National Institute on Drug Abuse Intramural Research Program

Position

Staff Scientist, Integrative Neurobiology Section

Contact

Triad Technology Center
333 Cassell Drive
Room 4500
Baltimore, MD 21224

Email: Cesar.Quiroz-Molina@nih.gov

Education

Postdoctoral research training, National Institute on Drug Abuse. Behavioral Neuroscience Research Branch, 2005-2010.

Postgraduate research training, Institute of Cellular Physiology, Autonomous National University of Mexico, 2004.

Ph. D. in Psychology, Faculty of Psychology, Autonomous National University of Mexico, 2004.

Postgraduate research training, Faculty of Medicine, University of Santiago de Compostela, Spain, 1999-2000, 2003-2004.

Master’s in Psychobiology, Faculty of Psychology, Autonomous National University of Mexico, 1999.

Bachelor’s Degree in Psychology, Autonomous National University of Mexico, 1997.

Research Interests

Dr. Quiroz earned his bachelor’s, master’s and Ph. D. degrees from the National Autonomous University of Mexico, in Mexico City. He further conducted postgraduate research on the University of Santiago de Compostela, Spain, and on the Institute of Cellular Physiology, in Mexico City. He joined NIDA in 2005 and has since worked on the discovery and characterization of new cellular receptor complexes and on uncovering long-lasting changes in the function of these cellular receptors following the exposure to drugs of abuse.

Dr. Quiroz doctoral research on the field of over-reinforced learning and memory met seamlessly with the field of substance abuse, which could arguably be viewed as a set of learned experiences with cues so salient that cannot be forgotten and are persistently recalled. Dr. Quiroz work is inspired by the search for the elusive biological substrates of overly reinforced experiences, for which receptor-receptor interactions as modulatory mechanisms in neuronal signaling may play an important role.

At NIDA, Dr. Quiroz has made several developments in the field of in vivo neurochemistry, specifically creating a technique that makes possible the delivery of large synthetic peptides into the living brain while allowing simultaneous sampling for the determination of neurotransmitter release within that same brain region. This innovation has made possible the application of synthetic peptides that are aimed at probing the molecular mechanism in the living brain that is involved in the modulation of receptor heteromeric complexes. He also has developed an implantable device that allows optogenetic stimulation of nerve terminals and simultaneous sampling of neurotransmitter release, a contribution used successfully to establish the functional circuitry on integrative brain regions.

As a scientist at NIDA, Dr. Quiroz works towards the discovery of biological mechanisms that reveal medicinal targets to help reduce the adverse consequences of the exposure to substances of abuse. His long-term research goal is to contribute to the understanding of the biological and behavioral factors contributing to initiation, maintenance, and elimination of drug abuse and addiction, and to translate this knowledge into improved strategies for eliminating the harmful consequences for the individual and for society caused by drug abuse and addiction.

Publications

PubMed

Selected Publications

2017

Yepes, Gabriel; Guitart, Xavier; Rea, William; Newman, Amy Hauck; Allen, Richard P; Earley, Christopher J; Quiroz, Cesar; Ferre, Sergi

Targeting hypersensitive corticostriatal terminals in restless legs syndrome. Journal Article

In: Ann Neurol, vol. 82, no. 6, pp. 951–960, 2017, ISSN: 1531-8249 (Electronic); 0364-5134 (Linking).

Abstract | Links | BibTeX

@article{Yepes:2017aab,

title = {Targeting hypersensitive corticostriatal terminals in restless legs syndrome.},

author = {Gabriel Yepes and Xavier Guitart and William Rea and Amy Hauck Newman and Richard P Allen and Christopher J Earley and Cesar Quiroz and Sergi Ferre},

url = {https://www.ncbi.nlm.nih.gov/pubmed/29171915},

doi = {10.1002/ana.25104},

issn = {1531-8249 (Electronic); 0364-5134 (Linking)},

year  = {2017},

date = {2017-12-08},

urldate = {2017-12-08},

journal = {Ann Neurol},

volume = {82},

number = {6},

pages = {951--960},

address = {Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD.},

abstract = {OBJECTIVE: The first aim was to demonstrate a previously hypothesized increased sensitivity of corticostriatal glutamatergic terminals in the rodent with brain iron deficiency (BID), a pathogenetic model of restless legs syndrome (RLS). The second aim was to determine whether these putative hypersensitive terminals could constitute a significant target for drugs effective in RLS, including dopamine agonists (pramipexole and ropinirole) and alpha2 delta ligands (gabapentin). METHODS: A recently introduced in vivo optogenetic-microdialysis approach was used, which allows the measurement of the extracellular concentration of glutamate upon local light-induced stimulation of corticostriatal glutamatergic terminals. The method also allows analysis of the effect of local perfusion of compounds within the same area being sampled for glutamate. RESULTS: BID rats showed hypersensitivity of corticostriatal glutamatergic terminals (lower frequency of optogenetic stimulation to induce glutamate release). Both hypersensitive and control glutamatergic terminals were significant targets for locally perfused pramipexole, ropinirole, and gabapentin, which significantly counteracted optogenetically induced glutamate release. The use of selective antagonists demonstrated the involvement of dopamine D4 and D2 receptor subtypes in the effects of pramipexole. INTERPRETATION: Hypersensitivity of corticostriatal glutamatergic terminals can constitute a main pathogenetic mechanism of RLS symptoms. Selective D4 receptor agonists, by specifically targeting these terminals, should provide a new efficient treatment with fewer secondary effects. Ann Neurol 2017;82:951-960.},

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pubstate = {published},

tppubtype = {article}

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Moreno, Estefania; Quiroz, Cesar; Rea, William; Cai, Ning-Sheng; Mallol, Josefa; Cortes, Antoni; Lluis, Carme; Canela, Enric I; Casado, Vicent; Ferre, Sergi

Functional mu-Opioid-Galanin Receptor Heteromers in the Ventral Tegmental Area. Journal Article

In: J Neurosci, vol. 37, no. 5, pp. 1176–1186, 2017, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).

Abstract | Links | BibTeX

@article{Moreno:2017aab,

title = {Functional mu-Opioid-Galanin Receptor Heteromers in the Ventral Tegmental Area.},

author = {Estefania Moreno and Cesar Quiroz and William Rea and Ning-Sheng Cai and Josefa Mallol and Antoni Cortes and Carme Lluis and Enric I Canela and Vicent Casado and Sergi Ferre},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28007761},

doi = {10.1523/JNEUROSCI.2442-16.2016},

issn = {1529-2401 (Electronic); 0270-6474 (Linking)},

year  = {2017},

date = {2017-02-01},

journal = {J Neurosci},

volume = {37},

number = {5},

pages = {1176--1186},

address = {Center for Biomedical Research in Neurodegenerative Diseases Network and.},

abstract = {The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of mu-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders. SIGNIFICANCE STATEMENT: The mu-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin-opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of mu-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders. SIGNIFICANCE STATEMENT: The mu-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin-opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.

2016

Quiroz, Cesar; Gulyani, Seema; Ruiqian, Wan; Bonaventura, Jordi; Cutler, Roy; Pearson, Virginia; Allen, Richard P; Earley, Christopher J; Mattson, Mark P; Ferre, Sergi

Adenosine receptors as markers of brain iron deficiency: Implications for Restless Legs Syndrome. Journal Article

In: Neuropharmacology, vol. 111, pp. 160–168, 2016, ISSN: 1873-7064 (Electronic); 0028-3908 (Linking).

Abstract | Links | BibTeX

@article{Quiroz:2016ab,

title = {Adenosine receptors as markers of brain iron deficiency: Implications for Restless Legs Syndrome.},

author = {Cesar Quiroz and Seema Gulyani and Wan Ruiqian and Jordi Bonaventura and Roy Cutler and Virginia Pearson and Richard P Allen and Christopher J Earley and Mark P Mattson and Sergi Ferre},

url = {https://www.ncbi.nlm.nih.gov/pubmed/27600688},

doi = {10.1016/j.neuropharm.2016.09.002},

issn = {1873-7064 (Electronic); 0028-3908 (Linking)},

year  = {2016},

date = {2016-12-11},

journal = {Neuropharmacology},

volume = {111},

pages = {160--168},

address = {Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.},

abstract = {Deficits of sensorimotor integration with periodic limb movements during sleep (PLMS) and hyperarousal and sleep disturbances in Restless Legs Syndrome (RLS) constitute two pathophysiologically distinct but interrelated clinical phenomena, which seem to depend mostly on alterations in dopaminergic and glutamatergic neurotransmission, respectively. Brain iron deficiency is considered as a main pathogenetic mechanism in RLS. Rodents with brain iron deficiency represent a valuable pathophysiological model of RLS, although they do not display motor disturbances. Nevertheless, they develop the main neurochemical dopaminergic changes found in RLS, such as decrease in striatal dopamine D2 receptor density. On the other hand, brain iron deficient mice exhibit the characteristic pattern of hyperarousal in RLS, providing a tool to find the link between brain iron deficiency and sleep disturbances in RLS. The present study provides evidence for a role of the endogenous sleep-promoting factor adenosine. Three different experimental preparations, long-term (22 weeks) severe or moderate iron-deficient (ID) diets (3- or 7-ppm iron diet) in mice and short-term (3 weeks) severe ID diet (3-ppm iron diet) in rats, demonstrated a significant downregulation (Western blotting in mouse and radioligand binding saturation experiments in rat brain tissue) of adenosine A1 receptors (A1R) in the cortex and striatum, concomitant to striatal D2R downregulation. On the other hand, the previously reported upregulation of adenosine A2A receptors (A2AR) was only observed with severe ID in both mice and rats. The results suggest a key role for A1R downregulation in the PLMS and hyperarousal in RLS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

Quiroz, Cesar; Orru, Marco; Rea, William; Ciudad-Roberts, Andres; Yepes, Gabriel; Britt, Jonathan P; Ferre, Sergi

Local Control of Extracellular Dopamine Levels in the Medial Nucleus Accumbens by a Glutamatergic Projection from the Infralimbic Cortex. Journal Article

In: J Neurosci, vol. 36, no. 3, pp. 851–859, 2016, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).

Abstract | Links | BibTeX

@article{Quiroz:2016aa,

title = {Local Control of Extracellular Dopamine Levels in the Medial Nucleus Accumbens by a Glutamatergic Projection from the Infralimbic Cortex.},

author = {Cesar Quiroz and Marco Orru and William Rea and Andres Ciudad-Roberts and Gabriel Yepes and Jonathan P Britt and Sergi Ferre},

url = {https://www.ncbi.nlm.nih.gov/pubmed/26791215},

doi = {10.1523/JNEUROSCI.2850-15.2016},

issn = {1529-2401 (Electronic); 0270-6474 (Linking)},

year  = {2016},

date = {2016-01-20},

journal = {J Neurosci},

volume = {36},

number = {3},

pages = {851--859},

address = {Integrative Neurobiology Section and.},

abstract = {It is generally assumed that infralimbic cortex (ILC) and prelimbic cortex, two adjacent areas of the medial prefrontal cortex (mPFC) in rodents, provide selective excitatory glutamatergic inputs to the nucleus accumbens (NAc) shell and core, respectively. It is also generally believed that mPFC influences the extracellular levels of dopamine in the NAc primarily by an excitatory collateral to the ventral tegmental area (VTA). In the present study, we first established the existence of a selective functional connection between ILC and the posteromedial portions of the VTA (pmVTA) and the mNAc shell (pmNAc shell), by measuring striatal neuronal activation (immunohistochemical analysis of ERK1/2 phosphorylation) and glutamate release (in vivo microdialysis) upon ILC electrical stimulation. A novel optogenetic-microdialysis approach allowed the measurement of extracellular concentrations of glutamate and dopamine in the pmNAc shell upon local light-induced stimulation of glutamatergic terminals from ILC. Cortical electrical and local optogenetic stimulation produced significant increases in the extracellular concentrations of glutamate and dopamine in the pmNAc shell. Local blockade of glutamate release by perfusion of an adenosine A2A receptor antagonist in the pmNAc shell blocked the dopamine release induced by local optogenetic stimulation but only partially antagonized dopamine release induced by cortical electrical stimulation. The results demonstrate that ILC excitatory afferents directly modulate the extracellular concentration of dopamine in the pmNAc shell, but also support the involvement of an indirect mechanism of dopamine control, through a concomitant ILC-mediated activation of the pmVTA. Significance statement: We established the existence of a functional connection between the infralimbic cortex (ILC) and the posteromedial portions of the ventral tegmental area (pmVTA) and the medial nucleus acumbens shell (pmNAc shell). A novel optogenetic-microdialysis approach allowed us to demonstrate that local glutamate release from glutamatergic terminals from the ILC exert a significant modulation of extracellular concentration of dopamine in the pmNAc shell. This mechanism provides the frame for a selective cortical-mediated tonic dopaminergic modulation of specific striatal compartments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

It is generally assumed that infralimbic cortex (ILC) and prelimbic cortex, two adjacent areas of the medial prefrontal cortex (mPFC) in rodents, provide selective excitatory glutamatergic inputs to the nucleus accumbens (NAc) shell and core, respectively. It is also generally believed that mPFC influences the extracellular levels of dopamine in the NAc primarily by an excitatory collateral to the ventral tegmental area (VTA). In the present study, we first established the existence of a selective functional connection between ILC and the posteromedial portions of the VTA (pmVTA) and the mNAc shell (pmNAc shell), by measuring striatal neuronal activation (immunohistochemical analysis of ERK1/2 phosphorylation) and glutamate release (in vivo microdialysis) upon ILC electrical stimulation. A novel optogenetic-microdialysis approach allowed the measurement of extracellular concentrations of glutamate and dopamine in the pmNAc shell upon local light-induced stimulation of glutamatergic terminals from ILC. Cortical electrical and local optogenetic stimulation produced significant increases in the extracellular concentrations of glutamate and dopamine in the pmNAc shell. Local blockade of glutamate release by perfusion of an adenosine A2A receptor antagonist in the pmNAc shell blocked the dopamine release induced by local optogenetic stimulation but only partially antagonized dopamine release induced by cortical electrical stimulation. The results demonstrate that ILC excitatory afferents directly modulate the extracellular concentration of dopamine in the pmNAc shell, but also support the involvement of an indirect mechanism of dopamine control, through a concomitant ILC-mediated activation of the pmVTA. Significance statement: We established the existence of a functional connection between the infralimbic cortex (ILC) and the posteromedial portions of the ventral tegmental area (pmVTA) and the medial nucleus acumbens shell (pmNAc shell). A novel optogenetic-microdialysis approach allowed us to demonstrate that local glutamate release from glutamatergic terminals from the ILC exert a significant modulation of extracellular concentration of dopamine in the pmNAc shell. This mechanism provides the frame for a selective cortical-mediated tonic dopaminergic modulation of specific striatal compartments.

2015

Navarro, Gemma; Quiroz, Cesar; Moreno-Delgado, David; Sierakowiak, Adam; McDowell, Kimberly; Moreno, Estefania; Rea, William; Cai, Ning-Sheng; Aguinaga, David; Howell, Lesley A; Hausch, Felix; Cortes, Antonio; Mallol, Josefa; Casado, Vicent; Lluis, Carme; Canela, Enric I; Ferre, Sergi; McCormick, Peter J

Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine. Journal Article

In: J Neurosci, vol. 35, no. 17, pp. 6639–6653, 2015, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).

Abstract | Links | BibTeX

@article{Navarro:2015aa,

title = {Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine.},

author = {Gemma Navarro and Cesar Quiroz and David Moreno-Delgado and Adam Sierakowiak and Kimberly McDowell and Estefania Moreno and William Rea and Ning-Sheng Cai and David Aguinaga and Lesley A Howell and Felix Hausch and Antonio Cortes and Josefa Mallol and Vicent Casado and Carme Lluis and Enric I Canela and Sergi Ferre and Peter J McCormick},

url = {https://www.ncbi.nlm.nih.gov/pubmed/25926444},

doi = {10.1523/JNEUROSCI.4364-14.2015},

issn = {1529-2401 (Electronic); 0270-6474 (Linking)},

year  = {2015},

date = {2015-04-29},

journal = {J Neurosci},

volume = {35},

number = {17},

pages = {6639--6653},

address = {Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain.},

abstract = {Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target sigma1 receptor (sigma1R) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the sigma1R-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking.},

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}