Selective enhancement of mesocortical dopaminergic transmission by noradrenergic drugs: therapeutic opportunities in schizophrenia

The superior efficacy of atypical vs. classical antipsychotic drugs to treat negative symptoms and cognitive deficits in schizophrenia appears related to their ability to enhance mesocortical dopamine (DA) function. Given that noradrenergic (NE) transmission contributes to cortical DA output, we assessed the ability of NE-targeting drugs to modulate DA release in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), with the aim of selectively increasing mesocortical DA. Extracellular DA was measured using brain microdialysis in rat mPFC and NAc after local/systemic drug administration, electrical stimulation and selective brain lesions. Local GBR12909 [a selective DA transporter (DAT) inhibitor] administration increased DA output more in NAc than in mPFC whereas reboxetine [a selective NE transporter (NET) inhibitor] had an opposite regional profile. DA levels increased comparably in both regions of control rats after local nomifensine (DAT+NET inhibitor) infusion, but this effect was much lower in PFC of NE-lesioned rats (DSP-4) and in NAc of 6-OHDA-lesioned rats. Electrical stimulation of the locus coeruleus preferentially enhanced DA output in mPFC. Consistently, the administration of reboxetine+RX821002 (an α2-adrenoceptor antagonist) dramatically enhanced DA output in mPFC (but not NAc). This effect also occurred when reboxetine+RX821002 were co-administered with haloperidol or clozapine. The preferential contribution of the NE system to PFC DA allows selective enhancement of DA transmission by simultaneously blocking NET and α2-adrenoceptors, thus preventing the autoreceptor-mediated negative feedback on NE activity. Our results highlight the importance of NET and α2-adrenoceptors as targets for treating negative/cognitive symptoms in schizophrenia and related psychiatric disorders.This work was supported by grant SAF 2007-62378 (MICIN, Spain). Support from SENY Fundació is also acknowledged. M.M. is a recipient of a predoctoral fellowship from CSIC (I3P programme). A.B. is supported by the research stabilization programme of the Health Department of Generalitat de Catalunya.Peer reviewe

Biomarkers predicting antidepressant treatment response - how can we advance the field?

Major depression, affecting an estimated 350 million people worldwide, poses a serious social and economic threat to modern societies. There are currently two major problems calling for innovative research approaches, namely, the absence of biomarkers predicting antidepressant response and the lack of conceptually novel antidepressant compounds. Both, biomarker predicting a priori whether an individual patient will respond to the treatment of choice as well as an early distinction of responders and nonresponders during antidepressant therapy can have a significant impact on improving this situation. Biosignatures predicting antidepressant response a priori or early in treatment would enable an evidence-based decision making on available treatment options. However, research to date does not identify any biologic or genetic predictors of sufficient clinical utility to inform the selection of specific antidepressant compound for an individual patient. In this review, we propose an optimized translational research strategy to overcome some of the major limitations in biomarker discovery. We are confident that early transfer and integration of data between both species, ideally leading to mutual supportive evidence from both preclinical and clinical studies, are most suitable to address some of the obstacles of current depression research

Selective Enhancement of Mesocortical Dopaminergic Transmission by Noradrenergic Drugs: Therapeutic Opportunities in Schizophrenia

The superior efficacy of atypical vs. classical antipsychotic drugs to treat negative symptoms and cognitive deficits in schizophrenia appears related to their ability to enhance mesocortical dopamine (DA) function. Given that noradrenergic (NE) transmission contributes to cortical DA output, we assessed the ability of NE-targeting drugs to modulate DA release in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), with the aim of selectively increasing mesocortical DA. Extracellular DA was measured using brain microdialysis in rat mPFC and NAc after local/systemic drug administration, electrical stimulation and selective brain lesions. Local GBR12909 [a selective DA transporter (DAT) inhibitor] administration increased DA output more in NAc than in mPFC whereas reboxetine [a selective NE transporter (NET) inhibitor] had an opposite regional profile. DA levels increased comparably in both regions of control rats after local nomifensine (DAT+NET inhibitor) infusion, but this effect was much lower in PFC of NE-lesioned rats (DSP-4) and in NAc of 6-OHDA-lesioned rats. Electrical stimulation of the locus coeruleus preferentially enhanced DA output in mPFC. Consistently, the administration of reboxetine+RX821002 (an α2-adrenoceptor antagonist) dramatically enhanced DA output in mPFC (but not NAc). This effect also occurred when reboxetine+RX821002 were co-administered with haloperidol or clozapine. The preferential contribution of the NE system to PFC DA allows selective enhancement of DA transmission by simultaneously blocking NET and α2-adrenoceptors, thus preventing the autoreceptor-mediated negative feedback on NE activity. Our results highlight the importance of NET and α2-adrenoceptors as targets for treating negative/cognitive symptoms in schizophrenia and related psychiatric disorders

Proceedings of the tenth international meeting on neuroacanthocytosis syndromes

The 10th International Meeting on Neuroacanthocytosis Syndromes was held online on March 10th12th, 2021. The COVID19 pandemic situation made our planned meeting in Barcelona on March 2020 to be suspended by one year, and finally took place online. The meeting followed the previous nine international symposia, the last of which was held in Dresden, Germany in March, 2018. The setting of the meeting encouraged interactions, exchange of ideas and networking opportunities among the high number of participants from around the globe, including scientists, neurologists and specially patients and caregivers. A total of 27 oral communications were distributed in 8 sessions with topics ranging from molecular and cellular functions of VPS13 genes and proteins, their involvement in Neuroacanthocytosis Syndromes and finally clinical aspects and patients care. In addition, 5 posters were presented. Altogether, scientists and neurologists discussed recent advances and set the bases for next steps, action points, and future studies in close collaboration with the patients associations, which are always actively involved in the whole process

Application of a Neural Network classifier for the generation of clean Small Magellanic Cloud stellar samples

Context. Previous attempts to separate Small Magellanic Cloud (SMC) stars from the Milky Way (MW) foreground stars are based only on the proper motions of the stars. Aims. In this paper, we aim to develop a statistical classification technique to effectively separate the SMC stars from the MW stars using a wider set of Gaia data. We aim to reduce the possible contamination from MW stars compared to previous strategies. Methods. The new strategy is based on a neural network classifier, applied to the bulk of the Gaia DR3 data. We produce three samples of stars flagged as SMC members, with varying levels of completeness and purity, obtained by application of this classifier. Using different test samples, we validated these classification results and compared them with the results of the selection technique employed in the Gaia Collaboration papers, which was based solely on the proper motions. Results. The contamination of the MW in each of the three SMC samples is estimated to be in the 10–40% range; the “best case” in this range is obtained for bright stars (G < 16), which belong to the Vlos sub-samples, and the “worst case” for the full SMC sample determined by using very stringent criteria based on StarHorse distances. A further check based on the comparison with a nearby area with uniform sky density indicates that the global contamination in our samples is probably close to the low end of the range, around 10%. Conclusions. We provide three selections of SMC star samples with different degrees of purity and completeness, for which we estimate a low contamination level and which we have successfully validated using SMC RR Lyrae, SMC Cepheids, and SMC-MW StarHorse samples

Dopamine neurotransmission and atypical antipsychotics in prefrontal cortex: a critical review

Schizophrenia has been historically characterized by the presence of positive symptomatology, however, decades of research highlight the importance of cognitive deficits in this disorder. At present, cognitive impairments remain one of the most important unmet therapeutic needs in schizophrenia. The prefrontal cortex (PFC) controls a large number of higher brain functions altered in a variety of psychiatric disorders, including schizophrenia. Histological studies indicate the presence of a large proportion of PFC neurons expressing monoaminergic receptors sensitive to the action of current atypical antipsychotics. Functional studies also show that these medications act at PFC level to increase dopamine neurotransmission in the mesocortical pathway. Here we focus on monoaminergic molecular targets that are actively being explored as potential therapeutic agents in the basic and clinical cognitive neuroscience research, to support the development of co-treatments used in conjunction with antipsychotic medications. These targets include dopamine and serotonin receptors in the prefrontal cortex, as well as elements of the noradrenergic system

Social Memory and Social Patterns Alterations in the Absence of STriatal-Enriched Protein Tyrosine Phosphatase

STriatal-Enriched protein tyrosine Phosphatase (STEP) is a neural-specific protein that opposes the development of synaptic strengthening and whose levels are altered in several neurodegenerative and psychiatric disorders. Since STEP is expressed in brain regions implicated in social behavior, namely the striatum, the CA2 region of the hippocampus, cortex and amygdala, here we investigated whether social memory and social patterns were altered in STEP knockout (KO) mice. Our data robustly demonstrated that STEP KO mice presented specific social memory impairment as indicated by the three-chamber sociability test, the social discrimination test, the 11-trial habituation/dishabituation social recognition test, and the novel object recognition test (NORT). This affectation was not related to deficiencies in the detection of social olfactory cues, altered sociability or anxiety levels. However, STEP KO mice showed lower exploratory activity, reduced interaction time with an intruder, less dominant behavior and higher immobility time in the tail suspension test than controls, suggesting alterations in motivation. Moreover, the extracellular levels of dopamine (DA), but not serotonin (5-HT), were increased in the dorsal striatum of STEP KO mice. Overall, our results indicate that STEP deficiency disrupts social memory and other social behaviors as well as DA homeostasis in the dorsal striatum

Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT1A receptors but not 5-HT2A receptors

Atypical antipsychotic drugs (APDs) increase dopamine (DA) release in prefrontal cortex (PFC), an effect probably mediated by the direct or indirect activation of the 5-HT1A receptor (5-HT1AR). Given the very low in-vitro affinity of most APDs for 5-HT1ARs and the large co-expression of 5-HT1ARs and 5-HT2A receptors (5-HT2ARs) in the PFC, this effect might result from the imbalance of 5-HT1AR and 5-HT2AR activation after blockade of these receptors by APDs, for which they show high affinity. Here we tested this hypothesis by examining the dependence of the APD-induced DA release in medial PFC (mPFC) on each receptor by using in-vivo microdialysis in wild-type (WT) and 5-HT1AR and 5-HT2AR knockout (KO) mice. Local APDs (clozapine, olanzapine, risperidone) administered by reverse dialysis induced a dose-dependent increase in mPFC DA output equally in WT and 5-HT2AR KO mice whereas the DA increase was absent in 5-HT1AR KO mice. To examine the relative contribution of both receptors to the clozapine-induced DA release in rat mPFC, we silenced G-protein-coupled receptors (GPCRs) in vivo with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) while 5-HT 1ARs or 5-HT2A/2CRs in the mPFC were selectively protected with the respective antagonists WAY-100635 or ritanserin. The inactivation of GPCRs while preserving ∼70% of 5-HT2A/2CRs prevented the clozapine-induced DA rise in mPFC. In contrast, clozapine increased DA in mPFC of EEDQ-treated rats whose 5-HT1ARs were protected (∼50% of control rats). These results indicate that (1) 5-HT1ARs are necessary for the APDs-induced elevation in cortical DA transmission, and (2) this effect does not require 5-HT2AR blockade by APDs. © 2010 CINP.This work was supported by grants SAF 2007-62378 and SENY Fundació. A. B. is recipient of a Ramón y Cajal contract from MICINN-IDIBAPS. M. M. is a recipient of a predoctoral fellowship from CSIC (I3P program).Peer Reviewe

The stress-inducible protein DRR1 exerts distinct effects on actin dynamics

Cytoskeletal dynamics are pivotal to memory, learning, and stress physiology, and thus psychiatric diseases. Downregulated in renal cell carcinoma 1 (DRR1) protein was characterized as the link between stress, actin dynamics, neuronal function, and cognition. To elucidate the underlying molecular mechanisms, we undertook a domain analysis of DRR1 and probed the effects on actin binding, polymerization, and bundling, as well as on actin-dependent cellular processes. METHODS: DRR1 domains were cloned and expressed as recombinant proteins to perform in vitro analysis of actin dynamics (binding, bundling, polymerization, and nucleation). Cellular actin-dependent processes were analyzed in transfected HeLa cells with fluorescence recovery after photobleaching (FRAP) and confocal microscopy. RESULTS: DRR1 features an actin binding site at each terminus, separated by a coiled coil domain. DRR1 enhances actin bundling, the cellular F-actin content, and serum response factor (SRF)-dependent transcription, while it diminishes actin filament elongation, cell spreading, and actin treadmilling. We also provide evidence for a nucleation effect of DRR1. Blocking of pointed end elongation by addition of profilin indicates DRR1 as a novel barbed end capping factor. CONCLUSIONS: DRR1 impacts actin dynamics in several ways with implications for cytoskeletal dynamics in stress physiology and pathophysiology

Dopamine Release Induced by Atypical Antipsychotics in Prefrontal Cortex Requires 5-HT(1A) Receptors but Not 5-HT(2A) Receptors

Atypical antipsychotic drugs (APDs) increase dopamine (DA) release in prefrontal cortex (PFC), an effect probably mediated by the direct or indirect activation of the 5-HT(1A) receptor (5-HT(1A)R). Given the very low in-vitro affinity of most APDs for 5-HT(1A)Rs and the large co-expression of 5-HT(1A)Rs and 5-HT(2A) receptors (5-HT(2A)Rs) in the PFC, this effect might result from the imbalance of 5-HT(1A)R and 5-HT(2A)R activation after blockade of these receptors by APDs, for which they show high affinity. Here we tested this hypothesis by examining the dependence of the APD-induced DA release in medial PFC (mPFC) on each receptor by using in-vivo microdialysis in wild-type (WT) and 5-HT(1A)R and 5-HT(2A)R knockout (KO) mice. Local APDs (clozapine, olanzapine, risperidone) administered by reverse dialysis induced a dose-dependent increase in mPFC DA output equally in WT and 5-HT(2A)R KO mice whereas the DA increase was absent in 5-HT(1A)R KO mice. To examine the relative contribution of both receptors to the clozapine-induced DA release in rat mPFC, we silenced G-protein-coupled receptors (GPCRs) in vivo with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) while 5-HT(1A)Rs or 5-HT(2A)/2CRs in the mPFC were selectively protected with the respective antagonists WAY-100635 or ritanserin. The inactivation of GPCRs while preserving ∼70% of 5-HT(2A)/(2C)Rs prevented the clozapine-induced DA rise in mPFC. In contrast, clozapine increased DA in mPFC of EEDQ-treated rats whose 5-HT(1A)Rs were protected (∼50% of control rats). These results indicate that (1) 5-HT(1A)Rs are necessary for the APDs-induced elevation in cortical DA transmission, and (2) this effect does not require 5-HT(2A)R blockade by APDs