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1.
J Neurosci ; 40(27): 5196-5207, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32482639

RESUMEN

Elevations in estrogen (17ß-estradiol, E2) are associated with increased alcohol drinking by women and experimentally in rodents. E2 alters the activity of the dopamine system, including the VTA and its projection targets, which plays an important role in binge drinking. A previous study demonstrated that, during high E2 states, VTA neurons in female mice are more sensitive to ethanol excitation. However, the mechanisms responsible for the ability of E2 to enhance ethanol sensitivity of VTA neurons have not been investigated. In this study, we used selective agonists and antagonists to examine the role of ER subtypes (ERα and ERß) in regulating the ethanol sensitivity of VTA neurons in female mice and found that ERα promotes the enhanced ethanol response of VTA neurons. We also demonstrated that enhancement of ethanol excitation requires the activity of the metabotropic glutamate receptor, mGluR1, which is known to couple with ERα at the plasma membrane. To investigate the behavioral relevance of these findings, we administered lentivirus-expressing short hairpin RNAs targeting either ERα or ERß into the VTA and found that knockdown of each receptor in the VTA reduced binge-like ethanol drinking in female, but not male, mice. Reducing ERα in the VTA had a more dramatic effect on binge-like drinking than reducing ERß, consistent with the ability of ERα to alter ethanol sensitivity of VTA neurons. These results provide important insight into sex-specific mechanisms that drive excessive alcohol drinking.SIGNIFICANCE STATEMENT Estrogen has potent effects on the dopamine system and increases the vulnerability of females to develop addiction to substances, such as alcohol. We investigated the mechanisms by which estrogen increases the response of neurons in the VTA to ethanol. We found that activation of the ERα increased the ethanol-induced excitation of VTA neurons. 17ß-Estradiol-mediated enhancement of ethanol-induced excitation required the metabotropic glutamate receptor mGluR1. We also demonstrated that ERs in the VTA regulate binge-like alcohol drinking by female, but not male, mice. The influence of ERs on binge drinking in female mice suggests that treatments for alcohol use disorder in women may need to account for this sex difference.


Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Receptor alfa de Estrógeno/metabolismo , Etanol/farmacología , Neuronas/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Animales , Consumo Excesivo de Bebidas Alcohólicas/psicología , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Antagonistas de Estrógenos/farmacología , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ovariectomía , Receptores AMPA/metabolismo , Área Tegmental Ventral/citología
2.
J Proteome Res ; 18(11): 3999-4012, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31550894

RESUMEN

Cocaine addiction afflicts nearly 1 million adults in the United States, and to date, there are no known treatments approved for this psychiatric condition. Women are particularly vulnerable to developing a cocaine use disorder and suffer from more serious cardiac consequences than men when using cocaine. Estrogen is one biological factor contributing to the increased risk for females to develop problematic cocaine use. Animal studies have demonstrated that estrogen (17ß-estradiol or E2) enhances the rewarding properties of cocaine. Although E2 affects the dopamine system, the molecular and cellular mechanisms of E2-enhanced cocaine reward have not been characterized. In this study, quantitative top-down proteomics was used to measure intact proteins in specific regions of the female mouse brain after mice were trained for cocaine-conditioned place preference, a behavioral test of cocaine reward. Several proteoform changes occurred in the ventral tegmental area after combined cocaine and E2 treatments, with the most numerous proteoform alterations on myelin basic protein, indicating possible changes in white matter structure. There were also changes in histone H4, protein phosphatase inhibitors, cholecystokinin, and calmodulin proteoforms. These observations provide insight into estrogen signaling in the brain and may guide new approaches to treating women with cocaine use disorder.


Asunto(s)
Encéfalo/efectos de los fármacos , Cocaína/farmacología , Estradiol/farmacología , Proteoma/metabolismo , Proteómica/métodos , Animales , Encéfalo/metabolismo , Condicionamiento Clásico/efectos de los fármacos , Dopamina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Estrógenos/farmacología , Femenino , Ratones Endogámicos C57BL , Ovariectomía , Recompensa , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismo
3.
Int J Neuropsychopharmacol ; 21(4): 382-392, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29294029

RESUMEN

Background: Females are more vulnerable to developing cocaine addiction compared with males, a phenomenon that may be regulated by the steroid hormone 17ß-estradiol. 17ß-Estradiol enhances cocaine reward as measured by the conditioned place preference test. It is currently not known which estrogen receptor is involved or the neuroanatomical locations in which estrogen receptors act to enhance cocaine responses. The purpose of this study was to determine if the estrogen receptors ERα and ERß regulate cocaine conditioned place preference in mice and whether they act in the nucleus accumbens, a brain region critically involved in the development of cocaine abuse. Methods: Ovariectomized mice were treated with 17ß-estradiol or agonists selective for ERα or ERß and tested for cocaine conditioned place preference and for c-fos expression in the nucleus accumbens. Female mice with intact ovaries were also tested for cocaine conditioned place preference after RNA interference-mediated knockdown of ERα or ERß in the nucleus accumbens. Results: We found that mice treated with 17ß-estradiol or an ERß agonist exhibited increased cocaine conditioned place preference, while knockdown of ERß, but not ERα, in the nucleus accumbens of females with intact ovaries abrogated cocaine conditioned place preference. Acute treatment with 17ß-estradiol or an ERß agonist induced expression of the immediate-early gene c-fos in the nucleus accumbens, whereas the ERα agonist did not. Conclusions: These data indicate that ERß in the nucleus accumbens regulates the development of cocaine conditioned place preference in female mice. 17ß-Estradiol may activate neurons in the nucleus accumbens via ERß. We speculate that this might increase the saliency of cocaine cues that predict drug reward.


Asunto(s)
Conducta Animal/efectos de los fármacos , Cocaína/farmacología , Condicionamiento Clásico/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Estradiol/metabolismo , Receptor beta de Estrógeno/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Recompensa , Animales , Estradiol/farmacología , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/agonistas , Femenino , Ratones , Ratones Endogámicos C57BL , Nitrilos/farmacología , Ovariectomía , Propionatos/farmacología
4.
Alcohol Clin Exp Res ; 42(2): 286-294, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29205408

RESUMEN

BACKGROUND: Recently, the incidence of binge drinking by women has increased. Binge drinking is detrimental to women's health, yet the biological mechanisms that promote excessive drinking by women are not well understood. One method of assessing binge-like ethanol (EtOH) consumption in mice is the drinking in the dark (DID) test, in which mice drink sufficient EtOH to achieve intoxication. In this study, we directly compared male, female, and ovariectomized (OVX) mice for DID and tested whether 17ß-estradiol (E2) contributes to DID. We also measured whether DID varies throughout the estrous cycle and whether repeated intermittent DID impacts the estrous cycle. METHODS: Male, female, and OVX C57BL/6J mice were tested for DID for 2 hours per day on days 1 to 3 and for 4 hours on day 4 using a single bottle containing 20% EtOH. To measure the effects of E2 on DID, OVX mice were treated with estradiol benzoate (EB) or vehicle daily starting 2 weeks prior to the drinking test and throughout the DID procedure. In a separate group of experiments, EtOH consumption and estrous cycle phase were measured in freely cycling mice that were drinking EtOH or water 5 days per week for 2 or 6 weeks. RESULTS: Female mice consumed more EtOH than male and OVX mice. Treatment with EB increased EtOH consumption by OVX mice compared with vehicle-treated controls. However, EtOH intake did not vary across the estrous cycle, nor did long-term DID alter the estrous cycle. CONCLUSIONS: These results demonstrate that ovarian hormones, specifically E2, contribute to increased EtOH consumption by female mice in the DID test. Although ovarian hormones contribute to this behavior, EtOH consumption is not affected by estrous cycle phase in freely cycling mice. This study provides a framework for understanding the factors that contribute to binge drinking in females.


Asunto(s)
Consumo de Bebidas Alcohólicas/metabolismo , Conducta Animal/fisiología , Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Depresores del Sistema Nervioso Central/administración & dosificación , Estradiol/metabolismo , Etanol/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Estradiol/análogos & derivados , Estradiol/farmacología , Estrógenos/farmacología , Ciclo Estral/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ovariectomía
5.
Hum Mol Genet ; 19(20): 3906-18, 2010 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-20693262

RESUMEN

Proximal spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. Traditionally, SMA has been described as a motor neuron disease; however, there is a growing body of evidence that arrhythmia and/or cardiomyopathy may present in SMA patients at an increased frequency. Here, we ask whether SMA model mice possess such phenotypes. We find SMA mice suffer from severe bradyarrhythmia characterized by progressive heart block and impaired ventricular depolarization. Echocardiography further confirms functional cardiac deficits in SMA mice. Additional investigations show evidence of both sympathetic innervation defects and dilated cardiomyopathy at late stages of disease. Based upon these data, we propose a model in which decreased sympathetic innervation causes autonomic imbalance. Such imbalance would be characterized by a relative increase in the level of vagal tone controlling heart rate, which is consistent with bradyarrhythmia and progressive heart block. Finally, treatment with the histone deacetylase inhibitor trichostatin A, a drug known to benefit phenotypes of SMA model mice, produces prolonged maturation of the SMA heartbeat and an increase in cardiac size. Treated mice maintain measures of motor function throughout extended survival though they ultimately reach death endpoints in association with a progression of bradyarrhythmia. These data represent the novel identification of cardiac arrhythmia as an early and progressive feature of murine SMA while providing several new, quantitative indices of mouse health. Together with clinical cases that report similar symptoms, this reveals a new area of investigation that will be important to address as we move SMA therapeutics towards clinical success.


Asunto(s)
Bradicardia , Atrofia Muscular Espinal , Animales , Bradicardia/tratamiento farmacológico , Bradicardia/fisiopatología , Modelos Animales de Enfermedad , Ecocardiografía , Electrocardiografía , Corazón/inervación , Bloqueo Cardíaco/etiología , Bloqueo Cardíaco/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Ratones , Ratones Noqueados , Ratones Transgénicos , Actividad Motora , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/fisiopatología , Miocardio/patología , Sistema Nervioso Simpático/patología , Sistema Nervioso Simpático/fisiopatología
6.
Trends Pharmacol Sci ; 30(2): 55-60, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19110320

RESUMEN

Recent advances in schizophrenia (SZ) research indicate that the telencephalic gamma-aminobutyric acid (GABA)ergic neurotransmission deficit associated with this psychiatric disorder probably is mediated by the hypermethylation of the glutamic acid decarboxylase 67 (GAD(67)), reelin and other GABAergic promoters. A pharmacological strategy to reduce the hypermethylation of GABAergic promoters is to induce a DNA-cytosine demethylation by altering the chromatin remodeling with valproate (VPA). When co-administered with VPA, the clinical efficacy of atypical antipsychotics is enhanced. This prompted us to investigate whether this increase in drug efficacy is related to a modification of GABAergic-promoter methylation via chromatin remodeling. Our previous and present results strongly indicate that VPA facilitates chromatin remodeling when it is associated with clozapine or sulpiride but not with haloperidol or olanzapine. This remodeling might contribute to reelin- and GAD(67)-promoter demethylation and might reverse the GABAergic-gene-expression downregulation associated with SZ morbidity.


Asunto(s)
Antipsicóticos/farmacología , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Ácido Valproico/farmacología , Animales , Antipsicóticos/uso terapéutico , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Citosina/metabolismo , Metilación de ADN , Sinergismo Farmacológico , Quimioterapia Combinada , Epigénesis Genética , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Predisposición Genética a la Enfermedad , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/metabolismo , Inhibidores de Histona Desacetilasas , Histonas/metabolismo , Humanos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Agonistas Nicotínicos/farmacología , Agonistas Nicotínicos/uso terapéutico , Receptores Nicotínicos/fisiología , Proteína Reelina , Proteínas Represoras/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Esquizofrenia/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Ácido Valproico/uso terapéutico , Ácido gamma-Aminobutírico/metabolismo
7.
PLoS One ; 12(11): e0187698, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29107956

RESUMEN

Gender differences in psychiatric disorders such as addiction may be modulated by the steroid hormone estrogen. For instance, 17ß-estradiol (E2), the predominant form of circulating estrogen in pre-menopausal females, increases ethanol consumption, suggesting that E2 may affect the rewarding properties of ethanol and thus the development of alcohol use disorder in females. The ventral tegmental area (VTA) is critically involved in the rewarding and reinforcing effects of ethanol. In order to determine the role of E2 in VTA physiology, gonadally intact female mice were sacrificed during diestrus II (high E2) or estrus (low E2) for electrophysiology recordings. We measured the excitation by ethanol and inhibition by dopamine (DA) of VTA DA neurons and found that both excitation by ethanol and inhibition by dopamine were greater in diestrus II compared with estrus. Treatment of VTA slices from mice in diestrus II with an estrogen receptor antagonist (ICI 182,780) reduced ethanol-stimulated neuronal firing, but had no effect on ethanol-stimulated firing of neurons in slices from mice in estrus. Surprisingly, ICI 182,780 did not affect the inhibition by DA, indicating different mechanisms of action of estrogen receptors in altering ethanol and DA responses. We also examined the responses of VTA DA neurons to ethanol and DA in ovariectomized mice treated with E2 and found that E2 treatment enhanced the responses to ethanol and DA in a manner similar to what we observed in mice in diestrus II. Our data indicate that E2 modulates VTA neuron physiology, which may contribute to both the enhanced reinforcing and rewarding effects of alcohol and the development of other psychiatric disorders in females that involve alterations in DA neurotransmission.


Asunto(s)
Dopamina/metabolismo , Dopamina/farmacología , Estradiol/farmacología , Etanol/farmacología , Neuronas/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Animales , Diestro , Femenino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Ovariectomía , Área Tegmental Ventral/citología , Área Tegmental Ventral/metabolismo
8.
Eur J Pharmacol ; 519(3): 246-52, 2005 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-16129424

RESUMEN

Gamma-hydroxybutyric acid (GHB) can be synthesized in the brain but is also a known drug of abuse. Although putative GHB receptors have been cloned, it has been proposed that, similar to the behavior-impairing effects of ethanol, the in vivo effects of pharmacological GHB may involve metabotropic gamma-aminobutyric acid (GABA) GABA(B) receptors. We developed a fruitfly (Drosophila melanogater) model to investigate the role of these receptors in the behavioral effects of exogenous GHB. Injecting GHB into male flies produced a dose-dependent motor impairment (measured with a computer-assisted automated system), which was greater in ethanol-sensitive cheapdate mutants than in wild-type flies. These effects of pharmacological concentrations of GHB require the presence and activation of GABA(B) receptors. The evidence for this was obtained by pharmacological antagonism of GABA(B) receptors with CGP54626 and by RNA interference (RNAi)-induced knockdown of the GABA(B(1)) receptor subtype. Both procedures inhibited the behavioral effects of GHB. GHB pretreatment diminished the behavioral response to subsequent GHB injections; i.e., it triggered GHB tolerance, but did not produce ethanol tolerance. On the other hand, ethanol pretreatment produced both ethanol and GHB tolerance. It appears that in spite of many similarities between ethanol and GHB, the primary sites of their action may differ and that recently cloned putative GHB receptors may participate in actions of GHB that are not mediated by GABA(B) receptors. These receptors do not have a Drosophila orthologue. Whether Drosophila express a different GHB receptor should be explored.


Asunto(s)
Conducta Animal/efectos de los fármacos , Drosophila melanogaster/efectos de los fármacos , Hidroxibutiratos/farmacología , Receptores de GABA-B/fisiología , Animales , Benzocicloheptenos/farmacología , Relación Dosis-Respuesta a Droga , Drosophila melanogaster/genética , Drosophila melanogaster/fisiología , Interacciones Farmacológicas , Etanol/farmacología , Antagonistas de Receptores de GABA-B , Masculino , Actividad Motora/efectos de los fármacos , Mutación , Compuestos Organofosforados/farmacología , Interferencia de ARN , ARN Bicatenario/farmacología , Receptores de GABA-B/genética , Factores de Tiempo
9.
Br J Pharmacol ; 138(1): 188-92, 2003 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-12522089

RESUMEN

1 The neuroleptic [(3)H]-haloperidol (HP) was taken up in synaptosomes prepared from rat brain, in a temperature-, sodium ion-, and energy-dependent process. 2 The highest concentration of uptake sites (V(max)=2.37 pmol mg(-1) protein min(-1)) was in the striatum with the other brain areas displaying lower (by 50-70%) values. 3 The affinity values (K(m) approximately equal to 40 nM) were similar in all brain areas considered. 4 The pharmacological characterization did not indicate a well-defined group of inhibitors, which suggested that HP might not use a transporter for recognized neurotransmitters. 5 The HP metabolites tested, including HPTP, were competitive inhibitors of [(3)H]-HP uptake, an indirect indication that they may actively enter the striatal nerve endings through the same carrier. 6 Since the uptake process was partially affected by the incubation of [(3)H]-HP in the presence of several antagonists of HP-transforming cytochrome P450 isoforms, the binding of HP at some enzyme sites inside the synaptosome cannot be excluded. 7 In conclusion, the present results suggest that HP may be actively transported in the rat brain.


Asunto(s)
Encéfalo/metabolismo , Haloperidol/metabolismo , Tritio/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-Dawley , Sinaptosomas/metabolismo
10.
Eur J Pharmacol ; 473(2-3): 149-52, 2003 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-12892832

RESUMEN

A solvent, 1,4-butanediol, is also abused as a recreational drug. In mammals, 1,4-butanediol is metabolized into gamma-hydroxybutyric acid (GHB), which stimulates metabotropic gamma-aminobutyric acid (GABA) GABAB and putative GHB receptors. Here we show that in vivo injection of 1,4-butanediol into adult Drosophila leads to GHB synthesis (GHB was detectable 5 min after 1,4-butanediol injection and increased dramatically 1-2 h later). This synthesis of GHB was accompanied by an impairment of locomotor activity that was mimicked by a direct injection of GHB into flies. We propose Drosophila as a model to study the molecular actions of 1,4-butanediol and GHB.


Asunto(s)
Butileno Glicoles/metabolismo , Drosophila melanogaster/metabolismo , Oxibato de Sodio/metabolismo , Animales , Cromatografía de Gases y Espectrometría de Masas , Masculino , Factores de Tiempo
11.
Neuropsychopharmacology ; 36(7): 1366-74, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21368748

RESUMEN

Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD(67)) expression. Here we explored the impact of synthetic α(4)ß(2) and α(7) nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at α(4)ß(2) and a lower affinity full agonist at α(7) neuronal nAChR, injected in doses of 1-5 mg/kg/s.c. twice daily for 5 days, elicited a 30-40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD(67) mRNA and protein. This upregulation of GAD(67) was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP(2) binding to GAD(67) promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD(67) expression were obtained after administration of A-85380, an agonist that binds to α(4)ß(2) but has negligible affinity for α(3)ß(4) or α(7) subtypes containing nAChR. In contrast, PNU-282987, an agonist of the homomeric α(7) nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD(67) expression. The present study suggests that the α(4)ß(2) nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the α(7) nAChR agonists.


Asunto(s)
Corteza Cerebral/citología , Epigenómica , Regulación de la Expresión Génica/efectos de los fármacos , Neuronas/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Ácido gamma-Aminobutírico/metabolismo , Análisis de Varianza , Animales , Azetidinas/farmacología , Conducta Animal , Benzazepinas/farmacología , Condicionamiento Clásico/fisiología , Señales (Psicología) , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Conducta Exploratoria/efectos de los fármacos , Miedo/psicología , Reacción Cataléptica de Congelación/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Regulación de la Expresión Génica/fisiología , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/metabolismo , Masculino , Mecamilamina/farmacología , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones , Neuronas/metabolismo , Nicotina/farmacología , Antagonistas Nicotínicos/farmacología , Regiones Promotoras Genéticas/efectos de los fármacos , Quinoxalinas/farmacología , ARN Mensajero/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Vareniclina
12.
Expert Rev Neurother ; 9(1): 87-98, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19102671

RESUMEN

The neuronal GABAergic mechanisms that mediate the symptomatic beneficial effects elicited by a combination of antipsychotics with valproate (a histone deacetylase inhibitor) in the treatment of psychosis (expressed by schizophrenia or bipolar disorder patients) are unknown. This prompted us to investigate whether the beneficial action of this combination results from a modification of histone tail covalent esterification or is secondary to specific chromatin remodeling. The results suggest that clozapine, or sulpiride associated with valproate, by increasing DNA demethylation with an unknown mechanism, causes a chromatin remodeling that brings about a beneficial change in the epigenetic GABAergic dysfunction typical of schizophrenia and bipolar disorder patients.


Asunto(s)
Metilación de ADN/genética , Epigénesis Genética , Regiones Promotoras Genéticas/genética , Esquizofrenia/genética , Ácido gamma-Aminobutírico/metabolismo , Animales , Antipsicóticos/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Moléculas de Adhesión Celular Neuronal/genética , Proteínas de la Matriz Extracelular/genética , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Glutamato Descarboxilasa/genética , Humanos , Proteínas del Tejido Nervioso/genética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Proteína Reelina , Esquizofrenia/tratamiento farmacológico , Serina Endopeptidasas/genética
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