Kalivas Laboratory

Kalivas

The lab conducts experiments intended to reveal the neurobiological underpinnings of drug addiction, and in doing so, rationally design pharmacotherapeutic treatments. Thus, our work spans animal models of addiction at the level of molecular physiology and morphology to strong clinical collaborations conducting clinical trials in human addicts. We are particularly focused on the neurobiology of relapse and the long-lasting changes in brain function produced by drug abuse that create the enduring vulnerability to relapse that defines addiction. In the course of the last 15-20 years of research we have come to a conclusion that impairments in how the prefrontal cortex regulates habit circuitry in the striatum are a critical drug-induced pathology. Accordingly, much of our work focuses on how addictive drugs regulate glutamatergic neurotransmission and synaptic plasticity in the nucleus accumbens (the portal whereby prefrontal cortex initiates behavioral change and adaptation). 

Major Projects 

Project 1 

Expanding on our recent discovery that relapse in the reinstatement model requires the rapid induction of transient synaptic potention (t-SP) in accumbens spiny cells. Thus showing the animal a drug-conditioned cue produces t-SP that correlates with the intensity of the behavioral response, regardless of whether the animal was trained to self-administer cocaine, heroin or nicotine. Following up on this finding has resulted in establishing the model shown below, whereby down-regulated glutamate transport causes synaptic glutamate spillover to stimulate nNOS interneurons, which activates matrix metalloproteases (MMPs). The activated MMPs create ligands for integrin receptors that signal postsynaptic insertion of AMPA receptors and dendritic spine enlargement (e.g. how we measure t-SP). In addition to clarifying details of this model, in future studies we are examining whether we can manipulate this microcircuit and thereby turn a biological reinforcer into a drug-like compulsive reinforcer. 

Key Recent Publications for Project 1

Gipson CD, YM Kupchik, H Shen, KJ Reissner, CA Thomas and PW Kalivas. 2013. Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron, 77: 867-872. PMID 23473317, PMCID: PMC3619421 

Gipson CD, KJ Reissner, YM Kupchik, AW Smith, NM Stankeviciute, ME Hensley-Simon and PW Kalivas. 2013. Nicotine relapse is mediated by glutamatergic plasticity. PNAS, 110: 9124-9129. PMID 23671067, PMCID: PMC3670307 

Shen, H, M.D. Scofield, H Boger, M Hensley and PW Kalivas. 2014. Synaptic glutamate spillover mediates heroin relapse. J Neuroscience, 34: 5649-5657. PMID 24741055, PMCID PMC3988415 

Shen H, CD Gipson, M Huits and PW Kalivas. 2014. Prelimbic cortex and ventral tegmental area modulate synaptic plasticity in nucleus accumbens during cocaine-reinstated drug seeking. Neuropsychopharmacology, 39: 169-177. PMID 24232172, PMCID: PMC3957111. 

Smith ACW, YM Kupchik, M.D. Scofield, CD Gipson and PW Kalivas. 2014. Synaptic plasticity mediating cocaine relapse requires matrix metalloproteinases. Nature Neuroscience, 17: 1655-1657, 2014. PMID 25226689, PMCID PMC4241163 

Scofield M.D., HA Boger, RJ Smith, PG Haydon and PW Kalivas. 2015. Gq-DREADD selectively initiates glial glutamate release and inhibits cue-induced cocaine seeking. Biol Psychiat, 78: 441-451. 

Project 2 

Another project is to examine circuitry distal to the nucleus accumbens mediating relapse to addictive drugs. We first used an optogenetic strategy to show that accumbens outputs to the ventral pallidum were critical relapse, and found that contrary to expectations this involved both D1- and D2-expressing cells projecting to the ventral pallidum (figure below). This contradicts widely held views that only D2 cells project to the pallidum. We have shown that there are changes in enkephalin regulation of GABAergic afferents to the ventral pallidum that are associated with relapse to cocaine, which contributes to a loss of synaptic plasticity at GABAergic synapses after cocaine. We continue using optogentic and DREADD chemogenic strategies in rats and mice to elucidate circuits and synaptic changes produced by addictive drugs in the ventral pallidum. 

Key Recent Publications for Project 2

Kupchik, Y and PW Kalivas. 2013. The rostral-medial ventral pallidum is a transition zone between the ventral pallidum and adjacent brain areas. Br Struct Func, 218: 1487-1500. PMID 23143342; PMCID: PMC3600056 

Stefanik MT, YM Kupchik, RM Brown and PW Kalivas. 2013. Optogenetic evidence that pallidal, not nigral projections from the nucleus accumbens core are necessary for reinstating cocaine seeking. J Neuroscience, 33: 13654-62. PMID 23966687; PMCID: PMC3755713 

Kupchik YM, MS Scofield, KC Rice, K Cheng, BP Roques and PW Kalivas. 2014. Cocaine self-administration causes enduring opioid inhibition of GABAergic synaptic transmission and plasticity in ventral pallidum. J Neuroscience, 34: 1057-1066. PMID 24431463, PMCID: PMC3891949 

Kupchik YM, RM Brown, DJ Schwartz and PW Kalivas. 2015. Coding the direct and indirect pathways by D1 and D2 receptors is no valid for projections from the nucleus accumbens. Nat Neuroscience, 18: 1230-1232. PMC4551610  

Project 3 

We collaborate with clinicians at MUSC to evaluate N-acetylcysteine in clinical trials for regulating neuropsychiatric disorders characterized in part by intrusive thinking. We hypothesize that dysregulation of the circuitry outlined above creates a vulnerability to thoughts becoming intrusive and difficult to control, which is a characteristic of addiction (e.g. craving), anxiety disorders (e.g. PTSD), major depression and OCD. N-acetylcysteine normalizes drug induced changes in the circuit by restoring glutamate transport, and we have successfully used N-acetylcysteine to reduce cocaine craving and PTSD. 

Key Recent Publications for Project 3

Reissner KJ, CA Thomas, RM Brown, S Spencer and PW Kalivas. 2013. The glial modulator propentofylline Impairs reinstatement in a rat model of cocaine relapse. Neuropsychopharmacology, 39: 499-506. PMID 23985782, PMCID: PMC3870775 

McClure EA, NL Baker, CD Gipson, MJ Carpenter, A Roper, B Froeliger, PW Kalivas and KM Gray. 2015. An open-label pilot trial of N-acetylcysteine and varenicline in adult cigarette smokers. Am J Drug Alcohol Abuse, 41: 52-56. 

Back SE, JL McCauley, KJ Korte, DF Gros, V Leavitt, KM Gray, MB Hamner, SM DeSantis, R Malcolm, KT Brady and PW Kalivas. 2015. A double-blind randomized controlled pilot trial of N-acetylcysteine in Veterans with PTSD and substance use disorders. J Clin Psychiatry, submitted. 

Reviews

Our perspective on drug addiction research and the important role played by prefrontal regulation of the striatum can be found in these two review articles:

Kalivas, PW. 2009. The glutamate homeostasis hypothesis of addiction. Nature Rev Neuroscience, 10: 561-572.

Kalivas PW and ND Volkow. 2011. New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiat, 16:974-986.

More Publications

People in the Lab 

Peter Kalivas

Peter received his Ph.D. from the University of Washington in 1980 with Akira Horita, and completed postdoctoral training at the University of North Carolina with Art Prange in 1982. He moved to Charleston from the West Coast and began his current position as Professor and Chair of Neurosciences in 1998. Outside the lab, Peter likes to travel to off beat places. 

Michael D. Scofield

Mike received his bachelor’s degree in biology and biotechnology from Worcester Polytechnic Institute in 2005 and his Ph.D. in biomedical sciences from the University of Massachusetts Medical School in 2010. In his graduate work he studied transcription factor assembly at the promoter of the b4 subunit of the neuronal nicotinic acetylcholine receptor. He joined the Kalivas lab in 2011 and is currently investigating the role that gliotransmission plays in mediating the changes in neuroplasticity responsible for relapse. Outside the lab, Michael enjoys music, movies and walking his dog. 

Sadé Spencer

Sade received her bachelor’s degree in biology from the University of Alabama and her Ph.D. in neuroscience from the University of Texas Southwestern Medical Center. During her graduate work with Colleen McClung she studied the role of the circadian clock in the regulation of dopamine transmission and mood-related behavior. She joined the lab in 2012 to study the neuroplasticity underlying relapse behavior and is developing a model to dissociate mechanisms of drug-primed versus cued reinstatement in the rat. 

Constanza Garcia Keller

Coti received her B.S. and her Ph.D. from the Universidad Nacional de Córdoba, Argentina in 2014. In her graduate studies Coti investigated acute stress induced long-term changes in nucleus accumbens dopamine and glutamate sensitive drug responses under the guidance of Prof. Cancela Liliana. Coti joined the Kalivas lab in August, 2014 and is currently working on part of a major project to identify the signaling and pathophysiological mechanisms in nucleus accumbens core that link synaptic glutamate spillover and activation of matrix metalloproteinases (MMPs). MMPs induce subsequent transient long-term plasticity (t-LTP) that is necessary for reinstated drug seeking after cocaine. In her spare time, Coti enjoys doing outdoor sports, listening to live music and watching good independent films; her main hobby is photography. 

Doug Roberts-Wolfe

Doug graduated with a BA in neuroscience and physics from Hampshire College (Amherst, MA) in 2008. He worked at the Britton Lab at Brown University (Providence, RI) studying the effects of mindfulness meditation on cognitive bias, and at a private neurofeedback clinic for three years before enrolling in the M.D./Ph.D. program at MUSC. Doug joined the Kalivas lab as a graduate student after completing the first two years of medical school. Doug’s current project in the lab is investigating transient plasticity in the infralimbic cortex à nucleus accumbens shell circuit during extinction training from cocaine. Outside of the lab, Doug enjoys running, weight lifting, mindfulness meditation, boogie boarding, playing piano, learning to speak Spanish, and travel. 

Jasper Heinsbroek

Jasper received his BSc in Biomedical Sciences (2010) and MSc in Neurosciences (2012) from Vrije Universiteit in Amsterdam, the Netherlands. He joined the lab in 2013 and is using optogenetic and pharmacogenetic circuit dissection strategies to investigating how basal ganglia inputs and subcircuits mediate addiction related behavior. Jasper likes listening to music, playing guitar and outdoor activities. 

Madhura Athreya 

Maddy graduated with a dual B.Sc. Degree in Biotechnology and Zoology from Osmania University, Hyderabad - India in 2009 and continued to pursue her MS at the Medical university of South Carolina. Maddy also earned a Post-Graduate Diploma in Management from the Institute of Clinical Research India. She joined the Kalivas lab as the lab manager in 2014 after spending a few years in clinical neuroscience working as a study coordinator at the MUSC Stroke Center. Maddy enjoys yoga, macro photography, cooking and trying new foods, hiking, camping and travelling. 

Ana Clara Bobadilla

Ana Clara received her Ph.D. in Neurosciences from the Pierre & Marie Curie University (Paris, France) in 2014. The main topic of her doctoral work, supervised by Dr. Jean-Pol Tassin, involved the long-term modifications of the serotonergic and noradrenergic transmissions induced by chronic amphetamine treatment. Ana Clara joined the Kalivas lab in November of 2014 to start her first post-doctoral position studying the role of glutamatergic uptake in reinstatement of cocaine self-administration. Outside of the lab, Ana Clara enjoys shooting portraits, dancing tango, listening to good music and discovering new places. 

Daniela Neuhofer

Daniela graduated in Biology from University of Vienna, Austria. In 2010 she received her Ph.D. in Neurobiology from the Humboldt University in Berlin, Germany. At the Behavioral Physiology group of Prof. Dr. Bernd Ronacher she investigated the impact of noise on auditory signal processing. For her first Post Doctoral Fellowship, she moved to Marseille, France to work at the INMED in the team of Olivier Manzoni. Using slice electrophysiology, pharmacology and optogenetics, she investigated the dysfunction of synaptic transmission and plasticity in the nucleus accumbens in a mouse model for Fragile X syndrome. She joined the Kalivas lab in 2015 and is using electrophysiological and optogenetic techniques to investigate synaptic plasticity in the ventral pallidum before and after cocaine abuse. Besides science, Daniela enjoys running, watching Dolphins at the battery and music: from Afrobeat to psychedelic Cumbia. 

Anna Kruyer

Anna received her BA in Natural Sciences from Fordham University in 2008 and her Ph.D. in Neurobiology and Genetics from the Rockefeller University in 2015. During her thesis work, Anna explored the role of the glutamate receptor subunit GluK4 in anxiety-related behaviors and excitotoxicity in the lab of Dr. Sidney Strickland. During her time in the Strickland lab, Anna became interested in the pathological changes that occur within the microvasculature as a result of Alzheimer’s disease. For this reason, she began studying the molecular and ultrastructural changes induced by hypertension in a mouse model of Alzheimer’s disease, under the co-mentorship of Dr. Erin Norris. Anna joined the Kalivas lab in 2016 and is using various imaging techniques to examine the glial changes that underlie synaptic glutamate spillover and lead to relapse. 

Lauren Beloate

Lauren, or "Nikki", received her B.A. in psychology at the University of Mississippi in 2010 and Ph.D in neuroscience at the University of Mississippi Medical Center in 2016. Under the mentorship of Dr. Lique Coolen, she used a multidisciplinary approach to study the neural mechanism of the effects of loss of the natural reward, sexual behavior, on drug-seeking behavior in male rats. Nikki joined the Kalivas lab in 2016 and plans to continue studying the neural mechanism of drug abuse. In her free time, she enjoys working out, brunching, outdoor activities and spending time with her dog, Macy, and cat, Luna. 

Vivian Chioma

Vivian received her Bachelor's degree in Interdisciplinary Studies: Neuroscience from the University of Maryland, Baltimore County in Baltimore, M.D. in 2014. During this time, she worked in the lab of Joseph Cheer investigating the role of endocannabinoids and dopamine in motivation and reward-seeking behavior using a shock avoidance behavioral paradigm. She then enrolled in the M.D./Ph.D. program at MUSC. Vivian joined the Kalivas lab in 2016 after completing the first two years of medical school. Her current project in the lab focuses on elucidating the neurobiology underlying THC self-administration and relapse in rodents. Outside of lab, Vivian enjoys Tae Bo, cooking, listening to music, and traveling. 

Davide Amato

Davide received a M.Sc. in Experimental Psychology in 2003 and a Ph.D. in Pharmacology in 2008 from Sapienza - University of Rome, Italy. Also, he worked as a scientist in Sigma-tau, a large pharmaceutical company, during the Ph.D. program. Davide completed a postdoctoral training in Psychiatry Neuroscience at King´s College London, UK, in 2010. He moved on to Germany working as Head of the Laboratory at the University of Erlangen-Nürnberg until 2017. In the same University he gained the title of Lecturer (Privatdozent). Davide joined the Kalivas Lab in April 2017 as Research Assistant Professor. He will be studying the cortico-striatal thalamo-cortical loop neurocircuitry in the context of cocaine addiction, psychosis and related treatments. Outside the lab, Davide enjoys cycling, swimming (triathlon and other outdoor activities), reading, eating and engaging in social life. 

Recent Post-Doctoral Fellows 

Behnam Ghasemzadeh
Ph.D. UPenn
1996-03
Associate Professor, Marquette U 

Roberto Melendez
2002-06
Assistant Professor, U Puerto Rico 

Dave Baker
Ph.D. Ariz St U
1999-02
Associate Professor, Marquette U 

Hao-Wei Shen
2004-2012
Assistant Professor, Peking U, Beijing 

Krista McFarland
Ph.D. UCSB
1999-03
ACADIA Pharm Inc 

Alejandra Pacchioni
2004-08
Assistant Professor, U Rosaria 

Jiang-Xiang Xi
2000-05
Scientist, NIDA IRP

Ryan Lalumiere
2005-10
Assistant Professor, U Iowa 

Karen Szumlinski
2000-05
Associate Professor, UCSB 

Mary Torregrosa
2005-07
Assistant Professor, University of Pittsburg 

Xing-Chun Tang
2001-06
Psychiatry Fellow, UT Southwestern 

Lori Knackstedt
2005-12
Assistant Professor, University of Florida 

Kate Reissner
UC Irvine, 2008-2013
Assistant Professor, University of North Carolina 

Robyn Brown
2012-13
Postdoctoral Fellow, Florey Institute of Neuroscience and Mental Health, Australia 

Rachel Smith
2010-13
Assistant Professor, Texas A&M University 

Yonatan Kupchik
2010-14
Professor, The Hebrew University of Israel 

Cassandra Gipson
2011-2015
Assistant Professor, Arizona State University 

Recent Ph.D and M.D./Ph.D. Students 

Scott Bowers
Ph.D. 2003
Assistant Professor, VCU 

Megan Moran
Ph.D. 2006
Assistant Professor, MUSC 

Mary Lee Gregory
Ph.D. 2006
Neurology Fellow, Johns Hopkins 

Jamie Peters
Ph.D. 2008
Assistant Professor, Medical University of South Carolina 

Armina Omole
Ph.D. 2010
Neurology Resident, University of Pennsylvania 

Khaled Moussawi
Ph.D. 2010
Neurology Resident, Harvard 

Michael Stefanik
Ph.D. 2014
Postdoctoral Fellow, Rosalind Franklin University 

Alexander Smith
Ph.D. 2015
Postdoctoral Fellow, Mount Saini Hospital 

Recent Visiting Scientists 

Liliana Cancela
2004-05
Professor, U Cordoba 

Gabriel Quintero
2012
Associate Investigator, Panama 

Wenua Zhou
2006, 2008
Dean
Ningbo U 

Mike Bardo
2002-03
Professor, U Kentucky 

Louis Alguacil
2002-03
Chair, San Pablo U, Madrid 

Sam Kombian
2006
Professor, U Kuwait 

Shigenobu Toda
2000-2009
Associate Professor, Kananzawa Med School, Japan 

Recent Lab Managers and Technicians 

Megan Hensley Megan Hensley
2008-12
Graphic Artist 

Charles Thomas
 2010-2014
Lab Manager
Dana-Farber Cancer Institute, Harvard University 

Neringa Stankevicuite
2012-15
Medical Assistant, Greenville-SC 

Nic Allen
2014-15
Student, LECOM Scool of Dental Medcine - Bradenton,FL 

Eric Dereschewitz Eric Dereschewitz
2017-Present
Research 

Life in the Lab 

Life in the Kalivas lab is very interconnected with the other addiction oriented research labs at MUSC, of which there are many. This allows postdocs and students to range across a full spectrum of cutting-edge biotechnologies as they proceed with their research programs. This strongly collaborative environment is supported by 3 NIH-funded addiction centers (see below) that many of the faculty partake in, as well as two addiction institutional training grants to support postdocs and students.  The technologies currently ongoing that you can potentially apply to your projects range from behavioral (drug self-administration, cognitive testing) to systems (cellular morphology and circuitry; optogenetic and DREADD manipulation of circuits) to molecular approaches. In addition, we have strong collaborations with clinicians at MUSC who manage large trials with cocaine, alcohol, nicotine and marijuana addicts. 

The Kalivas lab typically contains 2 graduate students and up to 8 postdoctoral fellows, visiting scientists or research-track faculty. In addition, the laboratory contains a number of undergraduate students who are completing their undergraduate degree at the College of Charleston. The Neuroscience degree requires that all students conduct a research thesis, making our laboratory a prime location for highly motivated students to spend a year conducting research in collaboration with our postdoctoral fellows or graduate students. 

Links (links to internal webpage) 

  • Neurobiology of Addiction Research Center (NARC)
  • Alcohol Research Center (ARC)
  • SCOR on Sex and Gender Factors Affecting Women’s Health

The Department of Neurosciences & the Neurosciences Institute 

The laboratory is located in the Department of Neurosciences, which has been ranked between 2nd and 7th nationally in research grant awards from the NIH since 2008. The Neurosciences Institute manages a graduate program in neuroscience offering Ph.D., M.D./Ph.D. and MS degrees. There are over 30 graduate students at any given time in the program. The department also contains over 40 postdoctoral fellows, and two T32 institutional training grants support both pre- and postdoctoral trainees, as well as clinical research fellows. The Neurosciences Institute also sponsors an annual retreat, often held at one of the local beach venues (below). 

Charleston

Charleston is a city of approximately 500,000 in the metro area and contains three undergraduate campuses (College of Charleston, Citadel and Charleston Southern) a law school (Charleston Law) and the Medical University of South Carolina (containing colleges of Medicine, Graduate Studies, Dentistry, Pharmacy, Nursing and Health Professions). The city is accordingly youthful, with a large district containing bars, pubs and excellent restaurants. Charleston is the intellectual and artistic center of South Carolina, with the annual Spoleto Arts Festival a three-week display of local and international artistic and musical talent. Charleston is surrounded by water, and many beaches are within 20 min of downtown.