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

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

Introducció de material exòtic per a l'obtenció de blat de moro farratger: resultats preliminars

Peer Reviewe

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

Clozapine and haloperidol differently suppress the MK-801-increased glutamatergic and serotonergic transmission in the medial prefrontal cortex of the rat

The administration of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and ketamine has been shown to increase the extracellular concentration of glutamate and serotonin (5-HT) in the medial prefrontal cortex (mPFC). In the present work, we used in vivo microdialysis to examine the effects of the more potent noncompetitive NMDA receptor antagonist, MK-801, on the efflux of glutamate and 5-HT in the mPFC, and whether the MK-801-induced changes in the cortical efflux of both transmitters could be blocked by clozapine and haloperidol given systemically or intra-mPFC. The systemic, but not the local administration of MK-801, induced an increased efflux of 5-HT and glutamate, which suggests that the NMDA receptors responsible for these effects are located outside the mPFC, possibly in GABAergic neurons that tonically inhibit glutamatergic inputs to the mPFC. The MK-801-induced increases of extracellular glutamate and 5-HT were dependent on nerve impulse and the activation of mPFC AMPA/kainate receptors as they were blocked by tetrodotoxin and NBQX, respectively. Clozapine and haloperidol blocked the MK-801-induced increase in glutamate, whereas only clozapine was able to block the increased efflux of 5-HT. The local effects of clozapine and haloperidol paralleled those observed after systemic administration, which emphasizes the relevance of the mPFC as a site of action of these antipsychotic drugs in offsetting the neurochemical effects of MK-801. The ability of clozapine to block excessive cortical 5-HT efflux elicited by MK-801 might be related to the superior efficacy of this drug in treating negative/cognitive symptoms of schizophrenia.This work was supported by the Spanish Ministry of Education and Science Grants SAF 2004-05525 and SAF 2003-04930 and by the Generalitat de Catalunya (SGR2005/00758 and SGR2005/00826). XL-G, ZB, and MA-B were recipients of predoctoral fellowships from the Consejo Superior de Investigaciones Científicas (CSIC), Spanish Ministry of Education and Science, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), respectively.Peer reviewe

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

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

Geology of the Cerro Quema Au-Cu deposit (Azuero Peninsula, Panama)

The Cerro Quema district, located on the Azuero Peninsula, Panama, is part of a large regional hydrothermal system controlled by regional faults striking broadly E-W, developed within the Río Quema Formation. This formation is composed of volcanic, sedimentary and volcano-sedimentary rocks indicating a submarine depositional environment, corresponding to the fore-arc basin of a Cretaceous-Paleogene volcanic arc. The structures observed in the area and their tectono-stratigraphic relationship with the surrounding formations suggest a compressive and/or transpressive tectonic regime, at least during Late Cretaceous-Oligocene times. The igneous rocks of the Río Quema Formation plot within the calc-alkaline field with trace and rare earth element (REE) patterns of volcanic arc affinity. This volcanic arc developed on the Caribbean large igneous province during subduction of the Farallon Plate. Mineralization consists of disseminations of pyrite and enargite as well as a stockwork of pyrite and barite with minor sphalerite, galena and chalcopyrite, hosted by a subaqueous dacitic lava dome of the Río Quema Formation. Gold is present as submicroscopic grains and associated with pyrite as invisible gold. A hydrothermal alteration pattern with a core of advanced argillic alteration (vuggy silica with alunite, dickite, pyrite and enargite) and an outer zone of argillic alteration (kaolinite, smectite and illite) has been observed. Supergene oxidation overprinted the hydrothermal alteration resulting in a thick cap of residual silica and iron oxides. The ore minerals, the alteration pattern and the tectono-volcanic environment of Cerro Quema are consistent with a high sulfidation epithermal system developed in the Azuero peninsula during pre-Oligocene times

Deep-water formation variability in the north-western Mediterranean Sea during the last 2500yr: A proxy validation with present-day data

Here we investigate the sensitivity of deep-water formation in the north-western Mediterranean Sea to climate variability during the last 2500 yr. With this purpose, the grain-size parameter UP10 (fraction > 10 μm) is used as a proxy for intensity of deep-water circulation. Such a proxy is first validated through the analysis of oceanographic data collected from October 2012 to October 2014 by means of two deep-water mooring lines equipped with sediment traps and currentmeters in the Gulf of Lion and north of Minorca Island. Enhancements of deep current speed resulted from dense shelf water cascading and open-sea deep convection in February 2013 leading to dense-water formation. The grain-size distribution of settling particles from sediment traps collected during 2012-2013 shows a distinctive particle mode and high UP10 values correlated to deep-water formation. These data are consistent with grain-size values in sediment cores from the north of Minorca, thus supporting the validity of the UP10 parameter to reconstruct changes of intensity in deep-water formation and associated near-bottom currents. The deep-water sediment record of the north of Minorca for the last 2.5 kyr shows that the strongest deep-water formation events occurred during relatively warm intervals, such as the Roman Period (123 BCE-470 CE2), the end of the Medieval Climate Anomaly (900-1275 CE) and the first part of the Little Ice Age (1275-1850 CE). By contrast, our data indicate a progressive reduction in the overturning conditions during the Early Middle Ages (470-900 CE) resulting in weaker deep-water formation events during most of the Medieval Climate Anomaly. Intense deep-water formation events appear to be mostly associated with periods of enhanced Evaporation-Precipitation balance rather than to buoyancy loss due to winter cooling only. Our results suggest that warm sea surface temperature during spring months could have played an important role by increasing the Evaporation-Precipitation balance and favouring buoyany loss by increased of salinity. The comparison our data with other oceanographic and climatic records indicates a change in the proxy relation before and after the Early Middle Ages. Western Mediterranean Deep Water and Levantine Intermediate Water behave in opposite way after the Early Middle Ages, thus indicating that the previously proposed Mediterranean see-saw pattern in the Evaporation-Precipitation balance also influenced convection patterns in the basins during the last 1500 yr. These changes are discussed in the frame of different configurations of the North Atlantic Oscillation and East Atlantic/ West Russian modes of atmospheric variation

RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis

Current antidepressants, which inhibit the serotonin transporter (SERT), display limited efficacy and slow onset of action. Here, we show that partial reduction of SERT expression by small interference RNA (SERT-siRNA) decreased immobility in the tail suspension test, displaying an antidepressant potential. Moreover, short-term SERT-siRNA treatment modified mouse brain variables considered to be key markers of antidepressant action: reduced expression and function of 5-HT(1A)-autoreceptors, elevated extracellular serotonin in forebrain and increased neurogenesis and expression of plasticity-related genes (BDNF, VEGF, Arc) in hippocampus. Remarkably, these effects occurred much earlier and were of greater magnitude than those evoked by long-term fluoxetine treatment. These findings highlight the critical role of SERT in serotonergic function and show that the reduction of SERT expression regulates serotonergic neurotransmission more potently than pharmacological blockade of SERT. The use of siRNA-targeting genes in serotonin neurons (SERT, 5-HT(1A)-autoreceptor) may be a novel therapeutic strategy to develop fast-acting antidepressants