Publications by authors named "J Javier Meana"

187 Publications

α- and α-adrenoceptor expression and functionality in postmortem prefrontal cortex of schizophrenia subjects.

Eur Neuropsychopharmacol 2021 Jun 19;52:3-11. Epub 2021 Jun 19.

Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain; Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain. Electronic address:

Previous evidence suggests that α-adrenoceptors (α-AR) may be involved in the pathophysiology of schizophrenia. However, postmortem brain studies on α-AR expression and functionality in schizophrenia are scarce. The aim of our work was to evaluate α-AR and α-AR expression in different subcellular fractions of prefrontal cortex postmortem tissue from antipsychotic-free (absence of antipsychotics in blood at the time of death) (n = 12) and antipsychotic-treated (n = 12) subjects with schizophrenia, and matched controls (n = 24). Functional coupling of α-AR to G proteins induced by the agonist UK14304 was also tested. Additionally, G protein expression was also evaluated. In antipsychotic-free schizophrenia subjects, α-AR and α-AR protein expression was similar to controls in all the subcellular fractions. Conversely, in antipsychotic-treated schizophrenia subjects, increased α-AR expression was found in synaptosomal plasma membrane and postsynaptic density (PSD) fractions (+60% and +79% vs controls, respectively) with no significant changes in α-AR. [S]GTPγS SPA experiments showed a significant lower stimulation of G and G proteins by UK14304 in antipsychotic-treated schizophrenia subjects, whereas stimulation in antipsychotic-free schizophrenia subjects remained unchanged. G protein stimulation was significantly decreased in both antipsychotic-free and antipsychotic-treated schizophrenia subjects compared to controls. Expression of G protein did not differ between groups, whereas G levels were increased in PSD of schizophrenia subjects, both antipsychotic-free and antipsychotic-treated. G protein expression was increased in PSD of antipsychotic-treated subjects and in the presynaptic fraction of antipsychotic-free schizophrenia subjects. The present results suggest that antipsychotic treatment is able to modify in opposite directions both the protein expression and the functionality of α-AR in the cortex of schizophrenia patients.
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http://dx.doi.org/10.1016/j.euroneuro.2021.05.012DOI Listing
June 2021

Characterization of dopamine D receptor coupling to G proteins in postmortem brain of subjects with schizophrenia.

Pharmacol Rep 2021 Jul 1. Epub 2021 Jul 1.

Department of Pharmacology, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain.

Background: Alterations of dopamine D (D1R) and D receptor (D2R) are proposed in schizophrenia but brain neuroimaging and postmortem studies have shown controversial results in relation to D1R and D2R density. Besides, scarce information on the functionality of brain D1R and D2R is available. The present study characterized G-protein activation by D1R and D2R agonists in postmortem human brain. Furthermore, D2R functional status was compared between schizophrenia and control subjects.

Methods: G-protein receptor coupling was assessed in control caudate nucleus and frontal cortex by [S]GTPγS-binding stimulation induced by increasing concentrations (10-10 M) of dopamine, and the selective dopaminergic agonists SKF38393 (D1R) and NPA (D2R). Concentration-response curves to NPA stimulation of [S]GTPγS binding were analyzed in antipsychotic-free (n = 10) and antipsychotic-treated (n = 7) schizophrenia subjects and matched controls (n = 17).

Results: In caudate, [S]GTPγS-binding responses to agonists were compatible with the existence of functional D2R. In contrast, stimulations in cortex showed responses that did not correspond to D1R or D2R. [S]GTPγS-binding activation by NPA in caudate displayed biphasic curves with similar profile in schizophrenia (EC = 7.94 nM; EC = 7.08 μM) and control (EC = 7.24 nM; EC = 15.14 μM) subjects. The presence or absence of antipsychotic medication did not influence the pharmacological parameters.

Conclusions: Feasibility of functional evaluation of dopamine receptors in postmortem human brain by conventional [S]GTPγS-binding assays appears to be restricted to signalling through inhibitory G proteins. These findings provide functional information about brain D2R status in subjects with schizophrenia and do not support the existence of D2R supersensitive in this mental disorder.
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http://dx.doi.org/10.1007/s43440-021-00305-4DOI Listing
July 2021

Paliperidone Reversion of Maternal Immune Activation-Induced Changes on Brain Serotonin and Kynurenine Pathways.

Front Pharmacol 2021 13;12:682602. Epub 2021 May 13.

Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Bizkaia, Madrid, Spain.

Emerging evidence indicates that early-life exposure to environmental factors may increase the risk for schizophrenia via inflammatory mechanisms. Inflammation can alter the metabolism of tryptophan through the oxidative kynurenine pathway to compounds with neurotoxic and neuroprotective activity and compromise serotonin (5-HT) synthesis. Here we investigate the role of serotonergic and kynurenine pathways in the maternal immune activation (MIA) animal model of schizophrenia. The potential reversion exerted by long-term antipsychotic treatment was also evaluated. MIA was induced by prenatal administration of polyinosinic:polycytidylic acid (poly (I:C)) in mice. Expression of different proteins and the content of different metabolites involved in the function of serotonergic and kynurenine pathways was assessed by RT-PCR, immunoblot and ELISA analyses in frontal cortex of the offspring after puberty. MIA decreased tissue 5-HT content and promoted changes in the expression of serotonin transporter, 5-HT and 5-HT receptors. Expression of indoleamine 2,3-dioxygenase 2 (IDO2) and kynurenine 3-monooxygenase (KMO) was increased by poly (I:C) whereas kynurenine aminotransferase II and its metabolite kynurenic acid were not altered. Long-term paliperidone was able to counteract MIA-induced changes in 5-HT and KMO, and to increase tryptophan availability and tryptophan hydroxylase-2 expression in poly (I:C) mice but not in controls. MIA-induced increase of the cytotoxic risk ratio of kynurenine metabolites (quinolinic/kynurenic acid) was also reversed by paliperidone. MIA induces specific long-term brain effects on serotonergic activity. Such effects seem to be related with alternative activation of the kynurenine metabolic pathway towards a cytotoxic status. Atypical antipsychotic paliperodine partially remediates abnormalities observed after MIA.
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http://dx.doi.org/10.3389/fphar.2021.682602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156415PMC
May 2021

Opposite alterations of 5-HT receptor brain density in subjects with schizophrenia: relevance of radiotracers pharmacological profile.

Transl Psychiatry 2021 05 20;11(1):302. Epub 2021 May 20.

Department of Pharmacology, University of the Basque Country, Leioa, Bizkaia, Spain.

The status of serotonin 5-HT receptors (5-HTRs) in schizophrenia has been controversial. In vivo positron emission tomography neuroimaging and in vitro post-mortem binding studies have reported conflicting results about 5-HTR density. Radiotracers bind different receptor conformations depending on their agonist, antagonist or inverse agonist properties. This study investigates 5-HTR density in the post-mortem prefrontal cortex from subjects with schizophrenia and controls using three radiotracers with a different pharmacological profile. The specific binding parameters of the inverse agonist [F]altanserin, the agonist [H]lysergic acid diethylamide (LSD) and the antagonist [H]MDL100907 to brain cortex membranes from 20 subjects with schizophrenia and 20 individually matched controls were evaluated under similar methodological conditions. Ten schizophrenia subjects were antipsychotic-free at death. Saturation curve analyses were performed by non-linear regression to obtain a maximal density of binding sites (B) and the affinity of the respective radiotracers (K). In schizophrenia subjects, 5-HTR density was decreased when quantified by [F]altanserin binding, whereas increased when evaluated by [H]LSD binding. However, [H]MDL100907 binding was unaltered. A slight loss of affinity (higher K) was observed exclusively in [H]LSD binding. The findings were more evident in antipsychotic-free subjects than in antipsychotic-treated subjects. In conclusion, a higher proportion of the 5-HTR-active functional conformation, which is rather identified by agonist radiotracers, was observed in schizophrenia patients. A consequent reduction of the inactive 5-HTR conformation, which is preferentially identified by inverse agonist radiotracers, was also obtained. Antagonist radiotracers do not distinguish between molecular conformations of the receptor, and accordingly, the absence of changes was shown. These results are compatible with the proposed increased functional activity of brain cortical 5-HTRs in schizophrenia.
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http://dx.doi.org/10.1038/s41398-021-01430-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137947PMC
May 2021

Correction to: Functional approaches to the study of G-protein-coupled receptors in postmortem brain tissue: [S]GTPγS binding assays combined with immunoprecipitation.

Pharmacol Rep 2021 May 6. Epub 2021 May 6.

Department of Pharmacology, Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain.

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http://dx.doi.org/10.1007/s43440-021-00268-6DOI Listing
May 2021
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