[Effect of stress on prepulse inhibition: a systematic review]. / Efecto del estrés sobre la inhibición por prepulso: revisión sistemática.

INTRODUCTION: Prepulse inhibition, one of the main indices of the autonomous inhibitory capacity of the central nervous system, is deficient in psychiatric pathologies associated with dopaminergic system alterations, such as schizophrenia, post-traumatic stress disorder, or substance use disorder. Stress is one of the main risk factors related to the development of these psychiatric disorders. AIM: To know the relationship between stress and prepulse inhibition as possible biomarker and predictor of related pathologies, based on recent literature. SUBJECTS AND METHODS: A systematic review was carried out in PubMed and Web of Science databases from 2011 to 2020. RESULTS: The studies reviewed, including both animal model studies and clinical articles, have shown that intense or repeated stress, whether social, physical or drug-induced, leads to a deterioration of prepulse inhibition, while moderate stress seems to improve its levels. CONCLUSIONS: The results demonstrate a clear relationship between stress and a deficit in prepulse inhibition, which occurs mainly through the dopaminergic system and the corticotropin-releasing factor in the extended amygdala. Prepulse inhibition levels reflect the state of brain dopaminergic activity, being able to identify the most vulnerable subjects to develop stress-related psychiatric pathologies.

TITLE: Efecto del estrés sobre la inhibición por prepulso: revisión sistemática.Introducción. La inhibición por prepulso, uno de los principales índices de la capacidad inhibitoria autónoma del sistema nervioso central, es deficitaria en patologías psiquiátricas asociadas con alteraciones del sistema dopaminérgico, como la esquizofrenia, el trastorno de estrés postraumático o el trastorno por uso de sustancias. El estrés es uno de los principales factores de riesgo relacionado con el desarrollo de estos trastornos psiquiátricos. Objetivo. Conocer la relación entre el estrés y la inhibición por prepulso como posible biomarcador y predictor de determinadas patologías asociadas a él, revisando la bibliografía reciente. Sujetos y métodos. Se realizó una revisión sistemática en las bases de datos PubMed y Web of Science desde 2011 hasta 2020. Resultados. Tanto los estudios con modelos animales como clínicos han demostrado que un estrés intenso o repetido, ya sea social, físico o inducido por fármacos, produce un deterioro de la inhibición por prepulso, mientras que un estrés moderado parece mejorar sus niveles. Conclusiones. Existe una clara relación entre el estrés y una disminución de la inhibición por prepulso, la cual se produce a través del sistema dopaminérgico, principalmente, y el factor liberador de corticotropina en la amígdala extendida. Los niveles de inhibición por prepulso reflejarían el estado de la actividad dopaminérgica cerebral y podrían señalar los sujetos más vulnerables a desarrollar patologías psiquiátricas relacionadas con el estrés.

Baseline prepulse inhibition of the startle reflex predicts the sensitivity to the conditioned rewarding effects of cocaine in male and female mice.

RATIONALE: Prepulse inhibition (PPI) of the startle reflex is a model of pre-attentional inhibitory function. The dopamine baseline in the nucleus accumbens plays a key role in PPI regulation as well as in the rewarding effects of cocaine. OBJECTIVES: The aim of this study was to evaluate the predictive ability of PPI to identify the more vulnerable mice of both sexes to the conditioned rewarding effects of cocaine. METHODS: Male and female OF1 mice were first tested in the PPI paradigm to classify them as high or low PPI. Afterwards, they were evaluated in the conditioned place preference (CPP) paradigm induced by cocaine (1, 6 and 12 mg/kg). Moreover, the D1R and D2R protein expressions in the striatum of high and low PPI animals were analysed by Western blot. RESULTS: Only high-PPI mice acquired CPP induced by low doses of cocaine (1 and 6 mg/kg), while the low-PPI mice needed a higher dose of cocaine (12 mg/kg) to acquire the CPP, but once mice were conditioned, males did not extinguish the conditioned preference and females reinstated the preference with lower doses of cocaine than their control counterparts. Low-PPI animals, especially females, showed higher basal levels of D2R than those with a higher PPI. CONCLUSIONS: Low-PPI mice presented a lower sensitivity to the conditioned rewarding effects of cocaine, but once they were conditioned with a higher dose, they displayed a stronger, perseverant conditioned preference. The predictive capacity of PPI to detect the more vulnerable mice to the conditioned effects of cocaine is discussed.

[Effects of cocaine on prepulse inhibition of the startle response]. / Efecto de la cocaina sobre la inhibicion por prepulso de la respuesta de sobresalto.

INTRODUCTION: Prepulse inhibition (PPI) of the startle response is an index used to evaluate how the pre-attention system works. PPI is altered in patients with a mental disorder such as schizophrenia and in subjects who are vulnerable to it. Likewise, cocaine users also frequently exhibit psychiatric disorders as schizophrenia. AIM: To know the alterations that cocaine produces on PPI. DEVELOPMENT: A comprehensive review is carried out, covering both clinical and preclinical studies with animal models that have evaluated the effects of cocaine exposure on the PPI paradigm. Underlying neural bases and mechanisms of action are suggested to explain these findings. CONCLUSIONS: Cocaine alters PPI through its action on the dopaminergic system. Acute exposure of cocaine decreases PPI by increasing dopamine, while with chronic use, depending on withdrawal time, PPI can be restored. However, the effects of cocaine on PPI appear to depend on the baseline levels of PPI shown by the individual. Thus, since a deficit in PPI has been associated with a greater vulnerability to developing mental pathologies such as schizophrenia, PPI level in subjects could be considered as a biomarker of psychiatric vulnerability. Therefore, a better understanding of the effect of drugs such as cocaine on PPI may help to understand the development of dual pathology.

TITLE: Efecto de la cocaina sobre la inhibicion por prepulso de la respuesta de sobresalto.Introduccion. La inhibicion por prepulso (IPP) de la respuesta de sobresalto es una medida de sincronizacion sensitivomotora basada en la respuesta del reflejo de sobresalto. Un deficit en la IPP se ha observado en pacientes psiquiatricos, especialmente con esquizofrenia, asi como en sujetos vulnerables a desarrollarla. Asimismo, los consumidores de cocaina presentan un alto indice de patologias psiquiatricas como la esquizofrenia. Objetivo. Conocer las alteraciones que el consumo de cocaina puede producir en la IPP. Desarrollo. Se realiza una revision exhaustiva de los estudios, tanto clinicos como con modelos animales, que hayan evaluado la IPP tras el consumo o la administracion de cocaina. Se sugieren bases neurales y mecanismos de accion subyacentes para explicar los resultados. Conclusiones. La cocaina altera la IPP a traves de su accion sobre el sistema dopaminergico. La administracion aguda de cocaina disminuye la IPP al aumentar la dopamina, mientras que con el consumo cronico, dependiendo del tiempo de abstinencia, la IPP puede restablecerse. Sin embargo, los efectos de la cocaina sobre la IPP parecen depender de los niveles basales de la IPP que muestre el individuo. Asi, dado que un deficit en la IPP se ha relacionado con una mayor vulnerabilidad a desarrollar patologias mentales como la esquizofrenia, los niveles de la IPP en los sujetos podrian considerarse como un biomarcador de vulnerabilidad psiquiatrica. Por ello, conocer mejor el efecto que drogas como la cocaina ejercen sobre la IPP puede ayudar a comprender el desarrollo de la patologia dual.

Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness.

RATIONALE: Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade. OBJECTIVES: The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs. METHODS: Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA). RESULTS: Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine. CONCLUSIONS: These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence. HIGHLIGHTS: • Topiramate increases the rewarding properties of cocaine in CPP • Topiramate alters dopaminergic signaling in the mesolimbic circuit • Topiramate delays the extinction of cocaine-induced CPP • TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine • Results show that it should limit the use of topiramate in cocaine-dependent subjects.

Sex differences in the long-lasting consequences of adolescent ethanol exposure for the rewarding effects of cocaine in mice.

RATIONALE: The practice of binge drinking is very common among adolescents of both sexes. It can have long-term consequences with respect to drug consumption during adulthood, but knowledge on these effects in females is limited. OBJECTIVES: The long-lasting effects of intermittent exposure to ethanol (EtOH) during adolescence on different cocaine-elicited behaviours, including locomotor reactivity, conditioned place preference (CPP) and intravenous self-administration, were evaluated in male and female adult mice. It was hypothesized that an EtOH binge during adolescence would increase sensitivity to the effects of a sub-threshold dose of cocaine and has a differential impact on the drug's effects in males and females. METHODS: Adolescent OF1 mice (postnatal day (PND) 26) underwent a 2-week pre-treatment schedule consisting of 16 doses of EtOH (2.5 g/kg) or saline (twice daily administrations separated by a 4-h interval i.p.) administered on two consecutive days separated by an interval of 2 days. Three weeks later (PND > 60), we assessed locomotor activity responses induced by an acute injection of different doses of cocaine in experiment 1 and the rewarding effects of cocaine on the CPP (1 mg/kg) and intravenous self-administration (1 mg/kg/infusion) paradigms in experiment 2. RESULTS: Pre-exposure to EtOH during adolescence altered motor reactivity to cocaine in a dose- and sex-dependent manner, increased sensitivity to cocaine in CPP and enhanced self-administration in adult mice. CONCLUSIONS: The effects of intermittent exposure to ethanol during adolescence are evident in adulthood, during which greater sensitivity and intake of cocaine is observed and differ in each sex.

Prevalence of EGFR mutations in newly diagnosed locally advanced or metastatic non-small cell lung cancer Spanish patients and its association with histological subtypes and clinical features: The Spanish REASON study.

BACKGROUND AND OBJECTIVES: The aim of the REASON study is to determine the frequency of EGFR mutation in advanced non-small cell lung cancer (aNSCLC) patients in Spain (all histologies), and to better understand the clinical factors (gender, smoking habits and histological subtypes) that may be associated with EGFR mutations, in an unselected sample of aNSCLC patients. METHODS: All newly diagnosed aNSCLC patients from 40 selected centers in Spain were prospectively included for a 6-month period. Patient characteristics were obtained from clinical records. Mutation testing was performed on available tumor samples. Exploratory analyses were performed to characterize the clinico-pathological factors associated with presence of EGFR mutations. RESULTS: From March 2010 to March 2011, 1113 patients were included in the study, of which 1009 patients provided sample for EGFR mutation analysis (90.7%). Mutation analysis was not feasible in 146/1113 patients (13.1%) due to either sample unavailability (79/1113; 7.1%) or sample inadequacy (67/1113; 6.0%). Twenty-five out of 1113 patients (2.3%) were excluded due to unavailable information. Most patients (99.5%) were Caucasian, 74.5% were male, and predominantly were current (38.1%) or former smokers (44.0%). Median age was 66 years (range 25-90) and 70.7% of patients had non-squamous histology (57.8% adenocarcinoma, 1.8% bronchoalveolar, 11.1% large-cell carcinoma). Exon 19 deletions and the exon 21 L858R point mutation were analyzed in 942/1009 (93.4%) samples. Mutation rate was 11.6% (82.6% exon 19 dels and 17.4% L858R). To be never smoker (38.1%), female (25.4%), with bronchioloalveolar carcinoma (22.2%) or adenocarcinoma (15.4%) histology was associated with a higher prevalence of EGFR mutations. Exons 18, 20 and 21 (excluding L858R) were analyzed in 505/942 samples, and EGFR mutations were found in 22/505 samples (4.4%). CONCLUSION: The estimated prevalence of sensitizing EGFR mutations (exon 19 del, exon 21 L858R) in an unselected samples of newly diagnosed aNSCLC patients in Spain (all histologies) is consistent with previous published data in Caucasian patients. When a sample is available, EGFR mutation testing is feasible in over 90% of cases, and may therefore be suitable for routine clinical practice. CLINICALTRIALS. GOV IDENTIFIER: NCT01081496.

Higher sensitivity to the conditioned rewarding effects of cocaine and MDMA in High-Novelty-Seekers mice exposed to a cocaine binge during adolescence.

RATIONALE: Exposure to drugs during adolescence can induce alterations in the central nervous system. The novelty-seeking personality trait influences differences observed among individuals exposed to drugs of abuse. OBJECTIVES: Long-term effects of intensive pre-treatment with cocaine during adolescence or adulthood were evaluated in High- and Low-Novelty Seeker (HNS and LNS) mice. It was hypothesized that a cocaine binge during adolescence would increase sensitivity to the rewarding effects of cocaine and MDMA, especially in HNS animals, and modify the spontaneous behaviour of adult animals. METHODS: Adolescent (PND 33) and adult (PND 60) mice were identified as HNS or LNS according to their performance in the hole-board test. Subsequently, they received pre-treatment with cocaine (three injections per day of an increasing dose for 10 days) or saline. Three weeks later, the mice performed the hole-board, elevated plus maze, spontaneous locomotor activity and cocaine- (1 mg/kg) or MDMA- (1.25 mg/kg) induced conditioning place preference (CPP) tests. In another set of mice, the effects of pre-treatment of cocaine during adulthood on MDMA- or cocaine-induced CPP were also evaluated 3 weeks later. RESULTS: Only HNS mice treated with cocaine during adolescence acquired MDMA- or cocaine-induced CPP in adulthood. Moreover, pre-exposure to cocaine during adolescence caused subsequent behavioural alterations, including reduced exploratory behaviour and increased locomotor reactivity. CONCLUSIONS: Cocaine binge administration during adolescence induces a higher sensitivity to the rewarding effects of MDMA and cocaine in HNS mice in adulthood. This may explain the greater vulnerability often seen among individuals exposed early in life to drugs of abuse.

Simple one-step ultrasonic synthesis of anatase titania/polypyrrole nanocomposites.

In this work, hybrid nanocomposites based on anatase titania:polypyrrole (TiO(2):PPy) were directly obtained from a simple, one-step, ultrasonic (UT)-assisted synthesis. The properties of these crystalline nanocomposites were compared with those of others fabricated using cold (Cold)-assisted synthesis without any UT assistance, which required a hydrothermal treatment (HT) to yield crystalline anatase titania in the nanocomposite (TiO(2):PPy) at low temperature (130°C) and in a short time (3h). The SEM results demonstrated that the UT-assisted synthesis is a feasible method to obtain anatase TiO(2):PPy nanocomposites with controlled morphology using low energy. The Fourier transform infrared (FT-IR) bands of the crystalline nanocomposites exhibited a shift with respect to neat components, which was attributed to the strong interaction between the secondary amine groups (N-H) of PPy and the oxygen from TiO(2). The acceptable absorption in the visible region (λ(max)=670nm) indicates that these nanocomposites are good candidates for harvesting energy in solar cells. Devices based on these nanocomposites were built to evaluate their electrical properties. An increase in the photocurrent was observed for the devices prepared with the nanocomposites from the UT-assisted synthesis.

Synthesis of conducting polyaniline nanofibers from single and binary dopant agents.

Conducting polyaniline nanofibers (nf-PANI) were successfully synthesized by simple polymerization of aniline in presence of single and binary dopant agents. Strong hydrochloride acid (HCl), two weak organic acids (poly acrylic acid, PAA, 2-acrylamido-2-methyl-1-propanesulfonic acid, AMPSA) and one anionic surfactant (sodium dodecyl sulfate, SDS) were used to form the binary dopant agents. The binary dopant agent PAA modified the morphology of the single doped PANI, whereas AMPSA and SDS modified the dimensions of the nanofibers: the length size single nanofibers is reduced 1.72 times with binary-doped AMPSA and increased by a factor of 0.7 with SDS. The surface roughness of the films decreases when the dimensions of the nanofibers increase: PANI-SDS film is flatter than PANI-AMPSA film. In general, the conductivity of the single-doped PANI nanofibers (nf-PANI-HCl) was improved by one order of magnitude with binary dopant agents (HCI-PAA, HCl-AMPSA, HCl-SDS). The influence of the binary dopant agents in the nf-PANI-HCl properties is analyzed by Transmission Electron Microscope (TEM), Atomic Force Microscopy (AFM), UV-VIS absorption spectra, thermogravimetric analysis (TGA) and Fourier-Transform infrared spectra (FT-IR).

Predicting how equipotent doses of chlorpromazine, haloperidol, sulpiride, raclopride and clozapine reduce locomotor activity in mice.

Distinguishing the specific effects of neuroleptics on one particular behaviour from its non-specific effects on motility is not easy. In this study, the effects of five neuroleptics on spontaneous motor activity were compared and the ED(50) values of these drugs to impair activity were calculated. Male and female mice were evaluated in an actimeter or in a shuttle-box used as an open field after the administration of chlorpromazine (0.4, 1.2, 3.6 mg/kg), haloperidol (0.1, 0.3, 0.9 mg/kg), raclopride (0.1, 0.3, 0.9 mg/kg), sulpiride (10, 30, 90 mg/kg) and clozapine (0.4, 1.2, 3.6 mg/kg), and two automatic and two observational activity measures were obtained. A very high correlation between automatic and observational measures, absence of sex differences, and a dose-dependent decrease of activity were observed with every compound. The results allow us to make accurate comparisons between these drugs in their potency in reducing spontaneous motor activity.

Fiebre prolongada en paciente con lesiones ocupantes de espacio hepáticas de larga evolución / Fever in a patient with spatial hepatic lesions of large evolution

No disponible

Sex differences in the effects of neuroleptics on escape-avoidance behavior in mice: a review.

The literature of the effects of dopamine antagonists on escape-avoidance, focusing on data obtained in our laboratory with male and female mice, is reviewed. The acute administration of haloperidol, raclopride, clozapine, and SCH 23390 impaired escape-avoidance behavior more in males than in females, and the subchronic administration of haloperidol had a similar effect. This appeared to be a reliable phenomenon, because it was observed in both kinds of administration, in two mouse strains, and with several drugs and doses. The observed results were dose dependent, although the dose-effect relationship was not the same in all drugs. The sex differences in escape avoidance did not seem related to sex differences in the well-known deteriorating effects of these drugs on motor activity. In addition, an analysis of all our studies showed that there were no sex differences in the variability of responses, reinforcing the idea that female subjects should be included in these types of studies.

Dose dependency of sex differences in the effects of repeated haloperidol administration in avoidance conditioning in mice.

Sex differences in the effects of haloperidol in active avoidance conditioning in mice have previously been found in various studies carried out in our laboratory. Males were more affected than females by the disruptive effects of this neuroleptic. The work described here broadens the study of these sex differences to higher doses of haloperidol (0.1 and 0.2 mg/kg) using a repeated administration schedule (5 days). The results did not show sex differences in the deteriorating effects of this dopamine antagonist in the escape-avoidance response, but a tendency in the number of nonresponses was observed in the same direction as former results: male animals were more sensitive than females to the inhibitory effect of the low dose of haloperidol. It is concluded that the appearance of sex differences in the effects of haloperidol on active avoidance conditioning is a dose-dependent phenomenon.

Gender differences in the effects of haloperidol on avoidance conditioning in mice.

Gender differences in the effects of haloperidol (0.075 mg/kg per day for 5 days) on avoidance conditioning were evaluated. We also studied performance of the subjects free of the drug and the acute effects of haloperidol in animals trained without drug 48 h after the last haloperidol administration. Latencies of escape and avoidance responses, number of nonresponses, escapes, avoidances, crossings during the adaptation period, crossings during intertrial intervals, and total crossings per minute were analyzed. This dosage impaired conditioning of the male animals but did not attain the same effects on females. Haloperidol did not deteriorate performance of the task when it had been learned previously without drug. The results confirm the existence of gender differences in haloperidol effects on avoidance conditioning in mice and suggest that these differences are related to the learning process and not only to the impairment of motor behavior characteristic of neuroleptic drugs.

Gender differences in escape-avoidance behavior of mice after haloperidol administration.

Gender differences in the disruptive effects of haloperidol on some reinforced behaviors have been observed in different species. However, the inhibitory action of haloperidol on the acquisition and performance of escape-avoidance behavior has only been investigated in male subjects. The present experiment was designed to investigate possible gender differences in the effects of haloperidol on the initial phase of an escape-avoidance learning task. Male and female mice of the OF1 strain were given a single training session in a shuttle-box. Thirty minutes prior to the behavioral test, mice were injected IP with haloperidol (0.25 mg/kg) or physiological saline (10 ml/kg). Latencies of escape and avoidance responses and the number of nonresponses, escapes, avoidances, pseudoavoidances, crossings during the adaptation period, and crossings during intertrial intervals (ITIs) were evaluated. The disruptive action of haloperidol on the escape-avoidance behavior of the mice was greater in males than in females. The number of nonresponses were higher and the number of escapes lower in treated males than in their female counterparts. These gender differences were not found in control subjects. Activity measures of spontaneous motor behavior (crossings in the adaptation period and during ITIs) did not present gender differences either. Several possible mechanisms responsible for this greater susceptibility of males to the inhibitory effects of haloperidol on escape-avoidance learning are discussed, especially the modulating role of female hormones on dopaminergic activity.