Cocaine-induced behavioral sensitization is associated with changes in the expression of endocannabinoid and glutamatergic signaling systems in the mouse prefrontal cortex.

BACKGROUND: Endocannabinoids modulate the glutamatergic excitatory transmission by acting as retrograde messengers. A growing body of studies has reported that both signaling systems in the mesocorticolimbic neural circuitry are involved in the neurobiological mechanisms underlying drug addiction. METHODS: We investigated whether the expression of both endocannabinoid and glutamatergic systems in the prefrontal cortex (PFC) were altered by an acute and/or repeated cocaine administration schedule that resulted in behavioral sensitization. We measured the protein and mRNA expression of the main endocannabinoid metabolic enzymes and the cannabinoid receptor type 1 (CB1). We also analyzed the mRNA expression of relevant components of the glutamate-signaling system, including glutamate-synthesizing enzymes, metabotropic receptors, and ionotropic receptors. RESULTS: Although acute cocaine (10 mg/kg) produced no significant changes in the endocannabinoid-related proteins, repeated cocaine administration (20 mg/kg daily) induced a pronounced increase in the CB1 receptor expression. In addition, acute cocaine administration (10 mg/kg) in cocaine-sensitized mice (referred to as cocaine priming) induced a selective increase in the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). These protein changes were accompanied by an overall decrease in the ratios of endocannabinoid synthesis/degradation, especially the N-acyl phosphatidylethanolamine phospholipase D/FAAH and diacylglycerol lipase alpha/MAGL ratios. Regarding mRNA expression, while acute cocaine administration produced a decrease in CB1 receptors and N-acyl phosphatidylethanolamine phospholipase D, repeated cocaine treatment enhanced CB1 receptor expression. Cocaine-sensitized mice that were administered priming injections of cocaine mainly displayed an increased FAAH expression. These endocannabinoid changes were associated with modifications in glutamatergic transmission-related genes. An overall decrease was observed in the mRNA expression of the glutamate-synthesizing gene kidney-type glutaminase (KGA), the metabotropic glutamate receptors (mGluR3 and GluR), and subunits of NMDA ionotropic receptors (NR1, NR2A, NR2B and NR2C) after acute cocaine administration, while mice repeatedly exposed to cocaine only displayed an increase in NR2C. However, in cocaine-sensitized mice primed with cocaine, this inhibition was reversed and a strong increase was detected in the mGluR5, NR2 subunits, and both GluR1 and GluR3. CONCLUSIONS: These findings indicate that cocaine sensitization is associated with an endocannabinoid downregulation and a hyperglutamatergic state in the PFC that, overall, contribute to an enhanced glutamatergic input into PFC-projecting areas.

Diet-dependent modulation of hippocampal expression of endocannabinoid signaling-related proteins in cannabinoid antagonist-treated obese rats.

Diet-induced obesity produces changes in endocannabinoid signaling (ECS), influencing the regulation of energy homeostasis. Recently, we demonstrated that, in high-fat-diet-fed rats, blockade of CB1 receptor by AM251 not only reduced body weight but also increased adult neurogenesis in the hippocampus, suggesting an influence of diet on hippocampal cannabinoid function. To further explore the role of hippocampal ECS in high-fat-diet-induced obesity, we investigated whether the immunohistochemical expression of the enzymes that produce (diacylglycerol lipase alpha and N-acyl phosphatidylethanolamine phospholipase D) and degrade (monoacylglycerol lipase and fatty acid amino hydrolase) endocannabinoids may be altered in the hippocampus of AM251 (3 mg/kg)-treated rats fed three different diets: standard diet (normal chow), high-carbohydrate diet (70% carbohydrate) and high-fat diet (60% fat). Results indicated that AM251 reduced caloric intake and body weight gain, and induced a modulation of the expression of ECS-related proteins in the hippocampus of animals exposed to hypercaloric diets. These effects were differentially restricted to either the 2-arachinodoyl glycerol or anandamide signaling pathways, in a diet-dependent manner. AM251-treated rats fed the high-carbohydrate diet showed a reduction of the diacylglycerol lipase alpha : monoacylglycerol lipase ratio, whereas AM251-treated rats fed the high-fat diet showed a decrease of the N-acyl phosphatidylethanolamine phospholipase D : fatty acid amino hydrolase ratio. These results are consistent with the reduced levels of hippocampal endocannabinoids found after food restriction. Regarding the CB1 expression, AM251 induced specific changes focused in the CA1 stratum pyramidale of high-fat-diet-fed rats. These findings indicated that the cannabinoid antagonist AM251 modulates ECS-related proteins in the rat hippocampus in a diet-specific manner. Overall, these results suggest that the hippocampal ECS participates in the physiological adaptations to different caloric diets.

Hyperactivity induced by the dopamine D2/D3 receptor agonist quinpirole is attenuated by inhibitors of endocannabinoid degradation in mice.

The present study was designed to investigate the effect of pharmacological inhibition of endocannabinoid degradation on behavioural actions of the dopamine D2/D3 receptor agonist quinpirole in male C57Bl/6J mice. In addition, we studied the effects of endocannabinoid degradation inhibition on both cocaine-induced psychomotor activation and behavioural sensitization. We analysed the effects of inhibition of the two main endocannabinoid degradation enzymes: fatty acid amide hydrolase (FAAH), using inhibitor URB597 (1 mg/kg); monoacylglycerol lipase (MAGL), using inhibitor URB602 (10 mg/kg). Administration of quinpirole (1 mg/kg) caused a temporal biphasic response characterized by a first phase of immobility (0-50 min), followed by enhanced locomotion (next 70 min) that was associated with the introduction of stereotyped behaviours (stereotyped jumping and rearing). Pretreatment with both endocannabinoid degradation inhibitors did not affect the hypoactivity actions of quinpirole. However, this pretreatment resulted in a marked decrease in quinpirole-induced locomotion and stereotyped behaviours. Administration of FAAH or MAGL inhibitors did not attenuate the acute effects of cocaine. Furthermore, these inhibitors did not impair the acquisition of cocaine-induced behavioural sensitization or the expression of cocaine-induced conditioned locomotion. Only MAGL inhibition attenuated the expression of an already acquired cocaine-induced behavioural sensitization. These results suggest that pharmacological inhibition of endocannabinoid degradation might exert a negative feedback on D2/D3 receptor-mediated hyperactivity. This finding might be relevant for therapeutic approaches for either psychomotor disorders (dyskinesia, corea) or disorganized behaviours associated with dopamine-mediated hyperactivity.

Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats.

Perinatal asphyxia (PA) increases the likelihood of suffering from dopamine-related disorders, such as ADHD and schizophrenia. Since dopaminergic transmission plays a major role in cocaine sensitization, the purpose of this study was to determine whether PA could be associated with altered behavioral sensitization to cocaine. To this end, adult rats born vaginally (CTL), by caesarean section (C+), or by C+ with 15 min (PA15, moderate PA) or 19 min (PA19, severe PA) of global anoxia were repeatedly administered with cocaine (i.p., 15 mg/kg) and then challenged with cocaine (i.p., 15 mg/kg) after a 5-day withdrawal period. In addition, c-Fos, FosB/ΔFosB, DAT, and TH expression were assessed in dorsal (CPu) and ventral (NAcc) striatum. Results indicated that PA15 rats exhibited an increased locomotor sensitization to cocaine, while PA19 rats displayed an abnormal acquisition of locomotor sensitization and did not express a sensitized response to cocaine. c-Fos expression in NAcc, but not in CPu, was associated with these alterations in cocaine sensitization. FosB/ΔFosB expression was increased in all groups and regions after repeated cocaine administration, although it reached lower expression levels in PA19 rats. In CTL, C+, and PA15, but not in PA19 rats, the expression of TH in NAcc was reduced in groups repeatedly treated with cocaine, independently of the challenge test. Furthermore, this reduction was more pronounced in PA15 rats. DAT expression remained unaltered in all groups and regions studied. These results suggest that moderate PA may increase the vulnerability to drug abuse and in particular to cocaine addiction.

Oleoylethanolamide dose-dependently attenuates cocaine-induced behaviours through a PPARα receptor-independent mechanism.

Oleoylethanolamide (OEA) is an acylethanolamide that acts as an agonist of nuclear peroxisome proliferator-activated receptor alpha (PPARα) to exert their biological functions, which include the regulation of appetite and metabolism. Increasing evidence also suggests that OEA may participate in the control of reward-related behaviours. However, direct experimental evidence for the role of the OEA-PPARα receptor interaction in drug-mediated behaviours, such as cocaine-induced behavioural phenotypes, is lacking. The present study explored the role of OEA and its receptor PPARα on the psychomotor and rewarding responsiveness to cocaine using behavioural tests indicative of core components of addiction. We found that acute administration of OEA (1, 5 or 20 mg/kg, i.p.) reduced spontaneous locomotor activity and attenuated psychomotor activation induced by cocaine (20 mg/kg) in C57Bl/6 mice. However, PPARα receptor knockout mice showed normal sensitization, although OEA was capable of reducing behavioural sensitization with fewer efficacies. Furthermore, conditioned place preference and reinstatement to cocaine were intact in these mice. Our results indicate that PPARα receptor does not play a critical, if any, role in mediating short- and long-term psychomotor and rewarding responsiveness to cocaine. However, further research is needed for the identification of the targets of OEA for its inhibitory action on cocaine-mediated responses.

Levels of Reading Comprehension in Higher Education: Systematic Review and Meta-Analysis.

Higher education aims for university students to produce knowledge from the critical reflection of scientific texts. Therefore, it is necessary to develop a deep mental representation of written information. The objective of this research was to determine through a systematic review and meta-analysis the proportion of university students who have an optimal performance at each level of reading comprehension. Systematic review of empirical studies has been limited from 2010 to March 2021 using the Web of Science, Scopus, Medline, and PsycINFO databases. Two reviewers performed data extraction independently. A random-effects model of proportions was used for the meta-analysis and heterogeneity was assessed with I 2. To analyze the influence of moderating variables, meta-regression was used and two ways were used to study publication bias. Seven articles were identified with a total sample of the seven of 1,044. The proportion of students at the literal level was 56% (95% CI = 39-72%, I 2 = 96.3%), inferential level 33% (95% CI = 19-46%, I 2 = 95.2%), critical level 22% (95% CI = 9-35%, I 2 = 99.04%), and organizational level 22% (95% CI = 6-37%, I 2 = 99.67%). Comparing reading comprehension levels, there is a significant higher proportion of university students who have an optimal level of literal compared to the rest of the reading comprehension levels. The results have to be interpreted with caution but are a guide for future research.

Docencia universitaria y estudiantes con discapacidad: cuestiones sobre accesibilidad y adaptación en el estudio / University teaching and students with disabilities: questions about accessibility and adaptation in the study

Este trabajo aborda la discapacidad en el contexto universitario, desde la adecuación a las necesidades y características de la persona. Esta mirada busca que quienes presenten necesidades especiales asociadas a la discapacidad, dispongan de los medios, apoyos y recursos suficientes para asegurar la igualdad real y efectiva de oportunidades dentro de la comunidad universitaria. De acuerdo con ese objetivo, con este artículo se pretende generar una reflexión en el docente universitario, sobre las cuestiones de accesibilidad y adaptación -como aspectos básicos- en la atención a su alumnado con discapacidad. Estos aspectos se relacionan con la búsqueda de desarrollo tecnológico, formativo y personal-social, propio de una Universidad abierta a la sociedad, apuntando hacia valores de normalización, integración e inclusión. En una primera parte, se tratan generalidades sobre el desarrollo tecnológico y usuarios con discapacidad, para pasar a una segunda en la que se abordan cuestiones de la accesibilidad y la discapacidad, continuando con su concreción en el currículum universitario del alumnado con discapacidad.

This work addresses disability in the higher education context, in terms of reasonable and achievable adjustments related to the individual's needs and features. This approach aims to ensure assistive technology, support, and resources as means to guarantee real and effective access to equal opportunities for those members that may present special needs, due to their disability situation, within the university community. Therefore, this paper attempts to generate a reflection for university lecturers about accessibility and adaptation, as basic aspects in their duty of supporting disabled students. These aspects are directly related to technological, educational and socio-personal development, present in those higher education institutions open to society and oriented to values such as integration and inclusion. In the first place, some general information is provided about technological development and users with disabilities. In the second place, certain aspects related to accessibility and disability are addressed, and their materialization in the university curriculum of disabled students.

Cocaine modulates both glutaminase gene expression and glutaminase activity in the brain of cocaine-sensitized mice.

RATIONALE: Glutaminase is considered the main glutamate (Glu)-producing enzyme. Two isoforms, liver (LGA)- and kidney (KGA)-type glutaminases, have been identified in neurons. The role of both enzymes in psychopharmacological responses to cocaine remains unknown. OBJECTIVES: We examined both mRNA and protein expression of KGA and LGA in the brain of mice sensitized to cocaine. Additionally, total glutaminase activity was also measured. METHODS: Total glutaminase activity and mRNA and protein expression of KGA and LGA were measured on the dorsal striatum, prefrontal cortex, hippocampus and cerebellum of cocaine-sensitized mice. RESULTS: Cocaine-sensitized animals (20 mg/kg × 5 days, followed by 5 drug-free days) exhibited a decrease of total glutaminase activity in both the dorsal striatum and the prefrontal cortex. This was associated with an increase in KGA mRNA expression in both brain areas that was not observed when protein KGA levels were measured by western blot. LGA mRNA expression was increased as results of acute cocaine administration in sensitized animals, although protein levels were only enhanced in the prefrontal cortex of sensitized mice. These findings suggest that chronic cocaine administration modulates glutamate production through the regulation of glutaminase expression and activity. These actions are mainly observed in the prefrontal cortex-dorsal striatum circuit, the neuroanatomical target for the psychostimulant sensitization properties of cocaine. CONCLUSIONS: The present results indicate that glutaminase enzymes (mainly KGA) are modulated by cocaine in both the prefrontal cortex and the dorsal striatum, as part of the neuroadaptions associated with behavioural sensitization to this drug of abuse.

Attenuation of cocaine-induced conditioned locomotion is associated with altered expression of hippocampal glutamate receptors in mice lacking LPA1 receptors.

RATIONALE: Lysophosphatidic acid is a phospholipid mediator that modulates neurodevelopment and neurogenesis in the hippocampus through its actions on LPA1 receptors. Emerging evidences support LPA(1) as a mediator of learning and emotional behaviour. There are no studies addressing its role on behaviours associated to drug abuse. OBJECTIVES: We examined whether genetic deletion of LPA1 receptor in maLPA(1)-null mice affected either cocaine-induced conditioned locomotion (CL) or behavioural sensitization (BS) induced by repeated cocaine exposure. We also analysed whether cocaine induced changes in the expression of functional markers of both dopamine- and glutamate-related genes in the striatum and the dorsal hippocampus. METHODS: We monitored cocaine-induced CL and BS in both genotypes of mice. Striatal dopamine and hippocampal glutamate-related genes were measured by real-time quantitative PCR, Western blot, and immunohistochemistry. RESULTS: maLPA(1)-null mice exhibit an attenuated CL response after cocaine conditioning but a normal BS after repeated cocaine exposure. These behavioural changes were associated to alterations on the expression of metabotropic mGLUR3 glutamate receptors and on the actions of cocaine on the GLUR1 subunit of AMPA glutamate receptors in the hippocampus of maLPA(1) animals. Striatal dopaminergic markers (tyrosine hydroxylase, dopamine D1 receptor, and dopamine transporter DAT), were similar in both genotypes and were equally affected by cocaine exposure. CONCLUSION: The present results indicate that the lack of LPA1 receptor affect cocaine-induced conditioned locomotion but not behavioural sensitization. The findings suggest that LPA1 receptor may be necessary for a normal associative contextual learning associated to cocaine, probably through the modulation of hippocampal glutamatergic circuits.

Aspectos psicoeducativos en la evaluación del alumnado con altas capacidades intelectuales: análisis de un caso / Psychoeducational aspects in the assessment of students with High intellectual abilities: a single-case study

El presente trabajo trata de favorecer la reflexión, desde la psicología educacional, sobre la respuesta a las necesidades específicas de apoyo educativo de los alumnos y alumnas con Altas Capacidades Intelectuales. Tras una breve exposición sobre las características de este tipo de alumnado, se realiza un análisis de caso con el que establecer la relación entre la evaluación psicoeducativa y la intervención psicopedagógica. Desde la labor de los psicólogos de la educación (interviniendo en todos los procesos psicológicos que afectan al aprendizaje o que se derivan de este) y otros colegas que actúan en el ámbito educativo, se buscaría, en última instancia, relacionar los objetivos de cualquier intervención psicoeducativa: la valoración diagnóstica y la planificación de la intervención pedagógica dentro de la atención a la diversidad desarrollada en el sistema educativo español.

The following paper aims to promote an educational psychology-based reflection on the response to those specific educational needs required by students with high intellectual abilities. After a brief discussion on the characterization of this kind of student, a single-case study is developed in order to establish a relationship between psycho-educational assessments and educational psychology interventions. The work of educational psychologists (intervening in all the psychological processes affecting learning or resulted therefrom) and other acting colleagues in the educational field would ultimately seek to relate the objectives of any psychoeducational intervention: diagnostic assessment and educational intervention planning within the diversity emphasis developed on the Spanish educational system.

Synthesis of fatty acid amides of catechol metabolites that exhibit antiobesity properties.

A series of fatty acid amides of 3,4-methylenedioxymethamphetamine (MDMA) catechol metabolites were synthesized in order to evaluate their biological activities. Upon administration, all synthesized compounds resulted in negative modulation of food intake in rats. The most active compounds have affinity for the CB(1) receptor and/or PPAR-α; part of their biological activity may be caused by these double interactions.