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Higuera Matas, Alejandro

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0000-0003-3438-9387
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Higuera Matas
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Alejandro
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2008 - 200912020 - 20234
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    Estudio de los efectos psiconeuroendocrinos en la edad adulta de un tratamiento crónico con el agonista cannabinoide CP55,940 en ratas adolescentes de ambos sexos
    (Universidad Nacional de Educación a Distancia (España). Facultad de Psicología. Departamento de Psicobiología, 2008-03-07) Higuera Matas, Alejandro; Ambrosio Flores, Emilio
    El consumo de marihuana durante la adolescencia representa un grave problema social. Esta droga es la sustancia ilegal consumida más ampliamente por la población adolescente y si bien hay un cierto corpus de conocimiento científico acerca de las consecuencias a largo plazo de este abuso, es todavía necesario abundar sobre este tipo de problemática. En los experimentos que componen esta Tesis Doctoral se ha estudiado si un consumo adolescente de marihuana (modelizado con un tratamiento crónico con el agonista no selectivo de receptores cannabinoides CP 55,940 –CP- en ratas adolescentes) puede promover una mayor susceptibilidad a la adicción a la cocaína cuando los individuos llegan a la edad adulta. Además hemos estudiado si este consumo adolescente deja secuelas a largo plazo sobre el funcionamiento cerebral, utilizando técnicas de neuroimagen funcional (Tomografía por Emisión de Positrones o TEP), así como técnicas propias de la neuroquímica y la neuropsicofarmacología (autorradiografía, hibridación in situ, etc…). En este aspecto hemos demostrado que los animales hembras adultos que fueron sometidos al tratamiento con el agonista en su adolescencia, mostraron una mayor tasa de respuesta cuando se les sometió a un paradigma de autoadministración de cocaína. Además hemos identificado cambios duraderos en el metabolismo cerebral basal en las ratas hembras tratadas y no en el resto de los animales. Estudiando la neuroquímica cerebral descubrimos que el tratamiento también modificaba el sistema dopaminérgico de manera dependiente del sexo. Dadas las posibles secuelas cognitivas y emocionales que el consumo de marihuana parece tener en los seres humanos, también evaluamos si nuestro tratamiento podría inducir déficits cognitivos y emocionales a largo plazo. Encontramos que, en la línea de investigaciones previas, los animales tratados con el CP, mostraron una ansiolisis duradera al llegar a la edad adulta y sorprendentemente, experimentaron una mejora de su memoria de referencia, sin que su memoria de trabajo (espacial o de reconocimiento) se viera afectada. Nuestro tratamiento indujo un aumento en los machos tratados, de las proteínas de adhesión celular neural (NCAM), mediadoras en la 20 plasticidad sináptica, pero no tuvo consecuencias en otros parámetros de plasticidad como por ejemplo la potenciación a largo plazo (PLP) en el hipocampo. Asimismo, no detectamos alteraciones hormonales, ni en los niveles de corticoesterona ni en los de estradiol, como consecuencia del tratamiento. Concluimos por tanto, que un tratamiento crónico con el agonista cannabinoide CP 55,940 durante la adolescencia, aumenta la susceptibilidad a la adicción a la cocaína durante la edad adulta, específicamente en las hembras. Además, altera el funcionamiento cerebral normal y el sistema dopaminérgico a la vez que produce una ansiolisis duradera y una mejora relativa en la memoria de referencia.
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    The long-term effects of adolescent Δ9-tetrahydrocannabinol on brain structure and function assessed through neuroimaging techniques in male and female rats
    (Elsevier, 2023-06-03) Orihuel Menéndez, Javier; Capellán, Roberto; Casquero Veiga, Marta; Soto Montenegro, María Luisa; Desco, Manuel; Oteo Vives, Marta; Ibáñez Moragues, Marta; Magro Calvo, Natalia; Luján, Víctor M.; Morcillo, Miguel Ángel; Ambrosio Flores, Emilio; Higuera Matas, Alejandro; https://orcid.org/0000-0001-9586-0684; https://orcid.org/0000-0003-0306-7916
    Several studies performed on human subjects have examined the effects of adolescent cannabis consumption on brain structure or function using brain imaging techniques. However, the evidence from these studies is usually heterogenous and affected by several confounding variables. Animal models of adolescent cannabinoid exposure may help to overcome these difficulties. In this exploratory study, we aim to increase our understanding of the protracted effects of adolescent Δ9-tetrahydrocannabinol (THC) in rats of both sexes using magnetic resonance (MR) to obtain volumetric data, assess grey and white matter microstructure with diffusion tensor imaging (DTI) and measure brain metabolites with 1H-MR spectroscopy (MRS); in addition, we studied brain function using positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-d-glucose as the tracer. THC-exposed rats exhibited volumetric and microstructural alterations in the striatum, globus pallidus, lateral ventricles, thalamus, and septal nuclei in a sex-specific manner. THC administration also reduced fractional anisotropy in several white matter tracts, prominently in rostral sections, while in vivo MRS identified lower levels of cortical choline compounds. THC-treated males had increased metabolism in the cerebellum and olfactory bulb and decreased metabolism in the cingulate cortex. By contrast, THC-treated females showed hypermetabolism in a cluster of voxels comprising the entorhinal piriform cortices and in the cingulate cortex. These results indicate that mild THC exposure during adolescence leaves a lingering mark on brain structure and function in a sex-dependant manner. Some of the changes found here resemble those observed in human studies and highlight the importance of studying sex-specific effects in cannabinoid research.
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    Publicación
    Effects of heroin self-administration and forced withdrawal on the expression of genes related to the mTOR network in the basolateral complex of the amygdala of male Lewis rats
    (Springer Nature, 2022-04-25) Ucha Tortuero, Marcos; Roura Martínez, David; Santos Toscano, Raquel; Capellán, Roberto; Ambrosio Flores, Emilio; Higuera Matas, Alejandro
    Rationale The development of substance use disorders involves long-lasting adaptations in specific brain areas that result in an elevated risk of relapse. Some of these adaptations are regulated by the mTOR network, a signalling system that integrates extracellular and intracellular stimuli and modulates several processes related to plasticity. While the role of the mTOR network in cocaine- and alcohol-related disorders is well established, little is known about its participation in opiate use disorders. Objectives To use a heroin self-administration and a withdrawal protocol that induce incubation of heroin-seeking in male rats and study the associated effects on the expression of several genes related to the mTOR system and, in the specific case of Rictor, its respective translated protein and phosphorylation. Results We found that heroin self-administration elicited an increase in the expression of the genes Igf1r, Igf2r, Akt2 and Gsk3a in the basolateral complex of the amygdala, which was not as evident at 30 days of withdrawal. We also found an increase in the expression of Rictor (a protein of the mTOR complex 2) after heroin self-administration compared to the saline group, which was occluded at the 30-day withdrawal period. The activation levels of Rictor, measured by the phosphorylation rate, were also reduced after heroin self-administration, an effect that seemed more apparent in the protracted withdrawal group. Conclusions These results suggest that heroin self-administration under extended access conditions modifies the expression profile of activators and components of the mTOR complexes and show a putative irresponsive mTOR complex 2 after withdrawal from heroin use.
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    Cocaine-induced Fos expression in the rat brain: Modulation by prior Δ9-tetrahydrocannabinol exposure during adolescence and sex-specific effects
    (Elsevier, 2021-04-24) Orihuel Menéndez, Javier; Gómez Rubio, Laura; Valverde, Claudia; Capellán, Roberto; Roura Martínez, David; Ucha Tortuero, Marcos; Ambrosio Flores, Emilio; Higuera Matas, Alejandro
    It has been suggested that cannabis consumption during adolescence may be an initial step to cocaine use in adulthood. Indeed, previous preclinical data show that adolescent exposure to cannabinoids (both natural and synthetic) potentiates cocaine self-administration in rats. Here we aimed at gaining a deeper understanding of the cellular activation patterns induced by cocaine as revealed by Fos imaging and how these patterns may change due to adolescent exposure to THC. Male and female Wistar rats were administered every other day THC (3 mg/kg i.p.) or vehicle from postnatal day 28–44. At adulthood (PND90) they were given an injection of cocaine (20 mg/kg i.p.) or saline and sacrificed 90 min later. Cocaine-induced Fos activation was measured by immunohistochemistry as an index of cellular activation. We found that cocaine-induced activation in the motor cortex was stronger in THC-exposed rats. Moreover, there was significant sex-dependent interaction between cocaine and adolescent THC exposure in the dorsal hypothalamus, suggesting that cocaine induced a more robust cellular activation in THC-exposed females but not in THC-treated males. Other THC- and cocaine-induced effects were also evident. These results add to the previous literature suggesting that the behavioral, cellular, molecular, and brain-activating actions of cocaine are modulated by early experience with cannabinoids and provide additional knowledge that may explain the enhanced actions of cocaine in rats exposed to cannabinoids during their adolescence.
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    The effects of combined intravenous cocaine and ethanol self-administration on the behavioral and amino acid profile of young adult rats
    (PLOS, 2020-03-23) Marcos, Alberto; Moreno, Mario; Orihuel Menéndez, Javier; Ucha Tortuero, Marcos; Paz Regidor, Ana María de; Higuera Matas, Alejandro; Capellán, Roberto; Crego, Antonio L.; Martínez Larrañaga, María Rosa; Ambrosio Flores, Emilio; Anadón, Arturo; PLOS; http://orcid.org/0000-0001-7639-6943; http://orcid.org/0000-0002-4083-5294
    Under paradigms of combined intravenous cocaine and ethanol self-administration, the effects on behavior have been poorly explored. Numerous studies have found sex differences in amino acids profile and behavioral responses to each drug, yet few have focused on the interactions between cocaine and ethanol. The main objective of this work was to explore the acquisition and maintenance of intravenous self-administration behavior with a combination of cocaine and ethanol in male and female young adult rats. Likewise, the amino acids profile in blood plasma was quantified 48 hours after the last self-administration session. Male and female 52 days old Wistar rats were randomly assigned to one of 3 groups: i) saline control, ii) cocaine (1 mg/kg bodyweight/injection) and iii) cocaine and ethanol (1 mg + 133 mg/kg bodyweight/ injection). After 24 self-administration sessions carried out on a fixed-ratio-1 schedule, with a limit of 15 doses per session, 14 plasma amino acids were quantified by mean Capillary Electrophoresis technique. The curve of cocaine and ethanol combined self-administration was similar to that associated with cocaine administration alone, with females acquiring self-administration criterion before males. The self-administration of cocaine and ethanol altered the plasma concentration and relative ratios of the aminoacid L-Tyrosine. In our intravenous self-administration model, females appeared more vulnerable to acquire abusive consumption of the cocaine and ethanol combination, which altered plasma L-Tyrosine levels.