
Contact Information
- Office: (301) 443-7695
- Lab: (301) 443-3769
- Fax: (301) 480-8035
- Mailing Address
Laboratory on Neurobiology of Compulsive Behaviors
5625 Fishers Lane, Room TN-41, MSC9411
Bethesda, MD 20892-9411
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.

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.

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:

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:

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. Matsui, V.A. Alvarez (2018) Cocaine inhibition of synaptic transmission in the ventral pallidum is pathway-specific and medidated by serotonin. Cell 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 (2018) Striatopallidal neurons control avoidance behavior in exploratory tasks. Molecular 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. (2018) Basal ganglia dysfunction contributes to physical inactivity in obesity. Cell Metabolism 25(2), 312–321.
D.M. Lovinger, V.A. Alvarez (2017) Alcohol and basal ganglia circuitry: Animal models. Neuropharmacology 122, 46–55.
A. Matsui, V.A. Alvarez (2017) Undercover Power of Endocannabinoids: Postsynaptic Ion-Channel Modulator. Neuron 93(6), 1243–1244.
M.A. Hutchison, X. Gu, M.F. Adrover, M.R. Lee, T.S. Hnasko, V.A. Alvarez, W. Lu (2017) Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior. Mol. 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 (2017) Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food. Biol. 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 (2017) Basal Ganglia Dysfunction Contributes to Physical Inactivity in Obesity. Cell Metab. 25(2), 312–21.
L.K Dobbs, J.C. Lemos, V.A. Alvarez (2017) Restructuring of basal ganglia circuitry and associated behaviors triggered by low striatal D2 receptor expression: implications for substance use disorders. Genes Brain Behav. 16(1), 56–70.
J.C. Lemos, D.M. Friend, A.R. Kaplan, J.H. Shin, M. Rubenstein, A.V. Kravitz, V.A. Alvarez (2016) Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling. Neuron 90(4), 824–38.
L.K Dobbs, A.R. Kaplan, J.C. Lemos, A. Matsui, M. Rubenstein, V.A. Alvarez (2016) Dopamine Regulation Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of Cocaine. Neuron 90(5), 1100–13.
V.A. Alvarez (2016) Clues on the coding of reward cues by the nucleus accumbens. PNAS USA 113(10, 2560–2.
J.H. Shin, M.F. Adrover, J. Wess, V.A. Alvarez (2015) Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens. PNAS USA 112(26), 8124–9.
K.B. Holroyd, M.F. Adrover, R.L. Fuino, R. Bock, A.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 cues. Neurophsychopharm advanced online publication 21 January 2015; doi: 10.1038/npp.2014.336.
M.F. Adrover, J.H. Shin, and V.A. Alvarez (2014). Glutamate and dopamine transmission from midbrain dopamine neurons share similar release properties but are differentially affected by cocaine. J. 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 addiction. Neuropharmacology 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 transmission. Neuropsychopharmacology 39(3):579–594.
R. Bock, J.H. Shin, A.R. Kaplan, A. Dobi, E. Markey, P.F. Kramer, C.M. Gremel, C.H. Christensen, M.F. Adrover, and V.A. Alvarez (2013). Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use. Nat. Neurosci. 16(5):632–638.
N. Sherazee, V.A. Alvarez (2013). DiOlistics: delivery of fluorescent dyes into cells. Methods Mol. Biol. 940:391–400.
A. Dobi, G.K. Seabold, C.H. Christensen, R. Bock, and V.A. Alvarez. (2011). Cocaine-Induced Plasticity in the Nucleus Accumbens Is Cell Specific and Develops without Prolonged Withdrawal. J. Neurosci. 31:1895–904.
P.F. Kramer, C.H. Christensen, L.A. Hazelwood, A. Dobi, R. Bock, D.R. Sibley, Y. Mateo, and V.A. Alvarez. (2011). Dopamine D2 receptor overexpression alters behavior and phsiology in Drd2-EGPFP mice. J. 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 autoreceptors. Nature 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 primates. Neuropsychopharm. 36: 2513–28
B.N. Mathur, N.A. Capik, V.A. Alvarez, and D.M. Lovinger (2011). Serotonin induces long-term depression at corticostriatal synapses. J 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' syndrome. Am. 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 slices. J. 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 learning. J. 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 images. Neuroinformatics 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 Stability. J. Neurosci. 28:7365–76.
V.A. Alvarez and B.L. Sabatini. (2007) Anatomical and physiological plasticity of dendritic spines. Annu. 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 interference. J. 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 Tsc2. Nat 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 internalization. J Neurosci. 22: 5769–76.
V.A. Alvarez , S. Arttamangkul, and J.T. Williams. (2001). A RAVE about Opioid Withdrawal. Neuron 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 glia. J. Neurosci. 20: 4091–4098.
Other Lab Resources
NIH Resources
- Neuroscience Seminar Series
- Research and Training Opportunities at the NIH
- Administrative Links
- NOTE the following may only be accessable from the NIH network:
Collaborators
present
- Dr Jose A. Moron-Concepcion
- Washington University School of Medicine in St Louis - Washington University Pain Center Missouri, USA
- Dr. Michael R. Bruchas
- Dr. Christoph Kellendonk
- Columbia University Irving Medical Center New York, USA
- Dr. Dorit Ron
- University of California San Francisco San Francisco, California, USA
- Dr. Alexxai Kravitz
past
- Dr. Marcelo Rubinstein
- Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires (UBA) Buenos Aires, Argentina
- Dr. Kathleen A. Grant
- Oregon National Primate Center and OHSU, Oregon, USA
- Dr. Todd Thiele
- University of North Carolina at Chapel Hill, North Carolina, USA
- Dr. David Sibley
Alumni
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![]() Tanisha London, BSc |
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![]() Sannidhi Shashikiran |
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![]() Julia Lemos, PhD |
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![]() Martin Adrover, PhD |
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![]() Elizabeth Kirby |
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![]() Mariah Blegen, BS |
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![]() He, PhD |
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![]() Alanna Kaplan, BS |
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![]() Jilian Iafrati, PhD |
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![]() Katie Holroyd, BS currently a neurology resident at the Brigham and Women's Hospital & Massachusetts General Hospital |
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![]() Alice Dobi (Yue Wu), PhD |
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![]() Mark Wilcox, BS currently a Ob/Gyn resident at the University of California, San Francisco and |
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![]() Robert Fuino, BS currently a neurology resident at the University of Vermont Medical Center |
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![]() Nyssa Sherazee, BA currently a junior architect in New York |
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![]() Paul Kramer, BA |
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![]() Eric Markey, BA |
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![]() Gail Seabold, PhD |
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![]() Christine Christensen, BS currently a graduate student of nursing at the University of Alabama |
Summer Students
Summer Internship Program in Biomedical Research (SIP) | Amgen Scholars Program | ||
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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 | |||
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Carloyn Bowering | 2017 | ||
Michael Montesino | 2014 |