Publications by authors named "Mariela F Pérez"

19 Publications

  • Page 1 of 1

Blood neutrophils from children with COVID-19 exhibit both inflammatory and anti-inflammatory markers.

EBioMedicine 2021 May 9;67:103357. Epub 2021 May 9.

División Infectología, Hospital General de Agudos Dr. Juan A. Fernández, Av. Cerviño 3356, CABA C1425, Argentina.

Background: Perhaps reflecting that children with COVID-19 rarely exhibit severe respiratory symptoms and often remain asymptomatic, little attention has been paid to explore the immune response in pediatric COVID-19. Here, we analyzed the phenotype and function of circulating neutrophils from children with COVID-19.

Methods: An observational study including 182 children with COVID-19, 21 children with multisystem inflammatory syndrome (MIS-C), and 40 healthy children was performed in Buenos Aires, Argentina. Neutrophil phenotype was analyzed by flow cytometry in blood samples. Cytokine production, plasma levels of IgG antibodies directed to the spike protein of SARS-CoV-2 and citrullinated histone H3 were measured by ELISA. Cell-free DNA was quantified by fluorometry.

Findings: Compared with healthy controls, neutrophils from children with COVID-19 showed a lower expression of CD11b, CD66b, and L-selectin but a higher expression of the activation markers HLA-DR, CD64 and PECAM-1 and the inhibitory receptors LAIR-1 and PD-L1. No differences in the production of cytokines and NETs were observed. Interestingly, the expression of CD64 in neutrophils and the serum concentration of IgG antibodies directed to the spike protein of SARS-CoV-2 distinguished asymptomatic from mild and moderate COVID-19.

Interpretation: Acute lung injury is a prominent feature of severe COVID-19 in adults. A low expression of adhesion molecules together with a high expression of inhibitory receptors in neutrophils from children with COVID-19 might prevent tissue infiltration by neutrophils preserving lung function.

Funding: This study was supported by the Ministry of Science and Technology (National Agency for Scientific and Technological Promotion, IP-COVID-19-0277 and PMO BID PICT 2018-2548), and University of Buenos Aires from Argentina (20020170100573BA).
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http://dx.doi.org/10.1016/j.ebiom.2021.103357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153212PMC
May 2021

Poloxamer 188-Coated Ammonium Methacrylate Copolymer Nanocarriers Enhance Loperamide Permeability across Pgp-Expressing Epithelia.

Mol Pharm 2021 02 12;18(2):743-750. Epub 2020 Oct 12.

Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380494, Chile.

Loperamide is a μ-opioid agonist with poor gastrointestinal absorption, mainly because of its modest aqueous solubility and being a P-glycoprotein (Pgp) efflux substrate. Nevertheless, studies associated with therapeutic effects strongly suggest that loperamide holds potential pharmacological advantages over traditional μ-opioid agonists commonly used for analgesia. Thus, in this Communication, we assessed in MDCK-hMDR1 cell lines the effects over loperamide uptake and efflux ratio, when loaded into Eudragit RS (ERS) nanocarriers coated with poloxamer 188 (P188). ERS was chosen for enhancing loperamide aqueous dispersibility and P188 as a potential negative Pgp modulator. In uptake assays, it was observed that Pgp limited the accumulation of loperamide into cells and that preincubation with P188, but not coincubation, led to increasing loperamide uptake at a similar extent of Pgp pharmacological inhibition. On the other hand, the efflux ratio displayed no alterations when Pgp was pharmacologically inhibited, whereas ERS/P188 nanocarriers effectively enhanced loperamide uptake and absorptive transepithelial transport. The latter suggests that loperamide transport across cells is significantly influenced by the presence of the unstirred water layer (UWL), which could hinder the visualization of Pgp-efflux effects during transport assays. Thus, results in this work highlight that formulating loperamide into this nanocarrier enhances its uptake and transport permeability.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00623DOI Listing
February 2021

Early Cognitive Impairment Behind Nigrostriatal Circuit Neurotoxicity: Are Astrocytes Involved?

ASN Neuro 2020 Jan-Dec;12:1759091420925977

Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba.

Cognitive dysfunction is one of the most severe nonmotor symptoms of nigrostriatal impairment. This occurs as a result of profound functional and morphological changes of different neuronal circuits, including modifications in the plasticity and architecture of hippocampal synapses. Such alterations can be implicated in the genesis and progression of dementia associated with neurodegenerative diseases including Parkinson-like symptoms. There are few studies regarding cognitive changes in nigrostriatal animal models. The aim of this study was to characterize the onset of memory deficit after induction of neurotoxicity with 6-hydroxydopamine (6-OHDA) and its correlation with hippocampal dysfunction. For this, we bilaterally microinjected 6-OHDA in dorsolateral Caudate-Putamen unit (CPu) and then, animals were tested weekly for working memory, spatial short-term memory, and motor performance. We evaluated tyrosine hydroxylase (TH) as a dopamine marker, aldehyde dehydrogenase 2 (ALDH2), a mitochondria detoxification enzyme and astrocyte glial fibrillar acid protein (GFAP) an immunoreactivity marker involved in different areas: CPu, substantia nigra, prefrontal cortex, and hippocampus. We observed a specific prefrontal cortex and nigrostriatal pathway TH reduction while ALDH2 showed a decrease-positive area in all the studied regions. Moreover, GFAP showed a specific CPu decrease and hippocampus increase of positively stained area on the third week after toxicity. We also evaluated the threshold to induce long-term potentiation in hippocampal excitability. Our findings showed that reduced hippocampal synaptic transmission was accompanied by deficits in memory processes, without affecting motor performance on the third-week post 6-OHDA administration. Our results suggest that 3 weeks after neurotoxic administration, astrocytes and ALDH2 mitochondrial enzyme modifications participate in altering the properties that negatively affect hippocampal function and consequently cognitive behavior.
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http://dx.doi.org/10.1177/1759091420925977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263115PMC
May 2020

Decrease of Rab11 prevents the correct dendritic arborization, synaptic plasticity and spatial memory formation.

Biochim Biophys Acta Mol Cell Res 2020 09 7;1867(9):118735. Epub 2020 May 7.

Universidad Nacional de Córdoba (UNC), Av. Haya de la Torre s/n Ciudad Universitaria, 5000 Córdoba, Argentina; Instituto de Investigación Médica Mercedes y Martıín Ferreyra (INIMEC-CONICET-UNC), Av. Friuli 2434, 5016 Córdoba, Argentina. Electronic address:

Emerging evidence shows that Rab11 recycling endosomes (REs Rab11) are essential for several neuronal processes, including the proper functioning of growth cones, synapse architecture regulation and neuronal migration. However, several aspects of REs Rab11 remain unclear, such as its sub-cellular distribution across neuronal development, contribution to dendritic tree organization and its consequences in memory formation. In this work we show a spatio-temporal correlation between the endogenous localization of REs Rab11 and developmental stage of neurons. Furthermore, Rab11-suppressed neurons showed an increase on dendritic branching (without altering total dendritic length) and misdistribution of dendritic proteins in cultured neurons. In addition, suppression of Rab11 in adult rat brains in vivo (by expressing shRab11 through lentiviral infection), showed a decrease on both the sensitivity to induce long-term potentiation and hippocampal-dependent memory acquisition. Taken together, our results suggest that REs Rab11 expression is required for a proper dendritic architecture and branching, controlling key aspects of synaptic plasticity and spatial memory formation.
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http://dx.doi.org/10.1016/j.bbamcr.2020.118735DOI Listing
September 2020

Selective Photoinduced Antibacterial Activity of Amoxicillin-Coated Gold Nanoparticles: From One-Step Synthesis to in Vivo Cytocompatibility.

ACS Omega 2018 Jan 30;3(1):1220-1230. Epub 2018 Jan 30.

Department of Chemistry and Biomolecular Sciences and Centre for Advanced Materials Research (CAMaR), University of Ottawa, 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada.

Photoinduced antibacterial gold nanoparticles were developed as an alternative for the treatment of antibiotic-resistant bacteria. Thanks to the amoxicillin coating, they possess high in vivo stability, selectivity for the bacteria wall, a good renal clearance, and are completely nontoxic for eukaryotic cells at the bactericidal concentrations. A simple one-step synthesis of [email protected] is described at mild temperatures using the antibiotic as both reducing and stabilizing agent. Time-resolved fluorescence microscopy proved these novel nano-photosensitizers, with improved selectivity, are bactericidal but showing excellent biocompatibility toward eukaryotic cells at the same dose (1.5 μg/mL) when co-cultures are analyzed. Their stability in biological media, hemocompatibility, and photo-antibacterial effect against sensitive and antibiotic-resistant were evaluated in vitro, whereas toxicity, renal clearance, and biodistribution were studied in vivo in male Wistar rats. The use of these nanoparticles to treat antibiotic-resistant infections is promising given their high stability and cytocompatibility.
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http://dx.doi.org/10.1021/acsomega.7b01779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045397PMC
January 2018

Reduced vasopressin receptors activation mediates the anti-depressant effects of fluoxetine and venlafaxine in bulbectomy model of depression.

Psychopharmacology (Berl) 2016 Mar 23;233(6):1077-86. Epub 2015 Dec 23.

Instituto de Fisiología, Instituto de Investigaciones en Ciencias de la Salud (INICSA, UNC-CONICET), Facultad de Ciencias Médicas, CONICET and Universidad Nacional de Córdoba, Córdoba, Argentina.

Rationale: In response to stress, corticotropin releasing hormone (CRH) and vasopressin (AVP) are released from the hypothalamus, activate their receptors (CRHR1, CRHR2 or AVPr1b), and synergistically act to induce adrenocorticotropic hormone (ACTH) release from the anterior pituitary. Overstimulation of this system has been frequently associated with major depression states.

Objective: The objective of the study is to assess the role of AVP and CRH receptors in fluoxetine and venlafaxine effects on the expression of depression-related behavior.

Methods: In an animal model of depression (olfactory bulbectomy in mice, OB), we evaluated the effects of fluoxetine or venlafaxine (both 10 mg/kg/day) chronic administration on depression-related behavior in the tail suspension test. Plasma levels of AVP, CRH, and ACTH were determined as well as participation of their receptors in the expression of depression related-behavior and gene expression of AVP and CRH receptors (AVPr1b, CRHR1, and CRHR2) in the pituitary gland.

Results: The expression of depressive-like behavior in OB animals was reversed by treatment with both antidepressants. Surprisingly, OB-saline mice exhibited increased AVP and ACTH plasma levels, with no alterations in CRH levels when compared to sham mice. Chronic fluoxetine or venlafaxine reversed these effects. In addition, a significant increase only in AVPr1b gene expression was found in OB-saline.

Conclusion: The antidepressant therapy used seems to be more likely related to a reduced activation of AVP rather than CRH receptors, since a positive correlation between AVP levels and depressive-like behavior was observed in OB animals. Furthermore, a full restoration of depressive behavior was observed in OB-fluoxetine- or venlafaxine-treated mice only when AVP was centrally administered but not CRH.
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http://dx.doi.org/10.1007/s00213-015-4187-4DOI Listing
March 2016

Involvement of nNOS/NO/sGC/cGMP signaling pathway in cocaine sensitization and in the associated hippocampal alterations: does phosphodiesterase 5 inhibition help to drug vulnerability?

Psychopharmacology (Berl) 2013 Sep 12;229(1):41-50. Epub 2013 Apr 12.

IFEC-CONICET, Departamento de Farmacología, Facultad de Ciencias Químicas, UNC, Haya de la Torre y Medina Allende 5000, Córdoba, Argentina.

Rationale: Repeated cocaine administration induces behavioral sensitization in about 50 % of treated animals. Nitric oxide could be involved in the acquisition and maintenance of behavioral cocaine effects, probably by activation of neuronal nitric oxide synthase (nNOS)/NO/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling pathway, since inhibition of the nNOS enzyme attenuates development of sensitization in rats. On the other hand, increased cGMP availability by phosphodiesterase 5 inhibitors has been correlated to the misuse and recreational use of these agents and also to the concomitant use with illicit drugs in humans. Hippocampus is an important brain region for conditioning to general context previously associated to drug availability, influencing drug-seeking behavior and sensitization. Moreover, cocaine and other drugs of abuse can affect the strength of glutamate synapses in this structure, lastly modifying neuronal activity in main regions of the reward circuitry.

Objective: The objective of this study is to determine whether the pharmacological manipulation of nNOS/NO/sGC/cGMP signaling pathway altered changes induced by repeated cocaine exposure.

Results: The present investigation showed a relationship between behavioral cocaine sensitization, reduced threshold to generate long-term potentiation (LTP) in hippocampal dentate gyrus, and increased nNOS activity in this structure. However, when nNOS or sGC were inhibited, the number of sensitized animals was reduced, and the threshold to generate LTP was increased. The opposite occurred when cGMP availability was increased.

Conclusion: We demonstrate a key role of the nNOS activity and NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic transmission.
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http://dx.doi.org/10.1007/s00213-013-3084-yDOI Listing
September 2013

Impact of contextual cues in the expression of the memory associated with diazepam withdrawal: involvement of hippocampal PKMζ in vivo, and Arc expression and LTP in vitro.

Eur J Neurosci 2012 Oct 4;36(8):3118-25. Epub 2012 Jul 4.

Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, IFEC-CONICET, Haya de la Torre y Medina Allende s/n, Ciudad Universitaria, Córdoba, CP 5000, Argentina.

Hippocampal synaptic plasticity has been related to learning and adaptive processes developed during chronic drug administration, suggesting the existence of a common neurobiological mechanism mediating drug addiction and memory. Moreover, protein kinase M zeta (PKMζ) is critical for the maintenance of hippocampal long-term potentiation (LTP) and spatial conditioned long-term memories. Also, a link between activity-regulated cytoskeleton-associated protein (Arc), PKMζ and LTP has been proposed. Our previous results demonstrated that re-exposure to the withdrawal environment was able to evoke the memory acquired when the anxiety measured as a diazepam (DZ) withdrawal sign was experienced. In the present work we evaluated if the memory associated with DZ withdrawal could be affected by changes in the contextual cues presented during withdrawal and by intrahippocampal administration of a PKMζ inhibitor. We found that the context was relevant for the expression of withdrawal signs as changes in contextual cues prevented the expression of the anxiety-like behavior observed during plus-maze (PM) re-exposure, the associated enhanced synaptic plasticity and the increase in Arc expression. Furthermore, intrahippocampal administration of PKMζ inhibitor previous to re-exposure to the PM test also impaired expression of anxiety-like behavior and the facilitated LTP. These results support the relevance of the hippocampal synaptic plasticity in the maintenance of the memory trace during benzodiazepines withdrawal, adding new evidences for common mechanisms between memory and drug addiction that can be intervened for treatment or prevention of this pathology.
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http://dx.doi.org/10.1111/j.1460-9568.2012.08206.xDOI Listing
October 2012

Inhibition of neuronal nitric oxide synthase prevents alterations in medial prefrontal cortex excitability induced by repeated cocaine administration.

Psychopharmacology (Berl) 2011 Nov 2;218(2):323-30. Epub 2010 Dec 2.

Departamento de Farmacología, Facultad de Ciencias Químicas, UNC, IFEC, CONICET, Haya de la Torre y Medina Allende s/n, 5000 Córdoba, Argentina.

Rationale: The medial prefrontal cortex (mPFC), a forebrain region that regulates cognitive function and reward-motivated behaviors, has been implicated in the neuropathological mechanisms of drug addiction and withdrawal. In cocaine-abstinent human addicts, neuronal activity of the mPFC is increased in response to cocaine re-exposure or drug-associated cues. Additionally, repeated cocaine exposure alters the membrane properties and ion channel function of mPFC pyramidal neurons in drug-withdrawn rats, leading to an increased firing in response to excitatory stimuli. Nitric oxide (NO), a diffusible neuromodulator of neuronal excitability, may play a role in initiating and maintaining behavioral effects of psychostimulants. However, the role of NO in the mechanisms by which cocaine affects membrane excitability is not well clarified.

Objectives: In this study, we attempted to determine whether inhibition of neuronal nitric oxide synthase (nNOS) altered the changes induced by repeated cocaine exposure and withdrawal.

Methods: Visualized whole-cell current clamp recordings in brain slices containing the mPFC of rats administered (once per day for 5 days) with either vehicle (10% Cremophor EL in saline 0.9%), cocaine (15 mg/kg, i.p.), or cocaine and the nNOS inhibitor 7-NI (50 mg/kg, i.p.) were employed.

Results: We found that nNOS inhibition prevented cocaine sensitization and the increased membrane excitability of pyramidal cells, evidenced by an increased number of evoked spikes and reductions in inward rectification observed after short-term withdrawal from cocaine.

Conclusions: These findings suggest that NO plays an important role in chronic cocaine-induced deregulation of the mPFC activity that may contribute to the development of behavioral sensitization and cocaine withdrawal.
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http://dx.doi.org/10.1007/s00213-010-2105-3DOI Listing
November 2011

Repeated cocaine exposure decreases dopamine D₂-like receptor modulation of Ca(2+) homeostasis in rat nucleus accumbens neurons.

Synapse 2011 Feb;65(2):168-80

IFEC, CONICET, Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende s/n, Ciudad Universitaria, 5000 Córdoba, Argentina.

The nucleus accumbens (NAc) is a limbic structure in the forebrain that plays a critical role in cognitive function and addiction. Dopamine modulates activity of medium spiny neurons (MSNs) in the NAc. Both dopamine D₁-like and D₂-like receptors (including D1R or D(1,5)R and D2R or D(2,3,4)R, respectively) are thought to play critical roles in cocaine addiction. Our previous studies demonstrated that repeated cocaine exposure (which alters dopamine transmission) decreases excitability of NAc MSNs in cocaine-sensitized, withdrawn rats. This decrease is characterized by a reduction in voltage-sensitive Na(+) currents and high voltage-activated Ca(2+) currents, along with increased voltage-gated K(+) currents. These changes are associated with enhanced activity in the D1R/cAMP/PKA/protein phosphatase 1 pathway and diminished calcineurin function. Although D1R-mediated signaling is enhanced by repeated cocaine exposure, little is known whether and how the D2R is implicated in the cocaine-induced NAc dysfunction. Here, we performed a combined electrophysiological, biochemical, and neuroimaging study that reveals the cocaine-induced dysregulation of Ca(2+) homeostasis with involvement of D2R. Our novel findings reveal that D2R stimulation reduced Ca(2+) influx preferentially via the L-type Ca(2+) channels and evoked intracellular Ca(2+) release, likely via inhibiting the cAMP/PKA cascade, in the NAc MSNs of drug-free rats. However, repeated cocaine exposure abolished the D₂R effects on modulating Ca(2+) homeostasis with enhanced PKA activity and led to a decrease in whole-cell Ca(2+) influx. These adaptations, which persisted for 21 days during cocaine abstinence, may contribute to the mechanism of cocaine withdrawal.
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http://dx.doi.org/10.1002/syn.20831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686293PMC
February 2011

The intra-hippocampal leucine administration impairs memory consolidation and LTP generation in rats.

Cell Mol Neurobiol 2010 Oct 26;30(7):1067-75. Epub 2010 Jun 26.

Laboratório de Bioenergética e Estresse Oxidativo, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário-Trindade, Florianópolis, SC, Brazil.

Leucine accumulates in fluids and tissues of patients affected by maple syrup urine disease, an inherited metabolic disorder, predominantly characterized by neurological dysfunction. Although, a variable degree of cognition/psychomotor delay/mental retardation is found in a considerable number of individuals affected by this deficiency, the mechanisms underlying the neuropathology of these alterations are still not defined. Therefore, the aim of this study was to investigate the effect of acute intra-hippocampal leucine administration in the step-down test in rats. In addition, the leucine effects on the electrophysiological parameter, long-term potentiation generation, and on the activities of the respiratory chain were also investigated. Male Wistar rats were bilaterally administrated with leucine (80 nmol/hippocampus; 160 nmol/rat) or artificial cerebrospinal fluid (controls) into the hippocampus immediately post-training in the behavioral task. Twenty-four hours after training in the step-down test, the latency time was evaluated and afterwards animals were sacrificed for assessing the ex vivo biochemical measurements. Leucine-treated animals showed impairment in memory consolidation and a complete inhibition of long-term potentiation generation at supramaximal stimulation. In addition, a significant increment in complex IV activity was observed in hippocampus from leucine-administered rats. These data strongly indicate that leucine compromise memory consolidation, and that impairment of long-term potentiation generation and unbalance of the respiratory chain may be plausible mechanisms underlying the deleterious leucine effect on cognition.
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http://dx.doi.org/10.1007/s10571-010-9538-4DOI Listing
October 2010

Ghrelin induced memory facilitation implicates nitric oxide synthase activation and decrease in the threshold to promote LTP in hippocampal dentate gyrus.

Physiol Behav 2010 Aug 6;101(1):117-23. Epub 2010 May 6.

IFEC, CONICET, Departamento de Farmacología, Facultad de Ciencias Químicas, UNC, Córdoba, Argentina.

Although the hypothalamus has been long considered the main ghrelin (Ghr) target organ mediating orexigenic effects, recently it has been shown that in-vivo Ghr hippocampus administration improves learning and memory in the inhibitory avoidance paradigm. However, the possible mechanisms underlying this memory facilitation effect have not been clarified. Given that the biochemical memory cascade into the hippocampus involves nitric oxide (NO) synthesis via NO synthase (NOS) activation, we investigated 1) if Ghr administration modulated NOS activity in the hippocampus; and 2) if hippocampal NOS inhibition influenced Ghr-induced memory facilitation, using a behavioral paradigm, biochemical determinations and an electrophysiological model. Our results showed that intra-hippocampal Ghr administration increased the NOS activity in a dose dependent manner, and reduced the threshold for LTP generation in dentate gyrus of rat hippocampus. Moreover, pre-administration of NG-nitro-l-arginine (l-NOArg) in the hippocampus partially prevented the Ghr-induced memory improvement, abolished the increase in NOS activity, and prevented the decreased threshold to generate LTP induced by Ghr. These findings suggest that activation of the NOS/NO pathway in hippocampus participates in the effects of Ghr on memory consolidation and is related with plastic properties of the hippocampal three-synaptic loop.
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http://dx.doi.org/10.1016/j.physbeh.2010.04.026DOI Listing
August 2010

Dopamine D(2) receptor modulation of K(+) channel activity regulates excitability of nucleus accumbens neurons at different membrane potentials.

J Neurophysiol 2006 Nov 2;96(5):2217-28. Epub 2006 Aug 2.

Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064-3095, USA.

The nucleus accumbens (NAc) is a forebrain area in the mesocorticolimbic dopamine (DA) system that regulates many aspects of drug addiction. Neuronal activity in the NAc is modulated by different subtypes of DA receptors. Although DA signaling has received considerable attention, the mechanisms underlying D(2)-class receptor (D(2)R) modulation of firing in medium spiny neurons (MSNs) localized within the NAc remain ambiguous. In the present study, we performed whole cell current-clamp recordings in rat brain slices to determine whether and how D(2)R modulation of K(+) channel activity regulates the intrinsic excitability of NAc neurons in the core region. D(2)R stimulation by quinpirole or DA significantly and dose-dependently decreased evoked Na(+) spikes. This D(2)R effect on inhibiting evoked firing was abolished by antagonism of D(2)Rs, reversed by blockade of voltage-sensitive, slowly inactivating A-type K(+) currents (I(As)), or eliminated by holding membrane potentials at levels in which I(As) was inactivated. It was also mimicked by inhibition of cAMP-dependent protein kinase (PKA) activity, but not phosphatidylinositol-specific phospholipase C (PI-PLC) activity. Moreover, D(2)R stimulation also reduced the inward rectification and depolarized the resting membrane potentials (RMPs) by decreasing "leak" K(+) currents. However, the D(2)R effects on inward rectification and RMP were blocked by inhibition of PI-PLC, but not PKA activity. These findings indicate that, with facilitated intracellular Ca(2+) release and activation of the D(2)R/G(q)/PLC/PIP(2) pathway, the D(2)R-modulated changes in the NAc excitability are dynamically regulated and integrated by multiple K(+) currents, including but are not limited to I(As), inwardly rectifying K(+) currents (I(Kir)), and "leak" currents (I(K-2P)).
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http://dx.doi.org/10.1152/jn.00254.2006DOI Listing
November 2006

Hippocampal synaptic plasticity in mice devoid of cellular prion protein.

Brain Res Mol Brain Res 2004 Nov;131(1-2):58-64

Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, 5000 Córdoba, Argentina.

The cellular prion protein plays a role in the etiology of transmissible and inherited spongiform encephalopathies. However, the physiological role of the cellular prion protein is still under debate. Results regarding the synaptic transmission using the same strain of animals where the cellular prion protein gene was ablated are controversial, and need further investigation. In this work, we have studied the hippocampal synaptic transmission in mice devoid of normal cellular prion protein, and have shown that these animals present an increased excitability in this area by the lower threshold (20 Hz) to generate long-term potentiation (LTP) in hippocampal dentate gyrus when compared to wild-type animals. The mice devoid of normal cellular prion protein are also more sensitive to the blocking effects of dizocilpine and 2-amino-5-phosphonopentanoic acid on the hippocampal long-term potentiation generation. In situ hydridization experiments demonstrated overexpression of the mRNAs for the N-methyl-D-aspartate (NMDA) receptor NR2A and NR2B subunits in mice devoid of normal cellular prion protein. Therefore, our results indicate that these animals have an increased hippocampal synaptic plasticity which can be explained by a facilitated glutamatergic transmission. The higher expression of specific N-methyl-d-aspartate receptor subunits may account for these effects.
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http://dx.doi.org/10.1016/j.molbrainres.2004.08.004DOI Listing
November 2004

MK-801 prevents the increased NMDA-NR1 and NR2B subunits mRNA expression observed in the hippocampus of rats tolerant to diazepam.

Brain Res 2004 May;1008(1):54-60

Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, 5000 Córdoba, Argentina.

The chronic diazepam administration in rats has been show from our previous results, to produce an increased synaptic plasticity. Furthermore, this occurs with a concomitant over expression of the mRNA NR1 and NR2B N-methyl-D-aspartate receptor subunits. MK-801, a non-competitive antagonist of N-methyl-D-aspartate receptor, impairs both the development of conditioned tolerance to diazepam and the hippocampal long-term potentiation generation. In the present study, we have further investigated the hippocampal glutamatergic transmission in the development of tolerance to diazepam. Our results demonstrate that the development of tolerance to the hypolocomotive effect of diazepam, along with the increased hippocampal synaptic plasticity and the associated over expression of the mRNA NR1 and NR2B N-methyl-D-aspartate receptor subunits, were blocked by previous MK-801 administration. We suggest that the participation of hippocampal glutamatergic transmission is relevant to increased hippocampal synaptic plasticity, the latter being a neurobiological mechanism behind the development of the conditioned tolerance to diazepam.
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http://dx.doi.org/10.1016/j.brainres.2004.01.080DOI Listing
May 2004

Increased susceptibility to LTP generation and changes in NMDA-NR1 and -NR2B subunits mRNA expression in rat hippocampus after MCH administration.

Peptides 2003 Sep;24(9):1403-11

Departamento de Farmacología, Facultad de Ciencias Químicas, Haya de La Torre esq. Medina Allende, Universidad Nacional de Córdoba, Córdoba 5000, Argentina.

The present study attempts to determine which mechanisms underlie the retrograde facilitation of memory induced by microinjection hippocampal melanin-concentrating hormone (MCH) on the inhibitory avoidance paradigm. Previous reports using this test on the hippocampus suggest that NMDA receptor-mediated mechanisms are involved in memory processing and are also necessary for the induction of long-term potentiation (LTP) of the hippocampal dentate gyrus. In addition, alterations in expression of synaptic NMDA subunits in the hippocampus have been associated with memory formation of an inhibitory avoidance task. We have studied the effects of the neuropeptide upon the electrophysiological parameters using hippocampal slices from rats injected with the peptide and tested in step-down tests as well as possible changes in the mRNA expression of NMDA receptor subunits. We postulate that the increased facility to induce LTP, and the overexpression of this N-methyl-D-aspartate mRNA receptor subunits induced by MCH, could be behind the retrograde facilitation observed after MCH hippocampal microinjection.
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http://dx.doi.org/10.1016/j.peptides.2003.09.006DOI Listing
September 2003

NMDA-NR1 and -NR2B subunits mRNA expression in the hippocampus of rats tolerant to Diazepam.

Behav Brain Res 2003 Sep;144(1-2):119-24

Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, 5000 Córdoba, Argentina.

The development of tolerance to the hypolocomotor effects of Diazepam (DZ) is thought to be a contingent or learning phenomenon. In previous reports, we demonstrated a positive correlation between the development of tolerance to the sedative effects of DZ and hippocampal synaptic plasticity. Furthermore, previous exposure to the drug administration context blocks both the tolerance to sedative effects of DZ and the increased hippocampal plasticity. The results of the present investigation show that the development of tolerance to hypolocomotor action of DZ (5 mg/kg/day) for 4 days results in a significant increase in the hybridization signals for mRNA for N-methyl-D-aspartate (NMDA) glutamatergic receptor NR1 and NR2B subunits in the hippocampal dentate gyrus. Furthermore, we have observed more benzodiazepine binding sites in the hippocampus of non-tolerant animals. We conclude that the increased hippocampal synaptic efficacy in DZ tolerant rats, may be NMDA receptor dependent due to an increased recombinant NR1-NR2B complex observed in the hippocampal formation of tolerant rats.
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http://dx.doi.org/10.1016/s0166-4328(03)00072-xDOI Listing
September 2003

Environmental changes modify the expression of Diazepam withdrawal.

Behav Brain Res 2002 Oct;136(1):75-81

Departamento de Farmacologi;a, Facultad de Ciencias Qui;micas, Universidad Nacional de Córdoba, Argentina.

Early results from our laboratory have demonstrated a positive correlation between increased hippocampal synaptic plasticity and development of tolerance to hypolocomotive effect of Diazepam (DZ). We have found recently, that pre-exposure to DZ administration context impairs increase of hippocampal synaptic plasticity in conjunction with tolerance to DZ. These findings have suggested, that the tolerance to DZ is context specific. Furthermore, the hippocampus can be critically involved in the behavioral expression of conditioned tolerance to DZ. The results of the present investigation show that animals chronically treated with DZ for 18 days exhibit withdrawal signs, evaluated as an increased anxiety in an elevated plus maze. These animals also show, a facilitation in the threshold to induce long-term potentiation in the hippocampal formation. These phenomena have a strong dependency on the drug administration context, since both are reversed after the introduction of some changes in the drug administration environment. Furthermore, the alteration of some environmental cues increased the locomotive activity in animals that did not show anxiety as a withdrawal signs. We conclude that a common neural system could underlie the behavioral expression of the conditioned tolerance and dependence on DZ.
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http://dx.doi.org/10.1016/s0166-4328(02)00108-0DOI Listing
October 2002

Perinatal undernutrition: changes in brain opiate receptor density.

Nutr Neurosci 2002 Feb;5(1):53-7

Departamento de Farmacologia, Facultad de Ciencias Quimicas, Ciudad Universitaria Córdoba, Argentina.

The present work sought to study the binding properties of central mu-opiate receptors in whole brain and in different central areas in adult rats undernourished at perinatal age. Rats were undernourished with a hypoproteic diet containing 8% casein from day 14 of gestation until 50 days of age. The animals were thereafter fed a balanced commercial chow until 140 days of age. At this time point the experiments started. 3H-D-Ala2, N-Me-Phe4, Gly5-ol-enkephalin (3H-DAMGO) was used to selectively label the mu-receptors. The results obtained demonstrated that perinatal undernutrition induced, in the adult animal, a decreased mu-receptors density (Bmax) both in whole brain as well as in midbrain, without significant changes in affinity. In addition, no changes were found in mu-specific binding in the cortex of these undernourished animals. Taking into account that recent evidences from our laboratory have demonstrated a lower stress-induced analgesia following exposure to different stressful situations in rats undernourished in early life, the present findings seem to suggest that this lower analgesic response could be due, at least in part, to a lower density of mu-opiate receptors in the brain.
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http://dx.doi.org/10.1080/10284150290007083DOI Listing
February 2002