J. Meana - Academia.edu (original) (raw)
Papers by J. Meana
The psychosis associated with schizophrenia is characterized by alterations in sensory processing... more The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception1,2. Some antipsychotic drugs were identified by their high affinity for serotonin 5HT2A receptors (2AR)3,4. Drugs that interact with metabotropic glutamate receptors (mGluR) also show potential for the treatment of schizophrenia5-7. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide (LSD), require the 2AR8-10 and resemble some of the core symptoms of schizophrenia10-12. Here we show that the mGluR2 interacts via specific transmembrane helix domains with the 2AR, a member of an unrelated G protein-coupled receptor (GPCR) family, to form functional complexes in brain cortex. The 2AR/mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen specific signalling and behavioural responses. In postmortem human brain from untreated schizophrenic subjects, the 2AR is ...
European Neuropsychopharmacology, 2015
Current Neuropharmacology, 2006
Schizophrenia Research, 2015
human prefrontal cortex schizophrenia major depression 14-3-3 proteins Western blot 14-3-3 is a f... more human prefrontal cortex schizophrenia major depression 14-3-3 proteins Western blot 14-3-3 is a family of conserved regulatory proteins that bind to a multitude of functionally diverse signalling proteins. Various genetic studies and gene expression and proteomic analyses have involved 14-3-3 proteins in schizophrenia (SZ). On the other hand, studies about the status of these proteins in major depressive disorder (MD) are still missing. Immunoreactivity values of cytosolic 14-3-3β and 14-3-3ζ proteins were evaluated by Western blot in prefrontal cortex (PFC) of subjects with schizophrenia (SZ; n = 22), subjects with major depressive disorder (MD; n = 21) and age-, gender-and postmortem delay-matched control subjects (n = 52). The modulation of 14-3-3β and 14-3-3ζ proteins by psychotropic medication was also assessed. The analysis of both proteins in SZ subjects with respect to matched control subjects showed increased 14-3-3β (Δ=33 ± 10%, p b 0.05) and 14-3-3ζ (Δ=29 ± 6%, p b 0.05) immunoreactivity in antipsychotic-free but not in antipsychotic-treated SZ subjects. Immunoreactivity values of 14-3-3β and 14-3-3ζ were not altered in MD subjects. These results show the specific up-regulation of 14-3-3β and 14-3-3ζ proteins in PFC of SZ subjects and suggest a possible down-regulation of both proteins by antipsychotic treatment.
Journal of Affective Disorders, 2014
![Research paper thumbnail of Increased [3H] raclopride binding sites in postmortem brains from schizophrenic violent suicide victims](https://attachments.academia-assets.com/117656492/thumbnails/1.jpg)
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Psychopharmacology, 2013
Rationale Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance s... more Rationale Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance serotonergic neurotransmission, are able to modulate other brain systems involved in depression. Objectives This study evaluates the neurochemical effect of the SSRI citalopram on brain noradrenergic activity and the serotonin receptor involved in this effect. Methods Dual-probe microdialysis in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely awake rats. Results Systemic citalopram (10 mg/kg, i.p.) increased noradrenaline (NA) in the LC (E max =141±13 %) and simultaneously decreased NA in the PFC (E max =−46±7 %). In the local presence into the LC of the α 2-adrenoceptor antagonist RS79948 (1 μM), systemic citalopram increased NA in the LC (E max =157±25 %) and PFC (E max =175±24 %). Local citalopram (0.1-100 μM) into the LC induced NA increase in the LC (E max =210±25 %) and decrease in the PFC (E max =−38±9 %). Local LC citalopram effect was abolished by LC presence of the 5-HT 3 receptor antagonist MDL72222 (1 μM) but not the 5-HT 1/2 receptor antagonist methiothepin (1 μM). Systemic citalopram in the LC presence of MDL72222 did not modify NA in the LC but increased NA in the PFC (E max =158±26 %). Local citalopram into the PFC enhanced NA (E max =376±18 %) in the area, which was prevented by MDL72222. Conclusions The SSRI citalopram modulates central noradrenergic neurotransmission by activation, through endogenous serotonin, of 5-HT 3 receptors expressed in the somatodendritic (LC) and terminal (PFC) areas, which subsequently promote an enhancement of local NA. Therefore, 5-HT 3 receptors and somatodendritic α 2-adrenoceptors in the LC play an important role in the global effect of SSRIs.
Psychopharmacology, 1994
The biochemical status of human brain gopioid receptors and e2-adrenoceptors during opiate depend... more The biochemical status of human brain gopioid receptors and e2-adrenoceptors during opiate dependence was studied by means of the binding of [-3HI [D-Ala 2, MePhe 4, Gly-ol s] enkephalin (DAGO) and [aH]clonidine, respectively, in postmortem brains of heroin addicts who had died by opiate overdose or other causes. In the frontal cortex, thalamus and caudate of heroin addicts the density ~m,x) and affinity (KD) of gopioid receptors were similar to those in controls. In contrast, the density of ez-adrenoceptors in heroin addicts was found to be significantly decreased in frontal cortex (Bm,x 31% lower), hypothalamus (Bm~x 40% lower) and caudate (Bmax 32% lower) without changes in KD values. When heroin addicts were divided into two subgroups according to the presence or absence of morphine in body fluids, only the group with positive screening for morphine showed relevant decreases in brain c%-adrenoceptor density (Bma x 36-48% lower), whereas the decreases in receptor density observed in the subgroup with negative screening for morphine did not reach statistical significance. The results suggest that desensitization of brain e2g-adrenceptors is a relevant adaptative receptor mechanism during opiate addiction in humans.
Psychopharmacology, 2009
Dopamine D2 receptors are the main target of antipsychotic drugs. In the brain, D2 receptors coex... more Dopamine D2 receptors are the main target of antipsychotic drugs. In the brain, D2 receptors coexpress with adenosine A2A and CB1 cannabinoid receptors, leading to functional interactions. The protein and messenger RNA (mRNA) contents of A2A, D2, and CB1 receptors were quantified in postmortem prefrontal cortex of subjects with schizophrenia. The study was performed in subjects suffering schizophrenia (n=31) who mainly died by suicide, matched with non-schizophrenia suicide victims (n=13) and non-suicide controls (n=33). The density of receptor proteins was evaluated by immunodetection techniques, and their relative mRNA expression was quantified by quantitative real-time polymerase chain reaction. In schizophrenia, the densities of A2A (90+/-6%, n=24) and D2-like receptors (95+/-5%, n=22) did not differ from those in controls (100%). Antipsychotic treatment did not induce changes in the protein expression. In contrast, the immunodensity of CB1 receptors was significantly decreased (71+/-7%, n=11; p<0.05) in antipsychotic-treated subjects with schizophrenia but not in drug-free subjects (104+/-13%, n=11). The relative mRNA amounts encoding for A2A, D2, and CB1 receptors were similar in brains of drug-free, antipsychotic-treated subjects with schizophrenia and controls. The findings suggest that antipsychotics induce down-regulation of CB1 receptors in brain. Since A2A, D2, and CB1 receptors coexpress on brain GABAergic neurons and reductions in markers of GABA neurotransmission have been identified in schizophrenia, a lower density of CB1 receptor induced by antipsychotics could represent an adaptative mechanism that reduces the endocannabinoid-mediated suppression of GABA release, contributing to the normalization of cognitive functions in the disorder.
Journal of Psychiatric Research, 2013
Negative symptoms are the most resilient manifestations in schizophrenia. An imbalance in dopamin... more Negative symptoms are the most resilient manifestations in schizophrenia. An imbalance in dopamine and glutamate pathways has been proposed for the emergence of these symptoms. SP1, SP3 and SP4 transcription factors regulate genes in these pathways, suggesting a possible involvement in negative symptoms. In this study, we characterized Sp factors in the brains of subjects with schizophrenia and explored a possible association with negative symptoms. We also included analysis of NR1, NR2A and DRD2 as Sp target genes. Postmortem cerebellum and prefrontal cortex from an antemortem clinically well-characterized and controlled collection of elderly subjects with chronic schizophrenia (n = 16) and control individuals (n = 14) were examined. We used the Positive and Negative Syndrome and the Clinical Global Impression Schizophrenia scales, quantitative PCR and immunoblot. SP1 protein and mRNA were reduced in the prefrontal cortex in schizophrenia whereas none of Sp factors were altered in the cerebellum. However, we found that SP1, SP3 and SP4 protein levels inversely correlated with negative symptoms in the cerebellum. Furthermore, NR2A and DRD2 mRNA levels correlated with negative symptoms in the cerebellum. In the prefrontal cortex, SP1 mRNA and NR1 and DRD2 inversely correlated with these symptoms while Sp protein levels did not. This pilot study not only reinforces the involvement of SP1 in schizophrenia, but also suggests that reduced levels or function of SP1, SP4 and SP3 may participate in negative symptoms, in part through the regulation of NMDA receptor subunits and/or Dopamine D2 receptor, providing novel information about the complex negative symptoms in this disorder.
European Neuropsychopharmacology, 2009
Clinical Neuropharmacology, 1992
Biological Psychiatry, 2013
Annals of the New York Academy of Sciences, 1999
Bipolar Disorders, 2011
Pinacho R, Villalmanzo N, Lalonde J, Haro JM, Meana JJ, Gill G, Ramos B. The transcription factor... more Pinacho R, Villalmanzo N, Lalonde J, Haro JM, Meana JJ, Gill G, Ramos B. The transcription factor SP4 is reduced in postmortem cerebellum of bipolar disorder subjects: control by depolarization and lithium. Bipolar Disord 2011: 13: 474–485. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S.Objectives: Regulation of gene expression is important for the development and function of the nervous system. However, the transcriptional programs altered in psychiatric diseases are not completely characterized. Human gene association studies and analysis of mutant mice suggest that the transcription factor specificity protein 4 (SP4) may be implicated in the pathophysiology of psychiatric diseases. We hypothesized that SP4 levels may be altered in the brain of bipolar disorder (BD) subjects and regulated by neuronal activity and drug treatment.Methods: We analyzed messenger RNA (mRNA) and protein levels of SP4 and SP1 in the postmortem prefrontal cortex and cerebellum of B...
Trastornos Adictivos, 2005
ObjectivesThe development of an scientific-based opinion on buprenorphine safety in opiate depend... more ObjectivesThe development of an scientific-based opinion on buprenorphine safety in opiate dependence.
The psychosis associated with schizophrenia is characterized by alterations in sensory processing... more The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception1,2. Some antipsychotic drugs were identified by their high affinity for serotonin 5HT2A receptors (2AR)3,4. Drugs that interact with metabotropic glutamate receptors (mGluR) also show potential for the treatment of schizophrenia5-7. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide (LSD), require the 2AR8-10 and resemble some of the core symptoms of schizophrenia10-12. Here we show that the mGluR2 interacts via specific transmembrane helix domains with the 2AR, a member of an unrelated G protein-coupled receptor (GPCR) family, to form functional complexes in brain cortex. The 2AR/mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen specific signalling and behavioural responses. In postmortem human brain from untreated schizophrenic subjects, the 2AR is ...
European Neuropsychopharmacology, 2015
Current Neuropharmacology, 2006
Schizophrenia Research, 2015
human prefrontal cortex schizophrenia major depression 14-3-3 proteins Western blot 14-3-3 is a f... more human prefrontal cortex schizophrenia major depression 14-3-3 proteins Western blot 14-3-3 is a family of conserved regulatory proteins that bind to a multitude of functionally diverse signalling proteins. Various genetic studies and gene expression and proteomic analyses have involved 14-3-3 proteins in schizophrenia (SZ). On the other hand, studies about the status of these proteins in major depressive disorder (MD) are still missing. Immunoreactivity values of cytosolic 14-3-3β and 14-3-3ζ proteins were evaluated by Western blot in prefrontal cortex (PFC) of subjects with schizophrenia (SZ; n = 22), subjects with major depressive disorder (MD; n = 21) and age-, gender-and postmortem delay-matched control subjects (n = 52). The modulation of 14-3-3β and 14-3-3ζ proteins by psychotropic medication was also assessed. The analysis of both proteins in SZ subjects with respect to matched control subjects showed increased 14-3-3β (Δ=33 ± 10%, p b 0.05) and 14-3-3ζ (Δ=29 ± 6%, p b 0.05) immunoreactivity in antipsychotic-free but not in antipsychotic-treated SZ subjects. Immunoreactivity values of 14-3-3β and 14-3-3ζ were not altered in MD subjects. These results show the specific up-regulation of 14-3-3β and 14-3-3ζ proteins in PFC of SZ subjects and suggest a possible down-regulation of both proteins by antipsychotic treatment.
Journal of Affective Disorders, 2014
Psychopharmacology, 2013
Rationale Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance s... more Rationale Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance serotonergic neurotransmission, are able to modulate other brain systems involved in depression. Objectives This study evaluates the neurochemical effect of the SSRI citalopram on brain noradrenergic activity and the serotonin receptor involved in this effect. Methods Dual-probe microdialysis in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely awake rats. Results Systemic citalopram (10 mg/kg, i.p.) increased noradrenaline (NA) in the LC (E max =141±13 %) and simultaneously decreased NA in the PFC (E max =−46±7 %). In the local presence into the LC of the α 2-adrenoceptor antagonist RS79948 (1 μM), systemic citalopram increased NA in the LC (E max =157±25 %) and PFC (E max =175±24 %). Local citalopram (0.1-100 μM) into the LC induced NA increase in the LC (E max =210±25 %) and decrease in the PFC (E max =−38±9 %). Local LC citalopram effect was abolished by LC presence of the 5-HT 3 receptor antagonist MDL72222 (1 μM) but not the 5-HT 1/2 receptor antagonist methiothepin (1 μM). Systemic citalopram in the LC presence of MDL72222 did not modify NA in the LC but increased NA in the PFC (E max =158±26 %). Local citalopram into the PFC enhanced NA (E max =376±18 %) in the area, which was prevented by MDL72222. Conclusions The SSRI citalopram modulates central noradrenergic neurotransmission by activation, through endogenous serotonin, of 5-HT 3 receptors expressed in the somatodendritic (LC) and terminal (PFC) areas, which subsequently promote an enhancement of local NA. Therefore, 5-HT 3 receptors and somatodendritic α 2-adrenoceptors in the LC play an important role in the global effect of SSRIs.
Psychopharmacology, 1994
The biochemical status of human brain gopioid receptors and e2-adrenoceptors during opiate depend... more The biochemical status of human brain gopioid receptors and e2-adrenoceptors during opiate dependence was studied by means of the binding of [-3HI [D-Ala 2, MePhe 4, Gly-ol s] enkephalin (DAGO) and [aH]clonidine, respectively, in postmortem brains of heroin addicts who had died by opiate overdose or other causes. In the frontal cortex, thalamus and caudate of heroin addicts the density ~m,x) and affinity (KD) of gopioid receptors were similar to those in controls. In contrast, the density of ez-adrenoceptors in heroin addicts was found to be significantly decreased in frontal cortex (Bm,x 31% lower), hypothalamus (Bm~x 40% lower) and caudate (Bmax 32% lower) without changes in KD values. When heroin addicts were divided into two subgroups according to the presence or absence of morphine in body fluids, only the group with positive screening for morphine showed relevant decreases in brain c%-adrenoceptor density (Bma x 36-48% lower), whereas the decreases in receptor density observed in the subgroup with negative screening for morphine did not reach statistical significance. The results suggest that desensitization of brain e2g-adrenceptors is a relevant adaptative receptor mechanism during opiate addiction in humans.
Psychopharmacology, 2009
Dopamine D2 receptors are the main target of antipsychotic drugs. In the brain, D2 receptors coex... more Dopamine D2 receptors are the main target of antipsychotic drugs. In the brain, D2 receptors coexpress with adenosine A2A and CB1 cannabinoid receptors, leading to functional interactions. The protein and messenger RNA (mRNA) contents of A2A, D2, and CB1 receptors were quantified in postmortem prefrontal cortex of subjects with schizophrenia. The study was performed in subjects suffering schizophrenia (n=31) who mainly died by suicide, matched with non-schizophrenia suicide victims (n=13) and non-suicide controls (n=33). The density of receptor proteins was evaluated by immunodetection techniques, and their relative mRNA expression was quantified by quantitative real-time polymerase chain reaction. In schizophrenia, the densities of A2A (90+/-6%, n=24) and D2-like receptors (95+/-5%, n=22) did not differ from those in controls (100%). Antipsychotic treatment did not induce changes in the protein expression. In contrast, the immunodensity of CB1 receptors was significantly decreased (71+/-7%, n=11; p<0.05) in antipsychotic-treated subjects with schizophrenia but not in drug-free subjects (104+/-13%, n=11). The relative mRNA amounts encoding for A2A, D2, and CB1 receptors were similar in brains of drug-free, antipsychotic-treated subjects with schizophrenia and controls. The findings suggest that antipsychotics induce down-regulation of CB1 receptors in brain. Since A2A, D2, and CB1 receptors coexpress on brain GABAergic neurons and reductions in markers of GABA neurotransmission have been identified in schizophrenia, a lower density of CB1 receptor induced by antipsychotics could represent an adaptative mechanism that reduces the endocannabinoid-mediated suppression of GABA release, contributing to the normalization of cognitive functions in the disorder.
Journal of Psychiatric Research, 2013
Negative symptoms are the most resilient manifestations in schizophrenia. An imbalance in dopamin... more Negative symptoms are the most resilient manifestations in schizophrenia. An imbalance in dopamine and glutamate pathways has been proposed for the emergence of these symptoms. SP1, SP3 and SP4 transcription factors regulate genes in these pathways, suggesting a possible involvement in negative symptoms. In this study, we characterized Sp factors in the brains of subjects with schizophrenia and explored a possible association with negative symptoms. We also included analysis of NR1, NR2A and DRD2 as Sp target genes. Postmortem cerebellum and prefrontal cortex from an antemortem clinically well-characterized and controlled collection of elderly subjects with chronic schizophrenia (n = 16) and control individuals (n = 14) were examined. We used the Positive and Negative Syndrome and the Clinical Global Impression Schizophrenia scales, quantitative PCR and immunoblot. SP1 protein and mRNA were reduced in the prefrontal cortex in schizophrenia whereas none of Sp factors were altered in the cerebellum. However, we found that SP1, SP3 and SP4 protein levels inversely correlated with negative symptoms in the cerebellum. Furthermore, NR2A and DRD2 mRNA levels correlated with negative symptoms in the cerebellum. In the prefrontal cortex, SP1 mRNA and NR1 and DRD2 inversely correlated with these symptoms while Sp protein levels did not. This pilot study not only reinforces the involvement of SP1 in schizophrenia, but also suggests that reduced levels or function of SP1, SP4 and SP3 may participate in negative symptoms, in part through the regulation of NMDA receptor subunits and/or Dopamine D2 receptor, providing novel information about the complex negative symptoms in this disorder.
European Neuropsychopharmacology, 2009
Clinical Neuropharmacology, 1992
Biological Psychiatry, 2013
Annals of the New York Academy of Sciences, 1999
Bipolar Disorders, 2011
Pinacho R, Villalmanzo N, Lalonde J, Haro JM, Meana JJ, Gill G, Ramos B. The transcription factor... more Pinacho R, Villalmanzo N, Lalonde J, Haro JM, Meana JJ, Gill G, Ramos B. The transcription factor SP4 is reduced in postmortem cerebellum of bipolar disorder subjects: control by depolarization and lithium. Bipolar Disord 2011: 13: 474–485. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S.Objectives: Regulation of gene expression is important for the development and function of the nervous system. However, the transcriptional programs altered in psychiatric diseases are not completely characterized. Human gene association studies and analysis of mutant mice suggest that the transcription factor specificity protein 4 (SP4) may be implicated in the pathophysiology of psychiatric diseases. We hypothesized that SP4 levels may be altered in the brain of bipolar disorder (BD) subjects and regulated by neuronal activity and drug treatment.Methods: We analyzed messenger RNA (mRNA) and protein levels of SP4 and SP1 in the postmortem prefrontal cortex and cerebellum of B...
Trastornos Adictivos, 2005
ObjectivesThe development of an scientific-based opinion on buprenorphine safety in opiate depend... more ObjectivesThe development of an scientific-based opinion on buprenorphine safety in opiate dependence.