Dopamine D3 Receptor Modulates Akt/mTOR and ERK1/2 Pathways Differently during the Reinstatement of Cocaine-Seeking Behavior Induced by Psychological versus Physiological Stress.

Stress triggers relapses in cocaine use that engage the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and dentate gyrus (DG). Preclinical research suggests that D3 receptor (D3R) antagonists may be a promising means to attenuate cocaine reward and relapse. As D3R regulates the activity of the Akt/mTOR and MEK/ERK1/2 pathways, we assessed the effects of SB-277011-A, a D3R antagonist, on the activity of these kinases during the reinstatement of cocaine-induced conditioned place preference (CPP) induced by psychological (restraint) and physiological (tail pinch) stress. Both stimuli reactivated an extinguished cocaine-CPP, but only restrained animals decreased their locomotor activity during reinstatement. Cocaine-seeking behavior reactivation was correlated with decreased p-Akt, p-mTOR, and p-ERK1/2 activation in both nuclei of restrained animals. While a D3R blockade prevented stress-induced CPP reinstatement and plasma corticosterone enhancement, SB-277011-A distinctly modulated Akt, mTOR, and ERK1/2 activation depending on the stressor and the dose used. Our data support the involvement of corticosterone in the SB-277011-A effects in restrained animals. Additionally, the ratios p-mTOR/mTOR and/or p-ERK1/2 /ERK1/2 in the BLA during stress-induced relapse seem to be related to the locomotor activity of animals receiving 48 mg/kg of the antagonist. Hence, our study indicates the D3R antagonist's efficacy to prevent stress-induced relapses in drug use through distinct modulation of Akt/mTOR and MEK/ERK1/2 pathways in memory-processing nuclei.

Distinct Regulation of Dopamine D3 Receptor in the Basolateral Amygdala and Dentate Gyrus during the Reinstatement of Cocaine CPP Induced by Drug Priming and Social Stress.

Relapse in the seeking and intake of cocaine is one of the main challenges when treating its addiction. Among the triggering factors for the recurrence of cocaine use are the re-exposure to the drug and stressful events. Cocaine relapse engages the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG), which are responsible for emotional and episodic memories. Moreover, D3 receptor (D3R) antagonists have recently arisen as a potential treatment for preventing drug relapse. Thus, we have assessed the impact of D3R blockade in the expression of some dopaminergic markers and the activity of the mTOR pathway, which is modulated by D3R, in the BLA and DG during the reinstatement of cocaine-induced conditioned place preference (CPP) evoked by drug priming and social stress. Reinstatement of cocaine CPP paralleled an increasing trend in D3R and dopamine transporter (DAT) levels in the BLA. Social stress, but not drug-induced reactivation of cocaine memories, was prevented by systemic administration of SB-277011-A (a selective D3R antagonist), which was able, however, to impede D3R and DAT up-regulation in the BLA during CPP reinstatement evoked by both stress and cocaine. Concomitant with cocaine CPP reactivation, a diminution in mTOR phosphorylation (activation) in the BLA and DG occurred, which was inhibited by D3R blockade in both nuclei before the social stress episode and only in the BLA when CPP reinstatement was provoked by a cocaine prime. Our data, while supporting a main role for D3R signalling in the BLA in the reactivation of cocaine memories evoked by social stress, indicate that different neural circuits and signalling mechanisms might mediate in the reinstatement of cocaine-seeking behaviours depending upon the triggering stimuli.

Blockade of D3 receptor prevents changes in DAT and D3R expression in the mesolimbic dopaminergic circuit produced by social stress- and cocaine prime-induced reinstatement of cocaine-CPP.

BACKGROUND: Cocaine may cause persistent changes in the brain, which are more apparent in DA transporter (DAT) and DA receptor availability within the nucleus accumbens (NAc). On the other hand, the DA D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for substance use disorders. AIMS: This study aims to assess the impact of selective D3R antagonism on DAT and D3R after reinstatement of cocaine preference (CPP) induced by an acute session of social defeat stress (SDS) and a cocaine prime in mice after a period of abstinence. METHODS: Male mice were conditioned with 25 mg/kg of cocaine for 4 days. After 60 days of extinction training mice were pretreated with the selective D3R antagonist SB-277011A before the re-exposure to a priming dose of cocaine or to a single SDS session. CPP scores were determined and levels of DAT, D3R, phospho Akt (pAkt) and phospho mTOR (pmTOR) were assessed in the NAc shell. RESULTS: An increase in DAT and D3R expression was seen in the NAc after both a cocaine prime- and SDS-induced reinstatement of CPP. Pretreatment with SB-277011A blocked elevated DAT and D3R expression as well as SDS-induced reinstatement. By contrast, the blockade of D3R did not modified the cocaine prime-induced CPP. Changes in DAT and D3R expression do not seem to occur via the canonic pathway involving Akt/mTOR. CONCLUSIONS: Our results suggest that the selective D3R antagonist ability to inhibit DAT and D3R up-regulation could represent a possible mechanism for its behavioral effects in cocaine-memories reinstatement induced by social stress.

Modulation of stress- and cocaine prime-induced reinstatement of conditioned place preference after memory extinction through dopamine D3 receptor.

Accumulating evidence indicates that dopamine (DA) D3 receptor (DAD3R) antagonists appear highly promising in attenuating cocaine reward and relapse in preclinical models of addiction. In the present study, we investigated the effects of the selective DAD3R antagonist SB-277011-A on the reinstatement of cocaine-induced conditioned place preference (CPP) produced by a priming dose of cocaine, by social defeat stress and by two kinds of physiological stressors (restraint and tail pinch) in male adult mice. We also explored reinstatement-related plasma corticosterone levels (as marker of stress response) and the effects of blocking DAD3R. Administration of SB-277011-A (24 or 48 mg/kg i.p.) did not modify conditioned reinstatement of cocaine seeking triggered by cocaine prime. By contrast, we found that the vulnerability to reinstatement of the CPP of defeated animals that have undergone CPP extinction was abolished by the DAD3R antagonist (24 mg/kg) given 30 min before the test session. Reactivation of the CPP response produced by physiological stress stimuli was also attenuated by SB-277011-A (48 mg/kg i.p.). On the other hand, the blockade of DAD3R significantly prevented the increased corticosterone release during reinstatement of cocaine-induced CPP that was seen in social defeated animals, in mice suffering physiological stress and after cocaine prime. Present results demonstrate a modulation by DAD3R of the reactivation of the incentive value of cocaine-associated cues induced by social and physiological stress stimuli, which was associated to a glucocorticoid-dependent mechanism. Our results also point to a possible potential therapeutic use of selective DAD3R antagonists for the prevention of stress-induced cocaine-seeking and relapse.

Poliposis adenomatosa familiar: a propósito de un caso / Familial adenomatous polyposis: a case report

La poliposis adenomatosa familiar (PAF) es la forma más frecuente y conocida de poliposis. Se trata de una enfermedad hereditaria autosómica dominante caracterizada por el desarrollo de múltiples pólipos adenomatosos, principalmente en el colon y recto. La prevalencia de esta enfermedad es de aproximadamente 1 de cada 10.000-20.000 individuos. La aparición de los pólipos suele iniciarse a una edad temprana, con un riesgo de casi el 100% de desarrollo de cáncer colorrectal (CCR) si el paciente no recibe tratamiento de forma precoz. Las lesiones suelen desarrollarse en la segunda y la tercera década de la vida: el 15% a los 10 años de edad, el 50% de los pacientes sobre los 15 años y un 95% a los 35 años. Este artículo tiene como objetivo presentar la evolución clínica y nutricional de una paciente de 54 años de edad diagnosticada de PAF que precisa nutrición parenteral complementaria (NPC) domiciliaria, así como evaluar los resultados clínicos de esta paciente. A través de la revisión de la historia clínica, se estudió la evolución de los datos antropométricos (peso y talla), así como los parámetros analíticos para su valoración. Paciente de 54 años de edad diagnosticada de PAF que acudió a nuestro hospital tras trasladarse temporalmente de ciudad para recibir soporte nutricional. El artículo describe la composición de la NPC recibida durante los 90 días de seguimiento. La NPC en este tipo de pacientes es importante, ya que presentan una insuficiencia del tracto gastrointestinal irreversible que les impide la absorción de nutrientes apropiados para mantener una adecuada calidad de vida (AU)

Familial adenomatous polyposis (FAP) is the most common known form of polyposis. It is an autosomal dominant inherited disease characterized by the development of multiple adenomatous polyps mainly in the colon and rectum. The prevalence of this disease is approximately about 1 in every 10,000-20,000 people. The appearance of the polyps usually starts at an early age with a 100% risk of developing colorectal cancer (CRC) if the patient does not receive early treatment. These lesions usually manifest during the second and third decades of life: 15% at the age of 10, 50% around 15 years of age and 95% at the age of 35. This article aims to present the clinical and nutritional evolution of a 54 years old patient diagnosed with FAP who requires complementary home parenteral nutrition (CPN), and the evaluation of these patient clinical outcomes. The evolution of anthropometric data (weight and height) and the results of laboratory parameters were followed and studied by review of medical records. The patient diagnosed with FAP was referred to our hospital after a temporary city transfer to receive nutritional support. This article describes the composition of the CPN received during the 90 days of follow up. CPN in these patients is important because of the irreversible gastrointestinal tract failure that prevents them from absorbing sufficient nutrients to maintain an adequate quality of life (AU)

Nab-Paclitaxel asociado a gemcitabina en el tratamiento del adenocarcinoma de páncreas metastásico: experiencia de uso / Nab-Paclitaxel plus gemcitabine in patients with metastatic pancreatic adenocarcinoma: experience of use

Objetivo: Describir los resultados obtenidos en el uso de nab-paclitaxel y gemcitabina en el tratamiento de pacientes con adenocarcinoma de páncreas metastático. Material y métodos: Estudio observacional retrospectivo. Se seleccionaron pacientes en tratamiento con nab-paclitaxel asociado a gemcitabina entre enero 2013 y enero 2014. Se recogieron datos demográficos y clínicos. Resultados: Se incluyeron 15 pacientes (edad media: 59,4 ± 10,3 años). Todos ellos recibieron la combinación de nab-paclitaxel y gemcitabina en primera línea para la enfermedad metastásica. Nueve recibieron tratamiento adyuvante antes de que la enfermedad fuera metastásica, siendo la media de líneas de tratamiento previamente al uso de la combinación de 1,1. La mediana de supervivencia libre de progresión fue de 5,6 meses (IC 95%: 4,44 - 8,03). Sólo dos pacientes suspendieron el tratamiento por toxicidad. Conclusiones: El tratamiento con nab-paclitaxel y gemcitabina en nuestros pacientes ha resultado en una supervivencia libre de progresión similar a la de los ensayos clínicos publicados, presentando además una buena tolerancia (AU)

Objective: To evaluate the results obtained with the combined use of nab-paclitaxel and gemcitabine in the treatment of patients with metastatic pancreatic adenocarcinoma. Materials and methods: Retrospective observational study. Patients treated with nab-paclitaxel and gemcitabine between January of 2013 and January of 2014 were selected. Demographical and clinical data were gathered. Results: 15 patients (mean age 59,4 ± 10,3 years) were included. All patients received the combination of nab-paclitaxel and gemcitabine in first-line metastatic disease. Nine received adjuvant treatment before the disease was metastatic. The median progression-free survival rate with combined nab-paclitaxel and gemcitabine was 5,6 months (95% CI: 4,44 - 8,03). In two patients the treatment was stopped due to toxicity. Conclusions: The treatment with nab-paclitaxel and gemcitabine in our patients resulted in progression-free survival rates similar to those published in clinical trials with good treatment tolerability (AU)

[Nab-Paclitaxel plus gemcitabine in patients with metastatic pancreatic adenocarcinoma: experience of use]. / Nab-Paclitaxel asociado a gemcitabina en el tratamiento del adenocarcinoma de páncreas metastásico: experiencia de uso.

OBJECTIVE: To evaluate the results obtained with the combined use of nab-paclitaxel and gemcitabine in the treatment of patients with metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Retrospective observational study. Patients treated with nab-paclitaxel and gemcitabine between January of 2013 and January of 2014 were selected. Demographical and clinical data were gathered. RESULTS: 15 patients (mean age 59,4 ± 10,3 years) were included. All patients received the combination of nab-paclitaxel and gemcitabine in first-line metastatic disease. Nine received adjuvant treatment before the disease was metastatic. The median progression-free survival rate with combined nab-paclitaxel and gemcitabine was 5,6 months (95% CI: 4,44 - 8,03). In two patients the treatment was stopped due to toxicity. CONCLUSIONS: The treatment with nab-paclitaxel and gemcitabine in our patients resulted in progression-free survival rates similar to those published in clinical trials with good treatment tolerability.

Objetivo: Describir los resultados obtenidos en el uso de nab-paclitaxel y gemcitabina en el tratamiento de pacientes con adenocarcinoma de páncreas metastático. Material y métodos: Estudio observacional retrospectivo. Se seleccionaron pacientes en tratamiento con nab-paclitaxel asociado a gemcitabina entre enero 2013 y enero 2014. Se recogieron datos demográficos y clínicos. Resultados: Se incluyeron 15 pacientes (edad media: 59,4 ± 10,3 años). Todos ellos recibieron la combinación de nab-paclitaxel y gemcitabina en primera línea para la enfermedad metastásica. Nueve recibieron tratamiento adyuvante antes de que la enfermedad fuera metastásica, siendo la media de líneas de tratamiento previamente al uso de la combinación de 1,1. La mediana de supervivencia libre de progresión fue de 5,6 meses (IC 95%: 4,44 - 8,03). Sólo dos pacientes suspendieron el tratamiento por toxicidad. Conclusiones: El tratamiento con nab-paclitaxel y gemcitabina en nuestros pacientes ha resultado en una supervivencia libre de progresión similar a la de los ensayos clínicos publicados, presentando además una buena tolerancia.

Enfermedad de Hirschsprung asociada al síndrome de Mowat-Wilson: a propósito de un caso / Hirschsprung disease associated with mowat-wilson syndrome: report of a case

Introducción: La enfermedad de Hirschsprung (EH) o megacolon agangliónico es un trastorno congénito que se caracteriza por la ausencia de células ganglionares intramurales de los plexos mioentéricos submucosos (de Auerbach y Meissner, respectivamente) en tramos distales del intestino, debido al fracaso de la migración de los precursores de estas células desde la cresta neural durante el desarrollo embrionario y asociada a otras anomalías en el 18% restante de los casos, en ocasiones formando parte de síndromes polimalformativos específicos. Objetivo: Este artículo tiene como objetivo presentar la evolución clínica y nutricional de un paciente pediátrico de 14 meses diagnosticado de EH al nacer asociado a MWS, así como evaluar los resultados clínicos de este paciente. Métodos: A través de la revisión de la historia clínica, se estudió la evolución de los datos antropométricos (peso y talla) así como los parámetros analíticos para su valoración. Adicionalmente, se evaluaron las complicaciones asociadas al soporte nutricional y la estrategia terapéutica en el contexto multidisciplinar. Resultados: Paciente de 14 meses, sexo masculino, hijo de padres sanos no consanguíneos inmigrantes de Colombia acude al servicio de urgencias de nuestro hospital por presentar distensión abdominal y vómitos con ausencia de deposiciones espontáneas. Descripción de la composición de la nutrición parenteral recibida durante los 28 días que duró su ingreso hospitalario. Conclusión: La asociación de la enfermedad de Hirschsprung y el síndrome de Mowat-Wilson puede conducir a la necesidad de nutrición parenteral de manera prolongada y presentar con mayor frecuencia desvío del estoma produciéndose un mayor número de complicaciones postoperatorias en estos pacientes, tal y como es el caso de nuestro paciente (AU)

Introduction: Hirschsprung’s disease (HD) or aganglionic megacolon is a congenital disorder characterized by the absence of ganglion intramural cells of the submucosal myenteric plexus (namely Auerbach and Meissner, respectively) in distal sections of the intestine. This is due to a failure in the migration of the precursors of these cells from the neural chalk during the embryonic development and also due to other abnormalities associated (18 % of cases), in some cases involving specific polymalformation syndromes. Objectives: The aim of the work is to present the clinical and nutritional evolution of a 14 months aged pediatric patient who was diagnosed with HD since was born associated with Mowat- Wilson syndrome (MWS). In addition, it is also targeted to evaluate the clinical results from this patient. Methods: Reviewing the medical history of the patient, the evolution of the anthropometric data (weight and height) as well as the analytical parameters for further studies were carried out. In addition, the upcoming issues associated with nutritional support and therapeutic strategies in the multidisciplinary context were evaluated. Results: A male, 14 months aged patient, son of not consanguineous healthy immigrants parents from Colombia went to the emergency department of our hospital suffering abdominal distension and vomiting with no spontaneous bowels. A detailed description of the composition of parenteral nutrition administered within the period of 28 days of hospital admission. Conclusion: As observed in this patient, the association of HD and MWS can lead to the need of prolonged parenteral nutrition and frequently present diverting stoma leading to a greater number of postoperative complications in this population (AU)

Hirschsprung disease associated with Mowat-Wilson syndrome: report of a case.

INTRODUCTION: Hirschsprung's disease (HD) or aganglionicmegacolon is a congenital disorder characterized by the absence of ganglion intramural cells of the submucosal myenteric plexus (namely Auerbach and Meissner,respectively) in distal sections of the intestine. This is due to a failure in the migration of the precursors of these cells from the neural chalk during the embryonic development and also due to other abnormalities associated(18 % of cases), in some cases involving specific polymalformation syndromes. OBJECTIVES: The aim of the work is to present the clinical and nutritional evolution of a 14 months aged pediatric patient who was diagnosed with HD since was born associated with Mowat-Wilson syndrome (MWS). In addition,it is also targeted to evaluate the clinical results from this patient. METHODS: Reviewing the medical history of the patient,the evolution of the anthropometric data (weight and height) as well as the analytical parameters for further studies were carried out. In addition, the upcoming issues associated with nutritional support and therapeutic strategies in the multidisciplinary context were evaluated. RESULTS: A male, 14 months aged patient, son of not consanguineous healthy immigrants parents from Colombia went to the emergency department of our hospital suffering abdominal distension and vomiting with no spontaneous bowels. A detailed description of the composition of parenteral nutrition administered within the period of 28 days of hospital admission. CONCLUSION: As observed in this patient, the association of HD and MWS can lead to the need of prolonged parenteral nutrition and frequently present diverting stoma leading to a greater number of postoperative complications in this population.

Introducción: La enfermedad de Hirschsprung (EH) o megacolon agangliónico es un trastorno congénito que se caracteriza por la ausencia de células ganglionares intramurales de los plexos mioentéricos submucosos (de Auerbach y Meissner, respectivamente) en tramos distales del intestino, debido al fracaso de la migración de los precursores de estas células desde la cresta neural durante el desarrollo embrionario y asociada a otras anomalías en el 18% restante de los casos, en ocasiones formando parte de síndromes polimalformativos específicos. Objetivo: Este artículo tiene como objetivo presentar la evolución clínica y nutricional de un paciente pediátrico de 14 meses diagnosticado de EH al nacer asociado a MWS, así como evaluar los resultados clínicos de este paciente. Métodos: A través de la revisión de la historia clínica, se estudió la evolución de los datos antropométricos (peso y talla) así como los parámetros analíticos para su valoración. Adicionalmente, se evaluaron las complicaciones asociadas al soporte nutricional y la estrategia terapéutica en el contexto multidisciplinar. Resultados: Paciente de 16 meses, sexo masculino, hijo de padres sanos no consanguíneos inmigrantes de Colombia acude al servicio de urgencias de nuestro hospital por presentar distensión abdominal y vómitos con ausencia de deposiciones espontáneas. Descripción de la composición de la nutrición parenteral recibida durante los 28 días que duró su ingreso hospitalario. Conclusión: La asociación de la enfermedad de Hirschsprung y el síndrome de Mowat-Wilson puede conducir a la necesidad de nutrición parenteral de manera prolongada y presentar con mayor frecuencia desvío del estoma produciéndose un mayor número de complicaciones postoperatorias en estos pacientes, tal y como es el caso de nuestro paciente.

Uso de pertuzumab y desensibilización a docetaxel en paciente oncológico; a propósito de un caso / Use of pertuzumab and docetaxel desensitization in oncological patient; apropos of a case

No disponible

Uso de anakinra en un caso de fiebre mediterránea familiar / Anakinra in a case of fever familial Mediterranean

No disponible