Research in the Kalivas Lab
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).
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, MD 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, MD 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 MD, 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.
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
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.
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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19571793
Kalivas PW and ND Volkow. 2011. New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiat, 16:974-986. http://www.ncbi.nlm.nih.gov/pubmed/21519339