Browsing by Author "Moya, Pablo R."

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    4-Methylthioamphetamine Increases Dopamine in the Rat Striatum and has Rewarding Effects In Vivo
    (2012) Sotomayor Zárate, Ramón Eduardo; Quiroz, Gabriel; Araya Gutiérrez, Katherine Angélica; Abarca, Jorge; Ibañez, Maria R.; Montecinos, Alejandro; Guajardo, Carlos; Nuñez, Gabriel; Fierro Huerta, Angélica; Moya, Pablo R.; Iturriaga-Vasquez, Patricio; Gomez-Molina, Cristobal; Gysling Caselli, Katia
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    Improving Amphetamine Therapeutic Selectivity: N,N-dimethyl-MTA has Dopaminergic Effects and does not Produce Aortic Contraction
    (2014) Sotomayor-Zarate, Ramon; Jara, Pablo; Araos, Patricio; Vinet, Raul; Quiroz, Gabriel; Renard, Georgina M.; Espinosa, Pedro; Hurtado-Guzman, Claudio; Moya, Pablo R.; Iturriaga-Vasquez, Patricio; Gysling, Katia; Reyes-Parada, Miguel
    Amphetamine derivatives have therapeutic potential in diseases such as attention deficit hyperactivity disorder, narcolepsy and obesity. However, their prolonged use has been associated with cardiovascular toxicity and addiction. In recent years, we have studied the pharmacological effects of amphetamine derivatives such as methylthioamphetamine (MTA) and N,N-dimethyl-thioamphetamine, with the aim of improving their therapeutic selectivity. In this work, we show that similarly to MTA, N,N-dimethyl-thioamphetamine has effects on the dopamine system, producing a significant increase in extracellular levels of dopamine (as measured by in vivo brain microdialysis) and locomotor activity, which is a behavioural measure of dopaminergic activation. However, unlike MTA, N,N-dimethyl- thioamphetamine does not produce aortic contraction in vitro. Our results show that N,N-dimethyl-thioamphetamine is a drug that retains the dopaminergic effects of amphetamine derivatives but exhibits a lower potential for producing cardiovascular side effects.
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    Ketamine-Treatment During Late Adolescence Impairs Inhibitory Synaptic Transmission in the Prefrontal Cortex and Working Memory in Adult Rats
    (2019) Angel Perez, Miguel; Morales, Camila; Santander, Odra; Garcia, Francisca; Gomez, Isabel; Penaloza-Sancho, Valentin; Fuentealba, Pablo; Dagnino-Subiabre, Alexies; Moya, Pablo R.; Fuenzalida, Marco
    Schizophrenia (SZ) is associated with changes in the structure and function of several brain areas. Several findings suggest that these impairments are related to a dysfunction in gamma-aminobutyric acid (GABA) neurotransmission in brain areas such as the medial prefrontal cortex (mPFC), the hippocampus (HPC) and the primary auditory cortex (A1); however, it is still unclear how the GABAergic system is disrupted in these brain areas. Here, we examined the effect of ketamine (Ket) administration during late adolescence in rats on inhibition in the mPFC-, ventral HPC (vHPC), and A1. We observe that Ket treatment reduced the expression of the calcium-binding protein parvalbumin (PV) and the GABA-producing enzyme glutamic acid decarboxylase 67 (GAD67) as well as decreased inhibitory synaptic efficacy in the mPFC. In addition, Ket- treated rats performed worse in executive tasks that depend on the integrity and proper functioning of the mPFC. Conversely, we do not find such changes in vHPC or A1. Together, our results provide strong experimental support for the hypothesis that during adolescence, the function of the mPFC is more susceptible than that of HPC or A1 to NMDAR hypofunction, showing apparent structure specificity. Thus, the impairment of inhibitory circuitry in mPFC could be a convergent primary site of SZ-like behavior during the adulthood.
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    Loss of protein tyrosine phosphatase receptor delta PTPRD increases the number of cortical neurons, impairs synaptic function and induces autistic-like behaviors in adult mice
    (2024) Cortés, Bastián I.; Meza, Rodrigo C.; Ancatén-González, Carlos; Ardiles, Nicolás M.; Aránguiz, María-Ignacia; Tomita, Hideaki; Kaplan, David R.; Cornejo, Francisca; Nunez-Parra, Alexia; Moya, Pablo R.; Chávez, Andrés E.; Cancino, Gonzalo I.
    Background: The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development. Loss of Ptprd expression induced an aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRβ in neural precursor cells. However, whether these alterations have long-lasting consequences in adulthood remains unknown. Results: Here, we found that in Ptprd+/- or Ptprd-/- mice, the developmental increase of excitatory neurons persists through adulthood, affecting excitatory synaptic function in the medial prefrontal cortex. Likewise, heterozygosity or homozygosity for Ptprd also induced an increase of inhibitory cortical GABAergic neurons and impaired inhibitory synaptic transmission. Lastly, Ptprd+/- or Ptprd-/- mice displayed autistic-like behaviors and no learning and memory impairments or anxiety. Conclusions: These results indicate that loss of Ptprd has long-lasting effects on cortical neuron number and synaptic function that may aberrantly impact ASD-like behaviors.
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    Protein kinase B (AKT) upregulation and Thy‑1‑αvβ3 integrin‑induced phosphorylation of Connexin43 by activated AKT in astrogliosis
    (2023) Pérez-Núñez, Ramón; Chamorro, Alejandro; González, María F.; Contreras, Pamela; Artigas Barrenechea, Rocío; Corvalán R., Alejandro; van Zundert, Brigitte; Reyes, Christopher; Moya, Pablo R.; Avalos, Ana M.; Schneider, Pascal; Quest, Andrew F. G.; Leyton, Lisette
    Background: In response to brain injury or inflammation, astrocytes undergo hypertrophy, proliferate, and migrate to the damaged zone. These changes, collectively known as "astrogliosis", initially protect the brain; however, astrogliosis can also cause neuronal dysfunction. Additionally, these astrocytes undergo intracellular changes involving alterations in the expression and localization of many proteins, including αvβ3 integrin. Our previous reports indicate that Thy-1, a neuronal glycoprotein, binds to this integrin inducing Connexin43 (Cx43) hemichannel (HC) opening, ATP release, and astrocyte migration. Despite such insight, important links and molecular events leading to astrogliosis remain to be defined. Methods: Using bioinformatics approaches, we analyzed different Gene Expression Omnibus datasets to identify changes occurring in reactive astrocytes as compared to astrocytes from the normal mouse brain. In silico analysis was validated by both qRT-PCR and immunoblotting using reactive astrocyte cultures from the normal rat brain treated with TNF and from the brain of a hSOD1G93A transgenic mouse model. We evaluated the phosphorylation of Cx43 serine residue 373 (S373) by AKT and ATP release as a functional assay for HC opening. In vivo experiments were also performed with an AKT inhibitor (AKTi). Results: The bioinformatics analysis revealed that genes of the PI3K/AKT signaling pathway were among the most significantly altered in reactive astrocytes. mRNA and protein levels of PI3K, AKT, as well as Cx43, were elevated in reactive astrocytes from normal rats and from hSOD1G93A transgenic mice, as compared to controls. In vitro, reactive astrocytes stimulated with Thy-1 responded by activating AKT, which phosphorylated S373Cx43. Increased pS373Cx43 augmented the release of ATP to the extracellular medium and AKTi inhibited these Thy-1-induced responses. Furthermore, in an in vivo model of inflammation (brain damage), AKTi decreased the levels of astrocyte reactivity markers and S373Cx43 phosphorylation. Conclusions: Here, we identify changes in the PI3K/AKT molecular signaling network and show how they participate in astrogliosis by regulating the HC protein Cx43. Moreover, because HC opening and ATP release are important in astrocyte reactivity, the phosphorylation of Cx43 by AKT and the associated increase in ATP release identify a potential therapeutic window of opportunity to limit the adverse effects of astrogliosis.