in scopolamine-treated mice and the spatial learning deficit in aged rats were both attenuated by ASP2535 (0.1-3mg/kg, p.o. and 0.1mg/kg, p.o., respectively). These studies provide compelling evidence that ASP2535 is a novel and centrally-active GlyT1 inhibitor that can improve cognitive impairment in animal models of schizophrenia and Alzheimer's disease, suggesting that ASP2535 may satisfy currently unmet medical needs for the treatment of these diseases.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Trastornos del Conocimiento/tratamiento farmacológico , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Oxadiazoles/farmacología , Esquizofrenia/tratamiento farmacológico , Triazoles/farmacología , Administración Oral , Enfermedad de Alzheimer/fisiopatología , Animales , Encéfalo/metabolismo , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Maleato de Dizocilpina/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/fisiopatología , Ratones , Oxadiazoles/administración & dosificación , Oxadiazoles/farmacocinética , Permeabilidad , Ratas , Ratas Wistar , Esquizofrenia/fisiopatología , Triazoles/administración & dosificación , Triazoles/farmacocinética
8.
J Neurosci ; 32(6): 2037-50, 2012 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-22323718

RESUMEN

γ-Secretase inhibitors (GSIs) reduce amyloid-ß (Aß) peptides but inevitably increase the ß-C-terminal fragment (ß-CTF) of amyloid precursor protein (APP), potentially having undesirable effects on synapses. In contrast, γ-secretase modulators (GSMs) reduce Aß42 without increasing ß-CTF. Although the Aß-lowering effects of these compounds have been extensively studied, little effort has been made to investigate their effects on cognition. Here, we compared the effects of two GSIs--(2S)-2-hydroxy-3-methyl-N-[(2S)-1-{[(1S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]amino}-1-oxopropan-2-yl]butanamide (LY450139, semagacestat) and (2R)-2-[[(4-chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxazol-3-yl)phenyl]methyl]amino-5,5,5-trifluoropentanamide (BMS-708163)--and a second-generation GSM [{(2S,4R)-1-[(4R)-1,1,1-trifluoro-7-methyloctan-4-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetic acid (GSM-2)] on spatial working memory in APP-transgenic (Tg2576) and nontransgenic mice using the Y-maze task. While acute dosing with either GSI ameliorated memory deficits in 5.5-month-old Tg2576 mice, these effects disappeared after 8 d subchronic dosing. Subchronic dosing with either GSI rather impaired normal cognition in 3-month-old Tg2576 mice, with no inhibition on the processing of other γ-secretase substrates, such as Notch, N-cadherin, or EphA4, in the brain. LY450139 also impaired normal cognition in wild-type mice; however, the potency was 10-fold lower than that in Tg2576 mice, indicating an APP-dependent mechanism likely with ß-CTF accumulation. Immunofluorescence studies revealed that the ß-CTF accumulation was localized in the presynaptic terminals of the hippocampal stratum lucidum and dentate hilus, implying an effect on presynaptic function in the mossy fibers. In contrast, both acute and subchronic dosing with GSM-2 significantly ameliorated memory deficits in Tg2576 mice and did not affect normal cognition in wild-type mice. We demonstrated a clear difference between GSI and GSM in effects on functional consequences, providing new insights into strategies for developing these drugs against Alzheimer's disease.


Asunto(s)
Alanina/análogos & derivados , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/fisiología , Precursor de Proteína beta-Amiloide/fisiología , Azepinas/farmacología , Cognición/efectos de los fármacos , Cognición/fisiología , Inhibidores de Proteasas/farmacología , Alanina/farmacología , Precursor de Proteína beta-Amiloide/genética , Animales , Línea Celular Tumoral , Femenino , Humanos , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos
9.
Life Sci ; 88(17-18): 761-5, 2011 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-21356217

RESUMEN

AIMS: Clinical use of olanzapine has been suggested to be associated with weight gain and adiposity in schizophrenic patients. While studies in experimental animals have noted weight gain in olanzapine-treated female rats, these findings have yet to be replicated in males. This study investigated the effect of chronic subcutaneous infusion of olanzapine in male rats via a recently developed electrical microinfusion pump. MAIN METHODS: An electrical microinfusion pump was subcutaneously implanted in male Sprague-Dawley rats who were then chronically administered olanzapine. Plasma olanzapine concentration and body weight were monitored, and fat pads were weighed after six weeks' olanzapine treatment. KEY FINDINGS: Plasma olanzapine concentration plateaued within 4h of commencement of chronic olanzapine 1.5mg/animal/day infusion and remained constant until day 21. Six-week infusion of olanzapine at 1.5 but not 1mg/animal/day induced significant adiposity in subcutaneous, epididymal, and retroperitoneal fat. Body weight and food intake values did not differ between olanzapine- and vehicle-treated rats throughout the experiment. SIGNIFICANCE: The present study demonstrated that chronic infusion of olanzapine induced adiposity in male rats without inducing weight gain or hyperphagia, even with sufficient plasma concentration. This report is the first to provide information about adiposity-inducible plasma concentration of olanzapine in male rats.


Asunto(s)
Tejido Adiposo/efectos de los fármacos , Antipsicóticos/farmacología , Benzodiazepinas/farmacología , Animales , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacocinética , Benzodiazepinas/administración & dosificación , Benzodiazepinas/farmacocinética , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Bombas de Infusión Implantables , Infusiones Subcutáneas , Masculino , Olanzapina , Ratas , Ratas Sprague-Dawley
10.
Behav Brain Res ; 216(2): 561-8, 2011 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-20816897

RESUMEN

Body weight gain is one of the most serious side effects associated with clinical use of antipsychotics. However, the mechanisms by which antipsychotics induce body weight gain are unknown, and no reliable animal models of antipsychotics-induced weight gain have been established. The present studies were designed to establish male rat models of weight gain induced by chronic and acute treatment with antipsychotics. Six-week chronic treatment with olanzapine (5, 7.5, and 10mg/kg/day) in male Sprague-Dawley rats fed a daily diet resembling a human macronutrient diet, significantly increased body weight gain and weight of fatty tissues. In contrast, ziprasidone (1.25, 2.5, and 5mg/kg/day) administration caused no observable adverse effects. We then investigated feeding behavior with acute antipsychotic treatment in male rats using an automated food measurement apparatus. Rats were allowed restricted access to normal laboratory chow (4h/day). With acute olanzapine (0.5, 1, and 2mg/kg, i.p.) treatment in the light phase, food intake volume and duration were significantly increased, while treatment with ziprasidone (0.3, 1, and 3mg/kg, i.p.) did not increase food intake volume or meal time duration. Findings from the present studies showed that chronic treatment with olanzapine in male rats induced body weight gain, and acute injection induced hyperphagia, suggesting that hyperphagia may be involved in the weight gain and obesity-inducing properties of chronically administered olanzapine. These animal models may provide useful experimental platforms for analysis of the mechanism of hyperphagia and evaluating the potential risk of novel antipsychotics to induce weight gain in humans.


Asunto(s)
Antipsicóticos/efectos adversos , Benzodiazepinas/efectos adversos , Modelos Animales de Enfermedad , Hiperfagia/inducido químicamente , Piperazinas/efectos adversos , Tiazoles/efectos adversos , Aumento de Peso/efectos de los fármacos , Animales , Antipsicóticos/administración & dosificación , Benzodiazepinas/administración & dosificación , Relación Dosis-Respuesta a Droga , Conducta Alimentaria/efectos de los fármacos , Masculino , Olanzapina , Piperazinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Tiazoles/administración & dosificación
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