The Neurobiology of Addiction Research Center (NARC)
Peter Kalivas, Ph.D.Project 1 - Neuroplasticity Associated with Cocaine Seeking
A major objective of the NARC is to understand why addicts have difficulty controlling their habitual drug taking and frequency relapse. By discovering the biological basis of this loss of control, pharmacological interventions can be designed to restore the ability of addicts to choose whether or not to take drugs. Normally we change our habits when they are no longer adaptive to achieving success in our ever-changing environment. While striatal habit circuitry regulates the execution of well-learned habit behaviors, like drug seeking, normally this habit circuitry can be updated by the prefrontal cortex. The primary goal of Project #1 of the NARC is to examine the cellular and physiological changes produced by cocaine use in the primary connection of the prefrontal cortex to striatal habit circuitry through the nucleus accumbens. This is a glutamatergic connection and three experimental strategies are used:
Experimental Strategy #1. Measure changes in proteins controlling glutamate transmission from the prefrontal cortex to the accumbens. This includes both synaptic proteins and glial proteins responsible for regulating metabotropic glutamate receptors controlling glutamate release and potentiation or depotentiation of the synapse. Figure 1 below illustrates some of these proteins.
Figure 1: Changes in proteins that contribute to alterations in glutamate transmission. Key proteins are the cystine-glutamate exchanger (xc-) and the glutamate transporter (GluT), both of which are primarily glial. Down-regulation of these proteins reduces the ability of the nucleus accumbens to regulate both extrasynaptic and synaptic glutamate transmission. This is associated with changes in a number of postsynaptic proteins, notably actin binding proteins which indicate that the dendritic spine is primed to be able to rapidly change its structure. (adapted from Hu and Kalivas, Tr Neurosci, 2006)
Experimental Strategy #2. Dendritic spines are the morphological subcompartment regulating synaptic grading. Using a method involving filling neurons combined with an automated procedure for quantifying spine morphology and density we have determined that marked changes are produced in the ability of spines to respond to glutamate release after chronic cocaine. Primarily this is a marked change in spine head diameter produced by the release of glutamate after a cocaine in cocaine trained animals, not control animals. Figure 2 illustrates some of these data.
Figure 2. Dendritic spine change rapidly after a cocaine injection in cocaine trained animals, but not controls. Coc T=0 shows spines before a cocaine injection. By 45 min after a cocaine injection there is a thickening of spines and by 120 min this has reversed and spines are now thinner than T=0. By 360 min after injection spines have returned to baseline.
Experimental Strategy #3. Rapid changes in dendritic spine morphology and glutamate-related proteins indicates their may be an inability to move synapses into a potentiated or depotentiated state. Potentiation and depotentiation of synapses is measured as longterm potentiation (LTP) or depression (LTD). Using an in vivo model we stimulate the prefrontal cortex and measure field responses in the nucleus accumbens, and have found exactly that, both LTP and LTD are markedly reduced. LTP and LTD are thought to be necessary to establish new behaviors. In the case of addiction, behaviors that may compete with cocaine relapse.
Translating to Animal Models and the Clinic. The final step in the NARC is to use this information to develop new treatments for addiction. This is done primarily in Project #4 where new compounds are examined in the animal model of relapse. Also, compounds are examined in preliminary clinical trials in cocaine addicts by investigators in the Pilot Core. The references below describe compounds characterized by the NARC in the animal model and pilot clinical trials. For more information please go to these pages in the NARC website.
Recent Primary Papers from the NARC, Project #1.
LaLumiere RT and PW Kalivas. 2008. Glutamate release in the nucleus accumbens core is necessary for heroin-seeking. J Neuroscience, 28:3170-3177.
Peters J, R LaLumiere and PW Kalivas. 2008. Activity in infralimbic cortex suppresses cocaine relapse. J Neuroscience, 28: 6046-6053.
Shen H, L Korutla, N Champtieux, S Toda, R LaLumiere, J Vallone, M Klugmann, JA Blendy, SA Mackler and PW Kalivas. 2007. NAC1 translocates the proteasome complex into dendritic spines. J Neuroscience, 27: 8903-8913.
Shih AY, H Erb, X Sun, S Toda, PW Kalivas and TH Murphy. 2006. Cystine/glutamate exchange modulates glutathione supply for cell proliferation and neuroprotection from oxidative stress. J Neuroscience, 26:10514-10523.
Nogueira, L, PW Kalivas and A Lavin. 2006. Long-term neuroadaptations produced by withdrawal from repeated cocaine treatment: Role of dopaminergic receptors in modulating cortical excitability. J Neuroscience, 26: 12308-12313.
Toda, S., H-W Shen, S Cagle and PW Kalivas. 2006. Regulation of actin binding proteins contributes to cocaine-induced behavioral plasticity. J Neuroscience, 26: 1579-1587.
Szumlinski, KK, KE Abernathy, EB Oleson, M Klugmann, KD Lominac, D-Y He, D Ron, M During and PW Kalivas. 2006. Homer isoforms differentially regulate cocaine-induced neuroplasticity. Neuropsychopharmacol, 31: 768-777.
Recent Review Papers from the NARC, Project #1.
Thomas MJ, PW Kalivas, Y Shaham. 2008. Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Brit J Pharmacol, 154: 327-342.
Kalivas PW and O’Brien C. 2008. Addiction as a disease of staged neuroplasticity. Neuropsychopharm Rev, 33:166-180.
Kalivas PW. 2007. Cocaine and amphetamine-like psychostimulants: neurocircuitry and glutamate neuroplasticity. Dialogues Clin Neuro 9: 167-175.
Kalivas PW. 2007. Neurobiology of cocaine addiction: Implications for new pharmacotherapy. Am J Addict, 16: 71-78, 2007.
Kalivas PW and XT Hu. 2006. Exciting inhibition in psychostimulant addiction. Tr Neurosci, 29:610-616.
Szumlinski, KK, PW Kalivas and PF Worley. 2006. Homer proteins: implications for neuropsychiatric disorders. Curr Op Neurobiol, 16: 251-257.
Recent Papers Translating Project #1 findings into animal models and pilot clinical trials.
Zhou W and PW Kalivas. 2008. N-acetylcysteine facilitates extinction and induces enduring reductions in cue- and heroin-induced drug-seeking. Biol Psychiat, 63: 338-340.
Peters J, Vallone J, Laurendi K and PW Kalivas. 2008. Oppossing roles for the ventral prefrontal cortex and basolateral amygdala on spontaneous recovery of cocaine-seeking. Psychopharmacol, 197: 319-326.
LaRowe, SD, H Myrick, S Hedden, P Mardikian, M Saladin, A McRae, K Brady, PW Kalivas and R Malcolm. 2007. Is cocaine desire reduced by N-acetylcysteine? Am J Psychiat, 164: 1115-1117.
Knackstedt L and PW Kalivas. 2007. Extended access to cocaine self-administration enhances drug-primed reinstatement but not behavioral sensitization. J Pharmacol Exp Ther, 322: 1103-1109.
Peters, J and PW Kalivas. 2006. A role for nucleus accumbens group II metabotropic glutamate receptors in cocaine-induced reinstatement. Psychopharmacol, 186: 143-149.