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). 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
Our most recent research is highlighted in the publications below. The key projects include investigation of our recent discovery that relapse in the reinstatement model requires the rapid induction of LTP in accumbens spiny cells, regardless of whether relapse is to a conditioned cue, context, cocaine, heroin or nicotine. The facts that the rapid LTP is associated with all drugs and modalities so far examined and is closely correlated with the intensity and time course of behavioral responding, leads us to suspect that this rapid LTP underpins the unmanageable motivation to relapse that characterizes addiction. The LTP appears to rely on the spill over of synaptic glutamate outside of the synaptic cleft to stimulate extrasynaptic glutamate receptors. Accordingly, a critical adaptation that is shared between cocaine, nicotine, heroin and alcohol is a down-regulation of glial glutamate transport, which markedly augments glutamate spill over. Based on this we have come to focus on drugs that restore glutamate transport to prevent relapse in our animal model. Importantly, we find that this class of drugs also normalizes other adaptations associated with LTP. Moreover, in collaboration with clinical colleagues here at MUSC, we have entered one of these drugs, N-acetylcysteine, into clinical trials for marijuana, cigarette and cocaine addiction.
Recent publications highlighted above:
Shen H, K Moussawi, W Zhou, S Toda and PW Kalivas. 2011. Heroin relapse requires LTP-like neuroplasticity mediated by NR2B-containing NMDA receptors. PNAS, 108: 19407-19412. http://www.ncbi.nlm.nih.gov/pubmed/22084102
Kupchik, YM, K Moussawi, XC Tan, X Wang, BC Kalivas, R Kolokithas, KB Ogburn and PW Kalivas. 2012. The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine. Biol Psychiat, 71: 978-986. http://www.ncbi.nlm.nih.gov/pubmed/22137594
Trantham-Davidson, H, R LaLumiere, K Reissner, PW Kalivas and LA Knackstedt. 2012. Ceftriaxone normalizes synaptic transmission, glutamate transport and export following cocaine self-administration and extinction training. J Neuroscience, 32:12406-12410. http://www.ncbi.nlm.nih.gov/pubmed/22956831
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. http://www.ncbi.nlm.nih.gov/pubmed/23671067
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. http://www.ncbi.nlm.nih.gov/pubmed/23473317
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, in press.
Other Recent Publications
Stankeviciute NM, MD Scofield, PW Kalivas and CD Gipson. 2013. Rapid, transient potentiation of dendritic spines in context-induced relapse to cocaine seeking. Addict Biol, in press.
Smith, RJ, MK Lobo, S Spencer and PW Kalivas. 2013. Cocaine-induced adaptations in D1- or D2-expressing accumbens projection neurons: Not synonymous with classical direct and indirect pathways. Curr Op Neurobiol, in press.
Shen H and PW Kalivas. 2013. Reduced LTP and LTD in prefrontal cortex synapses in the nucleus accumbens after heroin self-administration. Int J Neuropsychopharmacol, 16: 1165-1167.
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, in press.