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1.
Crit Rev Oncol Hematol ; 117: 38-47, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28807234

RESUMEN

The therapeutic landscape of Non Small Lung Cancer (NSCLC) has been profoundly changed over the last decade with the clinical introduction of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) and the discovery of EGFR activating mutations as the major predictive factor to these agents. Despite impressive clinical activity against EGFR-mutated NSCLCs, the benefit seen with 1st and 2nd generation EGFR TKIs is usually transient and virtually all patients become resistant. Several different mechanisms of acquired resistance have been reported to date, but the vast majority of patients develop a secondary exon 20 mutation in the ATP-binding site of EGFR, namely T790M. The discovery of mutant-selective EGFR TKIs that selectively inhibit EGFR-mutants, including T790M-harboring NSCLCs, while sparing EGFR wild type, provide the opportunity for overcoming the major mechanism of acquired resistance to 1st and 2nd generation EGFR TKIs, with a relatively favorable toxicity profile. The development of this novel class of EGFR inhibitors poses novel challenges in the rapidly evolving therapeutic paradigm of EGFR-mutated NSCLCs and the next few years will witness the beginning of a new era for EGFR inhibition in lung cancer. The aim of this paper is to provide a comprehensive overview of the increasing body of data emerging from the ongoing clinical trials with this promising novel therapeutic class of EGFR inhibitors.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Pronóstico
2.
J Pharmacol Exp Ther ; 348(3): 410-20, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24385388

RESUMEN

Nicotine, the primary psychoactive component in tobacco smoke, produces its behavioral effects through interactions with neuronal nicotinic acetylcholine receptors (nAChRs). α4ß2 nAChRs are the most abundant in mammalian brain, and converging evidence shows that this subtype mediates the rewarding and reinforcing effects of nicotine. A number of rare variants in the CHRNA4 gene that encode the α4 nAChR subunit have been identified in human subjects and appear to be underrepresented in a cohort of smokers. We compared three of these variants (α4R336C, α4P451L, and α4R487Q) to the common variant to determine their effects on α4ß2 nAChR pharmacology. We examined [(3)H]epibatidine binding, interacting proteins, and phosphorylation of the α4 nAChR subunit with liquid chromatography and tandem mass spectrometry (LC-MS/MS) in HEK 293 cells and voltage-clamp electrophysiology in Xenopus laevis oocytes. We observed significant effects of the α4 variants on nAChR expression, subcellular distribution, and sensitivity to nicotine-induced receptor upregulation. Proteomic analysis of immunopurified α4ß2 nAChRs incorporating the rare variants identified considerable differences in the intracellular interactomes due to these single amino acid substitutions. Electrophysiological characterization in X. laevis oocytes revealed alterations in the functional parameters of activation by nAChR agonists conferred by these α4 rare variants, as well as shifts in receptor function after incubation with nicotine. Taken together, these experiments suggest that genetic variation at CHRNA4 alters the assembly and expression of human α4ß2 nAChRs, resulting in receptors that are more sensitive to nicotine exposure than those assembled with the common α4 variant. The changes in nAChR pharmacology could contribute to differences in responses to smoked nicotine in individuals harboring these rare variants.


Asunto(s)
Receptores Nicotínicos/metabolismo , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Membrana Celular/metabolismo , Femenino , Células HEK293 , Humanos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Oocitos/fisiología , Fosforilación , Polimorfismo Genético , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Piridinas/farmacología , Receptores Nicotínicos/genética , Regulación hacia Arriba , Xenopus laevis
3.
G Chir ; 32(8-9): 388-93, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22018264

RESUMEN

AIM: To evaluate the role of Computed Tomography Colonography (CTC) in patients who failed an Optical Colonoscopy (OC). PATIENTS AND METHODS: Sixtyeight patients (48 female, 20 male; mean age 60,4 years) with a previous incomplete OC underwent CTC. RESULTS: A complete CTC examination was achieved in all 68 patients. We classified the detected polyps in relation to the diameter in small (<5mm), medium (from 5 to 10mm) and large (>10mm). In 19 patients (27,9%) any pathological finding was observed. In 11 patients (16,2%) one or more polyps not detected with the previous OC have been found.Only in one case the number of detected polyps corresponded to the OC findings. In 18 (26,4%) patients a diverticular disease was observed, and in 15 of them it was diagnosed by the previous OC (26,5%). In 8 patients (11,8%) the diverticular disease was associated to the presence of polyps. In 12 patients (17,6%) colonic stenosis or masses have been observed. CONCLUSIONS: CTC was performed in all patients with a previous incomplete OC, obtaining a complete and accurate visualization of the colon whithout any patient's discomfort.


Asunto(s)
Colonografía Tomográfica Computarizada , Anciano , Pólipos del Colon/diagnóstico , Pólipos del Colon/diagnóstico por imagen , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/diagnóstico por imagen , Diverticulosis del Colon/diagnóstico , Diverticulosis del Colon/diagnóstico por imagen , Femenino , Hemorragia Gastrointestinal/etiología , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada Multidetector , Estudios Retrospectivos
4.
Neuroscience ; 192: 500-6, 2011 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-21699961

RESUMEN

Ghrelin, an orexigenic hormone produced by the stomach, increases food intake and enhances the locomotor and rewarding effects of cocaine. Consistent with these behavioral effects, ghrelin increases dopamine cell activity in the mesolimbic system resulting in elevated levels of dopamine release and turnover in target regions such as the ventral striatum. In the current study, we examined the psychostimulant effects of acute and daily cocaine in mice with targeted deletion of the ghrelin gene (ghrelin knockout; KO) and that of their wild-type (WT) littermates. We hypothesized that ghrelin-KO mice would be hyporesponsive to the effects of cocaine as reflected in attenuated locomotor activity following both acute and chronic injections, and that this would be correlated with striatal dopamine and dopamine metabolite concentrations. Results show that the locomotor stimulating effect of cocaine (10 mg/kg) was decreased in ghrelin-KO mice as compared with their WT littermates. In addition, repeated daily injection of cocaine resulted in gradual increases in locomotor activity in WT mice, an effect that was attenuated in ghrelin-KO mice. These behavioral effects were correlated with changes in dopamine utilization in the striatum of WT mice that were not seen in ghrelin-KO mice unless these were pretreated with ghrelin. These data suggest that ghrelin is important for normal function of the mesolimbic dopaminergic system, potentially modulating both dopamine release and reuptake.


Asunto(s)
Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Ghrelina/metabolismo , Actividad Motora/efectos de los fármacos , Animales , Dopamina/metabolismo , Ghrelina/deficiencia , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados
5.
Phys Rev E Stat Nonlin Soft Matter Phys ; 80(1 Pt 2): 015302, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19658760

RESUMEN

Preferential concentration of inertial particles in turbulence is studied numerically by evaluating the Lagrangian compressibility of the particle velocity field using the "full Lagrangian method." This is compared with the "mesoscopic Eulerian particle velocity field" both in a direct numerical simulation of turbulence and in a synthetic flow field. We demonstrate that the Lagrangian method, in contrast to the Eulerian, accurately predicts the compressibility of the particle velocity field even when the latter is characterized by singularities. In particular we use the method to evaluate the growth rates of spatial moments of the particle number density which reflect the fractal structure of segregation and the occurrence of singularities.

6.
Genes Brain Behav ; 8(3): 257-66, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19077117

RESUMEN

High-affinity, beta2-subunit-containing (beta2*) nicotinic acetylcholine receptors (nAChRs) are essential for nicotine reinforcement; however, these nAChRs are found on both gamma-aminobutyric acid (GABA) and dopaminergic (DA) neurons in the ventral tegmental area (VTA) and also on terminals of glutamatergic and cholinergic neurons projecting from the pedunculopontine tegmental area and the laterodorsal tegmental nucleus. Thus, systemic nicotine administration stimulates many different neuronal subtypes in various brain nuclei. To identify neurons in which nAChRs must be expressed to mediate effects of systemic nicotine, we investigated responses in mice with low-level, localized expression of beta2* nAChRs in the midbrain/VTA. Nicotine-induced GABA and DA release were partially rescued in striatal synaptosomes from transgenic mice compared with tissue from beta2 knockout mice. Nicotine-induced locomotor activation, but not place preference, was rescued in mice with low-level VTA expression, suggesting that low-level expression of beta2* nAChRs in DA neurons is not sufficient to support nicotine reward. In contrast to control mice, transgenic mice with low-level beta2* nAChR expression in the VTA showed no increase in overall levels of cyclic AMP response element-binding protein (CREB) but did show an increase in CREB phosphorylation in response to exposure to a nicotine-paired chamber. Thus, CREB activation in the absence of regulation of total CREB levels during place preference testing was not sufficient to support nicotine place preference in beta2 trangenic mice. This suggests that partial activation of high-affinity nAChRs in VTA might block the rewarding effects of nicotine, providing a potential mechanism for the ability of nicotinic partial agonists to aid in smoking cessation.


Asunto(s)
Condicionamiento Psicológico/fisiología , Locomoción/fisiología , Nicotina/farmacología , Receptores Nicotínicos/genética , Área Tegmental Ventral/metabolismo , Animales , Condicionamiento Psicológico/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Dopamina/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Locomoción/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Agonistas Nicotínicos/farmacología , Fosforilación/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Recompensa , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Tabaquismo/genética , Tabaquismo/metabolismo , Tabaquismo/fisiopatología , Área Tegmental Ventral/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismo
7.
Cell Mol Life Sci ; 65(12): 1872-9, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18500649

RESUMEN

There has been increasing interest in the ability of neuropeptides involved in feeding to modulate circuits important for responses to drugs of abuse. A number of peptides with effects on hypothalamic function also modulate the mesolimbic dopamine system (ventral tegmental area and nucleus accumbens). Similarly, common stress-related pathways can modulate food intake, drug reward and symptoms of drug withdrawal. Galanin promotes food intake and the analgesic properties of opiates; thus it initially seemed possible that galanin might potentiate opiate reinforcement. Instead, galanin agonists decrease opiate reward, measured by conditioned place preference, and opiate withdrawal signs, whereas opiate reward and withdrawal are increased in knock-out mice lacking galanin. This is consistent with studies showing that galanin decreases activity-evoked dopamine release in striatal slices and decreases the firing rate of noradrenergic neurons in locus coeruleus, areas involved in drug reward and withdrawal, respectively. These data suggest that polymorphisms in genes encoding galanin or galanin receptors might be associated with susceptibility to opiate abuse. Further, galanin receptors might be potential targets for development of novel treatments for addiction.


Asunto(s)
Galanina/farmacología , Trastornos Relacionados con Sustancias/etiología , Acetilcolina/metabolismo , Consumo de Bebidas Alcohólicas , Animales , Dopamina/metabolismo , Galanina/fisiología , Humanos , Locomoción/efectos de los fármacos , Ratones , Morfina/efectos adversos , Morfina/farmacología , Recompensa , Transducción de Señal , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Trastornos Relacionados con Sustancias/metabolismo
8.
Neuroscience ; 147(2): 419-27, 2007 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-17543464

RESUMEN

Children exposed to cocaine during gestation have a higher incidence of neurobehavioral deficits. The neurochemical bases of these deficits have not been determined, but the pharmacology of cocaine and the nature of the abnormalities suggest that disruptions in catecholaminergic systems may be involved. In the current study, we used a rat model of prenatal cocaine exposure to examine the impact that this exposure has on the locus coeruleus (LC) noradrenergic system in offspring. Pregnant rats received twice-daily i.v. injections of cocaine (3 mg/kg) or saline between gestational days 10 and 20, and progeny were tested as juveniles. Exposure to a mild stressor elevated an index of norepinephrine turnover in the prefrontal cortex and also increased Fos expression in tyrosine hydroxylase-positive LC neurons in rats exposed to prenatal cocaine but not in rats exposed to prenatal saline. No change in the number of tyrosine hydroxylase-positive neurons in the LC was observed between the two prenatal treatment groups. Specific binding of [125I]-para-iodoclonidine, a radioligand with specificity for high affinity alpha2A-adrenergic receptors, was decreased in the LC of rats exposed to prenatal cocaine compared with prenatal saline controls. As alpha2-adrenergic receptors on LC norepinephrine neurons function as autoreceptors, their down-regulation by prenatal cocaine exposure provides a plausible mechanism for the observed heightened reactivity of norepinephrine neurons in these animals. These data indicate that prenatal cocaine exposure results in lasting changes to the regulation and responsivity of rat LC norepinephrine neurons. A similar dysregulation of LC norepinephrine neurons may occur in children exposed to cocaine during gestation, and this may explain, at least partly, the increased incidence of cognitive deficits that have been observed in these subjects.


Asunto(s)
Autorreceptores/fisiología , Cocaína/toxicidad , Locus Coeruleus/fisiología , Neuronas/fisiología , Norepinefrina/fisiología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Animales , Autorradiografía , Clonidina/metabolismo , Cocaína/administración & dosificación , Femenino , Genes fos/genética , Inmunohistoquímica , Inyecciones Intravenosas , Locus Coeruleus/citología , Masculino , Neuronas/metabolismo , Norepinefrina/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Embarazo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/fisiopatología , Tirosina 3-Monooxigenasa/metabolismo
9.
Psychopharmacology (Berl) ; 189(3): 395-401, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17016705

RESUMEN

RATIONALE: Increases in cholinergic transmission are linked to depression in human subjects and animal models. We therefore examined the effect of decreasing nicotinic acetylcholine receptor (nAChR) activity in tests of antidepressant efficacy using C57BL/6J mice. OBJECTIVES: We determined whether the noncompetitive nAChR antagonist mecamylamine had antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST). These experiments were repeated in mice lacking either the beta2- or alpha7-nAChR subunits to identify the nAChR subunits involved in mediating the antidepressant response to mecamylamine. MATERIALS AND METHODS: Adult mice on the C57BL/6J background were acutely administered mecamylamine i.p. 30 min before testing in the FST or TST. RESULTS: A dose-response study showed that mecamylamine significantly decreased immobility time in the TST at the 1.0-mg/kg dose but did not alter baseline locomotor activity. The competitive nAChR antagonist dihydro-beta-erythroidine, but not the blood-brain barrier impermeant antagonist hexamethonium, also decreased immobility in the TST. One milligram per kilogram of mecamylamine also significantly decreased time immobile in the FST whereas both beta2- and alpha7-knockout mice were insensitive to the effects of mecamylamine in the FST. CONCLUSIONS: Decreased activity of central nAChRs has antidepressant-like effects in both the TST and FST and these effects are dependent on both beta2 and alpha7 subunits. Therefore, compounds that decrease nAChR activity may be attractive new candidates for development as antidepressants in humans.


Asunto(s)
Antidepresivos/farmacología , Mecamilamina/farmacología , Antagonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Animales , Femenino , Suspensión Trasera , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7
10.
Neuroscience ; 143(3): 851-61, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16996217

RESUMEN

Ezrin is a member of the ERM (ezrin-radixin-moesin) family of membrane-cytoskeletal linking proteins. ERM proteins are involved in a wide variety of cellular functions including cell motility, signal transduction, cell-cell interaction and cell-matrix recognition. A recent in situ hybridization study showed that the mRNA encoding ezrin is expressed in neurogenic regions of the mature brain including the subventricular zone (SVZ) and rostral migratory stream (RMS); however, the specific cell types expressing ezrin and their relationship to migrating and proliferating cells in these regions have not been characterized previously. In this study, we used immunocytochemistry to perform double labeling with a variety of cell-type specific markers to characterize the expression of ezrin in the SVZ and RMS of adult mice. Ezrin was expressed at high levels in both the SVZ and RMS where ezrin-immunopositive processes formed a trabecular network surrounding the proliferating and migrating cells. Ezrin-positive cells co-labeled with the glial makers S100beta and GFAP (glial fibrillary acidic protein), but only minimally with the early neuronal markers beta III tubulin and polysialylated form of neural cell adhesion molecule 1 (PSA-NCAM), indicating that ezrin was expressed primarily in the glial tube cells. Ezrin positive cells also expressed beta-catenin, a membrane-complex protein previously implicated in the regulation of stem-cell proliferation and neuronal migration. Glial tube cells act as both precursors of, and a physical channel for, migrating neuroblasts. Bi-directional signals between glial tube cells and migrating neuroblasts have been shown to regulate the rates of both proliferation of the precursor cells and migration of the newly generated neuroblasts. Our finding that ezrin and beta-catenin are both present at the cell membrane of the glial tube cells suggests that these proteins may be involved in those signaling processes.


Asunto(s)
Movimiento Celular/fisiología , Ventrículos Cerebrales/citología , Proteínas del Citoesqueleto/metabolismo , Vías Eferentes/metabolismo , Expresión Génica/fisiología , Neuroglía/metabolismo , Animales , Western Blotting , Bromodesoxiuridina/metabolismo , Proliferación Celular , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica/métodos , Ratones , Factores de Crecimiento Nervioso/metabolismo , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Subunidad beta de la Proteína de Unión al Calcio S100 , Proteínas S100/metabolismo , Ácidos Siálicos/metabolismo , Tubulina (Proteína)/metabolismo , beta Catenina/metabolismo
11.
CNS Neurol Disord Drug Targets ; 5(2): 225-32, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16611095

RESUMEN

Galanin is a neuropeptide synthesized in many neuronal types including brainstem norepinephrine-producing cells of the locus coeruleus and the serotonin-producing neurons of the dorsal raphe nucleus. Galanin inhibits the firing of rodent norepinephrine, serotonin and dopamine neurons and reduces release of these neurotransmitters in forebrain target regions. The distribution of galanin and its receptors and its actions on monoamine signaling has fostered interest in this neuropeptide in the field of behavioral pharmacology and the potential role of galanin in the pathophysiology of neurological diseases such as Alzheimer's disease, epilepsy, stroke, and in psychiatric disorders such as anxiety, depression, and drug addiction, particularly withdrawal. In rodent models, expression of galanin in brain is altered by various stressors, while administration of galanin can modulate anxiety-like responses to stress. Emerging evidence further supports a role for galanin in the mediation of depression-related behaviors in rodents. Recently, galanin agonists have been shown to decrease behavioral signs of opiate withdrawal, which are thought to result from hyperactivation of brain stress pathways. Studies using genetically modified mice suggest that galanin normally plays a protective role against opiate reinforcement and withdrawal. The present article reviews current evidence on a potential role for galanin in modulating stress-related neural pathways and behaviors, and speculates on the therapeutic potential of targeting this galanin system for emotional disorders and opiate addiction.


Asunto(s)
Trastornos de Ansiedad/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Trastorno Depresivo/tratamiento farmacológico , Galanina/metabolismo , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Animales , Trastornos de Ansiedad/metabolismo , Trastornos de Ansiedad/fisiopatología , Aminas Biogénicas/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatología , Trastorno Depresivo/metabolismo , Trastorno Depresivo/fisiopatología , Galanina/agonistas , Humanos , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/metabolismo , Trastornos Relacionados con Sustancias/fisiopatología
12.
J Chemother ; 17(2): 242-6, 2005 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15920913

RESUMEN

Standard dose docetaxel is burdened by severe toxicity. Weekly schedules have been shown to be active as standard scheme with reduced side effects. In 20-30% of elderly patients (pts) the classic 6-week schedule induces grade 3/4 fatigue and other cumulative toxicities. We carried out this safety study in order to evaluate whether a modified weekly docetaxel schedule would improve the toxicity profile. Twenty-one untreated elderly (> or = 70 years) pts suffering from metastatic breast cancer were enrolled in the study. Pts were treated with a weekly dose of 35 mg/m2 docetaxel for 6 weeks, followed by a 2-week rest. Further cycles were performed with this modified schedule: docetaxel days 1, 8 and 15 every 29 days. All pts received at least the first cycle (6 weeks). A total of 261 doses were delivered. No toxic deaths occurred. The toxicity was mild: we recorded 1 episode of grade 3 neutropenia and severe asthenia in only 2 pts (10%). We recorded an overall response rate of 33% (1 CR, 6 PR). Our data showed a reduced incidence of severe asthenia (2/21), obtained with a light modification of a weekly docetaxel schedule.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Taxoides/administración & dosificación , Taxoides/efectos adversos , Factores de Edad , Anciano , Neoplasias Óseas/secundario , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Docetaxel , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Evaluación Geriátrica , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Metástasis Linfática , Dosis Máxima Tolerada , Estadificación de Neoplasias , Estudios Prospectivos , Medición de Riesgo , Neoplasias Cutáneas/secundario , Análisis de Supervivencia , Resultado del Tratamiento
13.
Neuroscience ; 129(1): 11-24, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15489024

RESUMEN

Nicotine can enhance contextual learning while ethanol impairs some forms of learning. Nicotine can overcome some of the impairing effects of ethanol when the two drugs are co-administered. The specific brain nicotinic acetylcholine receptors (nAChRs) that mediate nicotine's effects on contextual learning and whether any of ethanol's actions are mediated by nAChRs are unknown. The potential roles of nAChRs in contextual and cued fear conditioning as well as the effects of nicotine, ethanol, or co-administration of nicotine and ethanol were examined in wild type and homozygous null mutant mice from alpha7, beta2, beta3, and beta4 mouse lines at 24 h after training. Nicotine was given prior to training and testing, whereas ethanol was given only before training. Nicotine enhanced contextual learning in both alpha7 wild types and mutants when mice were trained at 0.17 mA, but not 0.35 mA. Mutants lacking the alpha7 subunit were less sensitive to the memory impairing effects of ethanol trained at 0.35 mA. beta2 Null mutants receiving saline showed a small, but significant, impairment in contextual learning compared with wild type littermates when the shock stimulus was 0.35 mA. Beta2 Null mutant mice also did not respond to the cognitive enhancing effects of nicotine alone, or after ethanol administration. beta3 and beta4 null mutants did not differ from wild types either after saline or any of drug treatments. These results show that beta2-containing nAChRs, but not beta3- or beta4-containing receptors, mediate the enhancing effects of nicotine on contextual learning and confirm previous studies implicating beta2 in other forms of learning. A new role for alpha7 nAChRs in regulating sensitivity to the cognitive disrupting effects of ethanol is proposed.


Asunto(s)
Etanol/farmacología , Miedo/fisiología , Nicotina/farmacología , Receptores Nicotínicos/fisiología , Animales , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Ratones , Ratones Noqueados , Mutación , Neuronas
14.
Psychopharmacology (Berl) ; 170(1): 94-101, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12879206

RESUMEN

RATIONALE: Knockout and transgenic mice provide a tool for assessing the mechanisms of action of antidepressants. The effectiveness of oral administration of the tricyclic antidepressant amitriptyline (AMI) was assessed in C57BL/6J (B6) mice, a common genetic background on which knockout and transgenic mice are maintained. OBJECTIVES: We determined whether oral AMI would have antidepressant-like effects in B6 mice and whether these effects varied according to sex, duration of treatment, and the depression model utilized. METHODS: Male and female B6 mice were administered AMI (200 microg/ml) in the drinking water as the sole source of fluid, along with 2% saccharin to increase palatability. Control mice were administered 2% saccharin alone. Mice were assessed for responsiveness to AMI in the tail suspension test (TST), the forced swim test (FST), and the learned helplessness (LH) paradigm. RESULTS: In the TST, AMI decreased immobility time regardless of sex or duration of treatment. AMI also decreased immobility time in the FST, but chronic treatment was necessary for full efficacy in both sexes. In the LH paradigm, both subchronic and chronic AMI treatment decreased escape latencies in female mice, but AMI was effective only after chronic treatment in males. The antidepressant-like effects of AMI could not be explained by differences in locomotor activity because activity levels were not altered by antidepressant treatment. CONCLUSIONS: Overall, oral AMI administration provides a valid model for behavioral assessment of antidepressant-like effects in knockout and transgenic mice maintained on a B6 background, but the effectiveness of oral AMI varies depending on sex, duration of treatment, and the depression model used.


Asunto(s)
Amitriptilina/farmacología , Antidepresivos Tricíclicos/farmacología , Trastorno Depresivo/tratamiento farmacológico , Administración Oral , Animales , Trastorno Depresivo/psicología , Modelos Animales de Enfermedad , Femenino , Desamparo Adquirido , Suspensión Trasera , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Factores Sexuales , Natación
15.
Eur J Neurosci ; 15(11): 1810-8, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12081661

RESUMEN

We have examined several neurochemical and behavioural parameters related to the function of the mesolimbic dopamine (DA) pathway in animals treated with nicotine following three modes of drug administration, i.e. systemic intraperitoneal injection, intra-accumbens (Acb) infusion or intraventral tegmental area (intra-VTA) microinjection. The present modes of systemic, intra-Acb and intra-VTA nicotine administration elicited comparable acute increases in dialysate DA levels from the Acb. The increase in extracellular DA levels was paralleled by a significant enhancement of locomotion in a habituated environment in the case of systemic or intra-VTA nicotine administration, whereas unilateral or bilateral intra-Acb nicotine infusion was ineffective, showing that accumbal DA increase is not sufficient to elicit locomotion in this experimental paradigm. Intra-VTA, but not systemic or intra-Acb, nicotine administration caused a long-term (at least 24-h) increase in basal dialysate DA levels from the Acb. In addition, significant increases in tyrosine hydroxylase (TH) and GluR1 (but not dopamine transporter or NR1) mRNA levels in the VTA were detected 24 h after intra-VTA nicotine administration. Systemic nicotine injection caused only an increase in TH mRNA levels while intra-Acb infusion did not modify any of the mRNAs tested. The long-term increase in basal DA levels in the Acb and TH, and GluR1 mRNA levels in the VTA upon intra-VTA nicotine microinjection indicates that even a single nicotine injection can induce plastic changes of the mesolimbic DA pathway.


Asunto(s)
Dopamina/metabolismo , Glicoproteínas de Membrana , Proteínas del Tejido Nervioso , Vías Nerviosas/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Nicotina/farmacología , Núcleo Accumbens/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Anfetamina/farmacología , Animales , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Vías de Administración de Medicamentos , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Habituación Psicofisiológica/efectos de los fármacos , Habituación Psicofisiológica/fisiología , Masculino , Proteínas de Transporte de Membrana/genética , Microdiálisis , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Vías Nerviosas/metabolismo , Plasticidad Neuronal/fisiología , Núcleo Accumbens/metabolismo , Terminales Presinápticos/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores AMPA/genética , Receptores de N-Metil-D-Aspartato/genética , Trastornos Relacionados con Sustancias/metabolismo , Trastornos Relacionados con Sustancias/fisiopatología , Factores de Tiempo , Tirosina 3-Monooxigenasa/genética , Área Tegmental Ventral/metabolismo
16.
Neuropsychopharmacology ; 24(5): 576-89, 2001 May.
Artículo en Inglés | MEDLINE | ID: mdl-11282258

RESUMEN

The reinforcing properties of nicotine and psychomotor stimulants are thought to be mediated through the mesolimbic dopamine (DA) system. This study investigates the role of high affinity nicotinic acetylcholine receptors (nAChRs) in cocaine place preference and examines some neurochemical changes in the mesolimbic DA system that might account for the interaction between nicotine and cocaine. 5 mg/kg is the lowest dose of cocaine able to condition a place preference in C57Bl/6 mice. Co-treatment with the nicotinic antagonist mecamylamine (1.0 mg/kg) disrupted place preference to 5 mg/kg cocaine. In addition, mice lacking the high affinity nAChR containing the beta2 subunit showed decreased place preference to 5 mg/kg cocaine, although higher doses of cocaine could condition a place preference in these knock out animals. In contrast, co-administration of a low dose of nicotine (0.2 mg/kg) potentiated place preference to a subthreshold dose of cocaine (3 mg/kg). DA turnover was monitored in several brain regions using tissue levels of DA and its primary metabolite DOPAC as an indication of DA release. Wild type mice showed decreased DA turnover following treatment with 5 mg/kg cocaine; whereas, this response was not seen in mice lacking the beta2 subunit of the nAChR. Induction of chronic fos-related antigens by cocaine was also reduced in mutant mice as compared to their wild type siblings, implying that downstream actions of cocaine were also affected by inactivation of the high affinity nAChR. These data indicate that activation of the high affinity nAChR may contribute to cocaine reinforcement.


Asunto(s)
Trastornos Relacionados con Cocaína/metabolismo , Cocaína/farmacología , Dopamina/metabolismo , Neuronas/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/deficiencia , Ácido 3,4-Dihidroxifenilacético/metabolismo , Acetilcolina/metabolismo , Animales , Fibras Colinérgicas/efectos de los fármacos , Fibras Colinérgicas/metabolismo , Trastornos Relacionados con Cocaína/fisiopatología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Ratones Noqueados , Neuronas/metabolismo , Nicotina/farmacología , Núcleo Accumbens/metabolismo , Receptores Nicotínicos/genética
17.
Biol Psychiatry ; 49(3): 300-6, 2001 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-11230881

RESUMEN

BACKGROUND: We have examined the effects of nicotine pretreatment on dopaminergic and behavioral responses to conditioned fear stress in the rat. METHODS: Rats were pretreated daily with saline or nicotine for 20 days then challenged with nicotine or saline on day 21. Animals were trained in a classical conditioned fear paradigm. Dopamine utilization in the medial prefrontal cortex and nucleus accumbens shell and conditioned fear stress-induced immobility responses were assessed. RESULTS: Saline pretreated animals rapidly acquired the conditioned fear stress response as assessed by preferential activation of mesoprefrontal dopamine metabolism and tone-elicited immobility responses. Repeated, but not acute, nicotine pretreatment significantly reduced conditioned fear stress-induced dopamine metabolism in the medial prefrontal cortex and nucleus accumbens shell. Repeated nicotine pretreatment did not modify the acquisition or expression of conditioned fear stress responses, however. CONCLUSIONS: The dissimilar effects of repeated nicotine exposure on the cortical dopamine and behavioral responses to conditioned fear stress suggest that nicotine differs from other agents with anxiolytic activity that produce coordinated changes in conditioned fear stress-induced cortical dopaminergic and behavioral responses. Furthermore, compared with results of acute footshock stress, repeated nicotine pretreatment appears to have differential effects on physical versus psychological stressors. Results are discussed within the clinical context of stress-related psychopathology syndromes and comorbid nicotine dependence.


Asunto(s)
Condicionamiento Clásico/efectos de los fármacos , Miedo/efectos de los fármacos , Nicotina/farmacología , Premedicación , Receptores Dopaminérgicos/efectos de los fármacos , Animales , Nivel de Alerta/efectos de los fármacos , Dopamina/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/complicaciones
18.
J Neurochem ; 76(1): 191-200, 2001 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11145992

RESUMEN

The galanin receptor-1 (GalR1) protein belongs to a family of G protein-coupled receptors for the neuropeptide galanin (GalR1, GalR2 and GalR3) distributed throughout the central and peripheral nervous system. Activation of galanin receptors by their ligands results in increased feeding, impaired learning, enhanced opiate analgesia and decreased opiate place preference. We have shown that opiate withdrawal, which is known to increase levels of cAMP in the locus coeruleus (LC), results in an increase in the number of galanin binding sites and the level of GalR1 mRNA in the LC. We have isolated a 3.6-kb fragment 5' of the inititiation codon of the mouse GalR1 gene and generated a series of deletion mutations of this fragment driving expression of luciferase for use in transient transfection assays in PC12 and Cath.a cell lines. Treatment with forskolin, but not dideoxyforskolin, up-regulates GalR1 transcription, likely through elevation of cAMP levels. The region between - 1050 and - 700 base pairs upstream of exon one is necessary both for basal activity of the GalR1 promoter and for forskolin-mediated increases in transcription. The forskolin effect can be blocked by simultaneous mutation of a CRE-like site and a CRE/DRE-like site, but not mutation of either site alone. Gel shift and super-shift experiments demonstrate that the transcription factor CREB can bind to both sites and is likely to be responsible for the cAMP-mediated increase in GalR1 promoter activity. This study provides a molecular mechanism for the increased GalR1 expression in the LC seen following opiate withdrawal.


Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Regulación de la Expresión Génica/fisiología , Receptores de Neuropéptido/biosíntesis , Animales , Secuencia de Bases , Línea Celular , Clonación Molecular , Codón Iniciador/genética , Colforsina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Factor de Crecimiento Nervioso/farmacología , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Regiones Promotoras Genéticas/efectos de los fármacos , Receptores de Galanina , Receptores de Neuropéptido/genética , Secuencias Reguladoras de Ácidos Nucleicos/efectos de los fármacos , Homología de Secuencia de Ácido Nucleico , Acetato de Tetradecanoilforbol/farmacología , Transfección
19.
J Neurochem ; 76(1): 258-68, 2001 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11145999

RESUMEN

Acetylcholine release stimulated by nicotinic agonists was measured as radioactivity released from perfused synaptosomes prepared from mouse interpeduncular nucleus (IPN) that had been loaded with [(3)H]choline. Agonist-stimulated release was dependent upon external calcium and over 90% of released radioactivity was acetylcholine. The release process was characterized by dose response curves for 13 agonists and inhibition curves for six antagonists. alpha-Conotoxin MII did not inhibit this release, while alpha-conotoxin AuIB inhibited 50% of agonist-stimulated release. Comparison of this process with [(3)H]dopamine release from mouse striatal synaptosomes indicated that different forms of nicotinic acetylcholine receptors (nAChRs) may mediate these processes. This was confirmed by assays using mice homozygous for the beta 2 subunit null mutation. The deletion of the beta 2 subunit had no effect on agonist-stimulated acetylcholine release, but abolished agonist-stimulated release of dopamine from striatal synaptosomes. Mice heterozygous for the beta 2 subunit null mutation showed decreased dopamine release evoked by L-nicotine with no apparent change in EC(50) value, as well as similar decreases in both transient and persistent phases of release with no changes in desensitization rates.


Asunto(s)
Acetilcolina/metabolismo , Dopamina/metabolismo , Mesencéfalo/metabolismo , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Alcaloides/farmacología , Animales , Azocinas , Calcio/metabolismo , Calcio/farmacología , Colina/metabolismo , Conotoxinas/farmacología , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Heterocigoto , Homocigoto , Masculino , Mesencéfalo/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Antagonistas Nicotínicos/farmacología , Terminales Presinápticos/metabolismo , Subunidades de Proteína , Quinolizinas , Receptores Nicotínicos/genética , Sinaptosomas/metabolismo
20.
Pharmacol Ther ; 92(2-3): 89-108, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11916531

RESUMEN

Nicotinic acetylcholine receptors (nAChRs) in the muscle, autonomic ganglia, and brain are targets for pharmacologically administered nicotine. Several of the subunits that combine to form neuronal nicotinic receptors have been deleted by knockout or mutated by knockin in mice using homologous recombination. We will review the biochemical, pharmacological, anatomical, physiological, and behavioral phenotypes of mice with genetically altered neuronal nAChR subunits. Clinically relevant mutations in nAChR genes will also be discussed. In addition, some of the signal transduction pathways activated through nAChRs will be described in order to delineate the longer-term changes that might result from persistent activation or inactivation of nAChRs. Genetically manipulated mice have greatly increased our understanding of the subunit composition and physiological properties of nAChRs in vivo. In addition, these mice have provided a model system to determine the molecular basis for many of the pharmacological actions of nicotine on neurotransmitter release and behavior. Genetic manipulations in mice have also elucidated the role of nAChR subunits in various disease states, and suggest several avenues for drug development.


Asunto(s)
Ratones Noqueados/genética , Neuronas/fisiología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/fisiología , Animales , Ansiedad , Electrofisiología , Aprendizaje , Memoria , Ratones , Fenotipo , Mutación Puntual , Receptores Nicotínicos/genética , Transducción de Señal
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