Image

Contact Information

Overview of the Lab

Our research is aimed at uncovering the circuits and synaptic mechanisms mediating reward motivated behaviors and compulsive drug use. Specifically, the goal is to better understand how cocaine and ethanol affect synapses and neuronal connectivity to drive the development of compulsive seeking that characterizes individuals suffering from cocaine abuse or alcohol use disorder. Our research focuses on drug actions in the cortico-mesolimbic circuit, with an emphasis on the nucleus accumbens. We combine physiological with behavioral analysis and use cutting-edge approaches, such as in vivo and in vitro optogenetic and chemico-genetic tools, to manipulate the activity of targeted neuronal populations and dissect their role in ethanol and cocaine related behaviors. Our overarching hypothesis is that cocaine and ethanol induce different adaptations on the two distinct subpopulations of medium spiny neurons in the striatum, direct- and indirect-pathway neurons, and that both pathways contribute differently to the psychomotor, rewarding and addictive properties of these drugs of abuse.

Research Projects

We are addressing three specific questions:

  • How does chronic exposure to cocaine and ethanol affect the structure and function of neurons and synapses?
  • Is there a difference in synaptic function and morphology between animals that display addictive-like behaviors and animals that do not after they all have been chronically exposed to cocaine or ethanol?
  • Are there differences in the function and morphology of synapses in animals with higher predisposition to become addicted to cocaine?

To answer these questions, we use a combination of techniques: electrophysiology, 2-photon laser scanning microscopy, biochemistry and behavior. The lab employs two models of drug exposure: a passive non-contigent administration (such as intraperitoneal injections of cocaine) and models of ethanol and cocaine self-administration in mice (see models of drug administration ).

Electrophysiological recordings (whole cell voltage clamp) from medium spiny neurons (MSN) of the nucleus accumbens and the striatum are performed in order to determine the functional properties of the synaptic inputs onto D2-positive neurons and D1-positive neurons.

Image
AMPA and NMDA receptor mediated synaptic currents of D2 positive (GFP) medium spiny neurons

We are also studying the morphological changes associated with chronic cocaine and with the development of addictive behaviors by fluorescently labeling MSN using ballistic methods and imaging spine morpholgy with confocal and 2-photon microscopes.

Image
Image of 3 panels with increasing magnification. Panel A shows striatum with stained medium spiny neurons, panel B a single medium spiny neuron and panel C a section of the neurons dendrite with clearly visible spines.

Findings from these studies will provide information about the short-term and long-term effects of drug of abuse, such as cocaine and alcohol, on synapses. In addition, we hope they will lead to the identification of neuronal markers associated with higher vulnerability to addiction and they will aid in the development of new therapies.

Models of drug administration in mice:

Cocaine intraperitoneal injections: Cocaine is a psychostimulant drug that acts by blocking the reuptake of monoamines, such as dopamine, from the synaptic cleft. One of the acute actions of cocaine on mouse behavior is to increase their locomotor activity. In the lab, mice receive single or repetitive cocaine injections and their locomotor activity is measured using infrared beams and detectors located across the sides of the cage (see schematic below). Horizontal locomotion is measured daily for 20—60 min after injection of either saline or cocaine (5—30 mg/kg) in the intraperitoneal cavity. An example of this response is shown in the graph below where an acute response to cocaine is observed on day 1 and subsequent injections increase the psychomotor response furthermore. The enhancement of the locomotor activity with repeated injections is what has been called locomotor sensitization.

Graph 1: Locomotor sensitization to cocaine:

Image
Schema and graph showing the locomotor sensitization to cocaine

Cocaine drug self-administration: The lab uses models of intravenous (IV) cocaine self-administration in mice to investigate the development of addictive-like behaviors in rodents. Mice undergo surgical implantation of a catheter in the jugular vein and, after recovery, are trained to poke their noses in a hole to gain an intravenous infusion of cocaine through this catheter (see a video of a mouse performing the task ). We analyze the number of rewards gained per daily session and track the progression of drug intake during consecutive days and weeks. In one of our models, daily sessions are intermingled with two time-out periods during which the drug is unavailable and nose pokes do not lead to infusions. (Graph below, gray area). We measure the perserverance of nose poking during the time-out periods as one determinant of the development of compulsive drug seeking behavior. The other two parameters are a breakpoint value obtained in sessions of progressive response ratio to test the motivation and one punishment session in which reward is paired to a mild foot shock to determine the perserverance of drug seeking despite aversive consequences (model based on Derroche-Gamonet et al. 2004).
Interestingly, different patterns of drug taking behavior are observed among different mice. The plot below shows an example of a regular (right side) and a more clustered or binging (left side) self-administration pattern.

Graph 2: Different patterns of cocaine self-administration:

Image
Self-administration response pattern to cocaine

Ethanol self-administration: In collaboration with the laboratory of Dr. Kathleen A. Grant ( Oregon National Primate Center and OHSU ) and Dr. Todd Thiele (University of North Carolina at Chapel Hill) we are studying the morphological changes at synapses that occur after chronic ethanol self-administration in non-human primates and rodents, respectively.

Lab Members

Selected Publications

Search for all publications from the Alvarez Lab on PubMed
 

A. MatsuiV.A. Alvarez (2018Cocaine inhibition of synaptic transmission in the ventral pallidum is pathway-specific and medidated by serotoninCell Report 23(13), 3852–3863.

K.H. LeBlanc, T.D. London, I. Szczot, M.E. Bocarsly, D.M. Friend, K.P. Nguygen, M.M. Mengesha, M. Rubenstein, V.A. Alvarez, A.V. Kravitz (2018Striatopallidal neurons control avoidance behavior in exploratory tasksMolecular Psychiatry (epub ahead of print doi:10.1038/s41380-018-0051-3).

D.M. Friend, K. Devarakonda, T.J. O'Neal, M. Skirzewski, I. Papazoglou, A. Kaplan, J.S.Liow, S.G. Rane, M. Rubenstein, V.A. Alvarez, K.D. Hall, A.V. Kravitz. (2018Basal ganglia dysfunction contributes to physical inactivity in obesityCell Metabolism 25(2), 312–321.

D.M. Lovinger, V.A. Alvarez (2017Alcohol and basal ganglia circuitry: Animal modelsNeuropharmacology 122, 46–55.

A. MatsuiV.A. Alvarez (2017Undercover Power of Endocannabinoids: Postsynaptic Ion-Channel ModulatorNeuron 93(6), 1243–1244.

M.A. Hutchison, X. Gu, M.F. Adrover, M.R. Lee, T.S. Hnasko, V.A. Alvarez, W. Lu (2017Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behaviorMol. Psychiatry advanced online publication 14 February 2017; doi:10.1038/mp.2017.7.

P. Charbogne, O. Gardon, E. Martín-García, H.L. Keyworth, A. Matsui, A.E. Mechling, T. Bienert, T. Nasseef, A. Robé, L. Moquin, E. Darcq, S. Ben Hamida, P. Robledo, A. Matifas, K. Befort, C. Gavériaux-Ruff, L.A. Harsan, D. von Elverfeldt, J. Hennig, A. Gratton, I. Kitchen, A. Bailey, V.A. Alvarez, R. Maldoado, B.L. Kiefer (2017Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable FoodBiol. Psychiatry 81(9):778–788.

D.M. Friend, K. Devarakonda, T.J. O'Neal, M. Skirzewski, I. Papazoglou, A.R. Kaplan, J.S. Liow, J. Guo, S.G. Rane, M. Rubenstein, V.A. Alvarez, K.D. Hall, A.V. Kravitz (2017Basal Ganglia Dysfunction Contributes to Physical Inactivity in ObesityCell Metab. 25(2), 312–21.

L.K DobbsJ.C. LemosV.A. Alvarez (2017Restructuring of basal ganglia circuitry and associated behaviors triggered by low striatal D2 receptor expression: implications for substance use disordersGenes Brain Behav. 16(1), 56–70.

J.C. Lemos, D.M. Friend, A.R. KaplanJ.H. Shin, M. Rubenstein, A.V. Kravitz, V.A. Alvarez (2016Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor SignalingNeuron 90(4), 824–38.

L.K DobbsA.R. KaplanJ.C. LemosA. Matsui, M. Rubenstein, V.A. Alvarez (2016Dopamine Regulation Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of CocaineNeuron 90(5), 1100–13.

V.A. Alvarez (2016Clues on the coding of reward cues by the nucleus accumbensPNAS USA 113(10, 2560–2.

J.H. ShinM.F. Adrover, J. Wess, V.A. Alvarez (2015Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbensPNAS USA 112(26), 8124–9.

K.B. HolroydM.F. AdroverR.L. FuinoR. BockA.R. Kaplan, C.M. Gremel, M. Rubinstein, V.A. Alvarez (2015). Loss of feedback inhibition via D2 autoreceptors enhances acquistion of cocaine taking and reactivity to drug-paired cuesNeurophsychopharm advanced online publication 21 January 2015; doi: 10.1038/npp.2014.336.

M.F. AdroverJ.H. Shin, and V.A. Alvarez (2014). Glutamate and dopamine transmission from midbrain dopamine neurons share similar release properties but are differentially affected by cocaineJ. Neurosci. 34 (9), 3183–3192.

C. Cui, A. Noronha, H. Morikawa, V.A. Alvarez, G.D. Stuber, K.K. Szumlinski, T.L. Kash, M. Roberto, and M.V. Wilcox (2013). New insights on neurobiological mechanisms underlying alcohol addictionNeuropharmacology 67:223–232.

M.V. Wilcox, V.C. Cuzon Carlson, N. Sherazee, G.M. Sprow, R. Bock, T.E. Thiele, D.M. Lovinger, and V.A. Alvarez (2014). Repeated binge-like ethanol drinking alters ethanol drinking patterns and depresses striatal GABAergic transmissionNeuropsychopharmacology 39(3):579–594.

R. BockJ.H. ShinA.R. KaplanA. DobiE. MarkeyP.F. Kramer, C.M. Gremel, C.H. ChristensenM.F. Adrover, and V.A. Alvarez (2013). Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine useNat. Neurosci. 16(5):632–638.

N. SherazeeV.A. Alvarez (2013). DiOlistics: delivery of fluorescent dyes into cellsMethods Mol. Biol. 940:391–400.

A. DobiG.K. SeaboldC.H. ChristensenR. Bock, and V.A. Alvarez. (2011). Cocaine-Induced Plasticity in the Nucleus Accumbens Is Cell Specific and Develops without Prolonged WithdrawalJ. Neurosci. 31:1895–904.

P.F. KramerC.H. Christensen, L.A. Hazelwood, A. DobiR. Bock, D.R. Sibley, Y. Mateo, and V.A. Alvarez. (2011). Dopamine D2 receptor overexpression alters behavior and phsiology in Drd2-EGPFP miceJ. Neurosci. 31:126–32. Faculty of 1000 "Recommended" list.

E. Bello Gay, Y. Mateo, D.M. Gelman, D. Noaín, J.H. Shin, C.M. Bäckman, M.J. Low, V.A. Alvarez, D.M. Lovinger and M. Rubinstein (2011). Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptorsNature Neurosci. 14: 1033–8

V. Cuzon Carlson, G.K. Seabold, C.M. Helms, N. Garg, M. Odagiri, A.R. Rau, J. Daunais, and V.A. Alvarez, D.M. Lovinger and K.A. Grant (2011). Synaptic and morphological neuroadaptations in the putamen associated with long-term, relapsing alcohol drinking in primatesNeuropsychopharm. 36: 2513–28

B.N. Mathur, N.A. Capik, V.A. Alvarez, and D.M. Lovinger (2011). Serotonin induces long-term depression at corticostriatal synapsesJ Neurosci. 31(20):7402–11.

M. Feyder, R.M. Karlsson, P. Mathur, M. Lyman, R. Bock, R. Momenan, J. Munasinghe, M.L. Scattoni, J. Ihne, M. Camp, C. Graybeal, D. Strathdee, V.A. Alvarez, P. Kirsch, M. Rietschel, S. Cichon, H. Walter, A. Meyer-Lichtenberg, S.G. Grant and A. Holmes. (2010). Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndromeAm. J. Psychiatry 167:1508–17.

G.K. Seabold, J.B. Daunais, A. Rau, K.A. Grant, V.A. Alvarez. (2010). DiOLISTIC labeling of neurons from rodent and non-human primate brain slicesJ. Vis. Exp. (41) pii:2081.

J.L. Brigman, T. Wright, G. Talani, S. Prasad-Mulcare, S. Jinde, G.K. Seabold, P. Mathur, M.I. Davis, R. Bock, R.M. Gustin, R.J. Colbran, V.A. Alvarez, K. Nakazawa, E. Delphire, D.M. Lovinger and A. Holmes. (2010). Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learningJ. Neurosci. 30:4590–600.

J. Cheng, X. Zhou, E.L. Miller, V.A. Alvarez, B.L. Sabatini, S.T. Wong. (2010). Oriented Markov random field based dendritic spine segmentation for fluorescence microscopy imagesNeuroinformatics 8(3):157–70.

V.A. Alvarez , D.A. Ridenour and B.L. Sabatini. (2007). Distinct Structural and Ionotropic Roles of NMDA Receptors in Controlling Spine and Synapse StabilityJ. Neurosci. 28:7365–76.

V.A. Alvarez and B.L. Sabatini. (2007Anatomical and physiological plasticity of dendritic spinesAnnu. Rev. Neurosci. 30:79–97.

V.A. Alvarez , D.A. Ridenour and B.L. Sabatini. (2006). Retraction of synapses and dendritic spines induced by off-target effects of RNA interferenceJ. Neurosci. 26:7820–5. Faculty of 1000 "Must Read" list.

S.F. Tavazoie*, V.A. Alvarez* , D.A. Ridenour, D.J. Kwiatkowski, B.L. Sabatini (2005). Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2Nat Neurosci. 8, 1727–34. Faculty of 1000 "Recommended" list.

V.A. Alvarez , C. Chow, E.J. Van Bockstaele and J.T. Williams. (2002). Frequency-dependent synchronization of locus coeruleus neurons: role of electrotonic coupling. Proc Natl Acad Sci U S A . 99: 4032–6.

V.A. Alvarez *, S. Arttamangkul*, J. Whistler, M. van Zastrow, D. Grandy and J.T. Williams. (2002). mu-Opioid receptors: Ligand-dependent activation of potassium conductance, desensitization, and internalizationJ Neurosci. 22: 5769–76.

V.A. Alvarez , S. Arttamangkul, and J.T. Williams. (2001). A RAVE about Opioid WithdrawalNeuron 32: 761–763. New and Views.

V.A. Alvarez , Maubecin, F. Garcia-Hernandez, J.T. Williams and E. Van Bockstaele. (2000). Functional coupling between neurons and gliaJ. Neurosci. 20: 4091–4098.

Other Lab Resources

NIH Resources

Collaborators

present
past

Alumni

Image
tanisha-london

Tanisha London, BSc
Postbaccalaureate IRTA
Fall 2017 — Summer 2018
currently graduate student University of Southern California (USC)

Image
Sannidhi S.

Sannidhi Shashikiran
Volunteer
Sommer 2017 — Sommer 2018
currently college student at Georgetown University

Image
Julia L.

Julia Lemos, PhD
Postdoctoral Fellow, IRTA
Summer 2012 — Winter 2017
currently Assistant Professor in the Medical Discovery Team Addiction at the MDT University of Minnesota

Image
Martin A.

Martin Adrover, PhD
Postdoctoral Visiting Fellow
Winter 2010 — Fall 2017
currently faculty at INGEBI - CONICET in Buenos Aires, Argentina

Image
Elizabeth kirby

Elizabeth Kirby
Lab Secretary

Image
Mariah blegen

Mariah Blegen, BS
Postbaccalaureate IRTA
Summer 2013 — Summer 2015
currently a medical student at School of Medicine & Dentistry University of Rochester

 

Image
Shan-He

He, PhD
Postdoctoral Visiting Fellow
Winter 2014 — Summer 2014
currently a industry researcher in Shanghai, China.

Image
Alanna kaplan

Alanna Kaplan, BS
Postbaccalaureate IRTA
Summer 2011 — Summer 2013
currently a graduate student (MD/PhD) at Yale School of Medicine

Image
JilianIafrati

Jilian Iafrati, PhD
Visting Fellow IRTA
Fall 2012 — Spring 2013
currently a post-doctoral fellow a University of California, San Francisco.

Image
katie h

Katie Holroyd, BS
Postbaccalaureate IRTA
Spring 2012 — Spring 2013

currently a neurology resident at the Brigham and Women's Hospital & Massachusetts General Hospital

Image
alice b.

Alice Dobi (Yue Wu), PhD
Postdoctoral Fellow
Summer 2008 — Summer 2012
currently a pathology resident at the PennState Health Milton S. Hershey Medical Center

Image
Mark W.

Mark Wilcox, BS
Postbaccalaureate IRTA
Summer 2011 — Summer 2012

currently a Ob/Gyn resident at the University of California, San Francisco and
Co-founder and Director of MERIT (Medical Education Resources Initiative for Teens)

Image
Robert F.

Robert Fuino, BS
Postbaccalaureate IRTA
Fall 2010 — Winter 2011

currently a neurology resident at the University of Vermont Medical Center

Image
Nyssa

Nyssa Sherazee, BA
Postbaccalaureate IRTA
Spring 2010 — Summer 2011

currently a junior architect in New York

Image
Paul K.

Paul Kramer, BA
Postbaccalaureate IRTA
Summer 2009 — Summer 2011
currently a post-doctoral fellow with Zayd Khaliq at NINDS

Image
Eric M

Eric Markey, BA
Postbaccalaureate IRTA
Summer 2009 — Fall 2010

Image
Gail S.

Gail Seabold, PhD
Postdoctoral Fellow, IRTA
Summer 2007 — Winter 2009
currently a Scientific Skill Coach at the Office of Intramural Training and Education (OITE) - seaboldg@mail.nih.gov

Image
Christine C.

Christine Christensen, BS
Postbaccalaureate IRTA
Summer 2008 — 2009

currently a graduate student of nursing at the University of Alabama

Summer Students

Summer Internship Program in Biomedical Research (SIP) Amgen Scholars Program
Sannidhi Shashikiran 2017 Meredith Crenca 2017
Daniel Rosenberg 2012 Mariana Rocha 2017
Tracy Ma 2010 Vanessa Kolb 2016
Natasha Garg 2009 Lindsay Eberhart 2016
    Allisen Goncalves 2015
(CCSEP) Community College Summer Enrichment Program  
Carloyn Bowering 2017    
Michael Montesino 2014    
Back to Top