Drug Addiction glutamate dysfunction, treatments, biomarkers. Peter Kalivas Department of Neurosciences Medical University of So Carolina Charleston

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1 Drug Addiction glutamate dysfunction, treatments, biomarkers Peter Kalivas Department of Neurosciences Medical University of So Carolina Charleston

2 What is Addiction? Inability to control drug-seeking habits. 1. A pathological strengthening of drug-seeking habits. 2. A cognitive pathology that reduces the ability to control drugseeking habits

3 Staging Addiction & Treatment Strategies Social Use Regulated Relapse Compulsive Relapse Replacement Therapies Restore Control (Reverse addiction pathology) Pharmacotherapeutic Interventions Psychosocial Interventions

4 One addiction pathology is impaired prelimbic glutamate input to the nucleus accumbens core Prelimbic Cortex Nuc Accumbens core Cortico-Striatal Habit Circuit Drug Seeking Reduced basal activity in prefrontal cortex Excessive activity during relapse or craving Jentsch, Taylor, Psychopharmacol, 1999 Goldstein, Volkow, Am J Psychiat, 2002 Kelley, Neuron, 2004 Kalivas et al., Neuron, 2005 Hyman et al, Ann Rev Neurosci, 2006 Glutamate GABA Peptides

5 Prefrontal-Accumbens Synaptic Neuropathology Prefrontal Neurons **shown with multiple addictive drugs Increased firing and membrane excitability- Sun, Rebec, J Neurosci, 2006; Dong et al., J Neurosci, 2005 **Increased blood flow- Goldstein, Volkow, Am J Psychiat, 2002 Presynaptic **Increased glutamate release probability- McFarland et al, J Neurosci, 2003; Conrad et al, Nature, 2008 **Due to reduced mglur2/3 signaling and elevated AGS3- Bowers et al., Postsynaptic Neuron, 2004 Increased GluR1 homomeric AMPA receptors- Conrad et al, Nature, 2008; Kourrich et al, J Neuro, 2007 **Increased NR2b and silent synapses- Huang et al., Neuron, 2009 Decreased mglur5 signaling- Knackstedt., J Neurosci, 2010 **Increased spine head diameter/density during relapse- Shen et al., J Neurosci, Metaplasticity 2009; submitted **Reduced LTP- Moussawi et al., Nat Neuro, 2009 **Reduced LTD- Martin et al., Nat Neuro, 2006; Moussawi et al., Nat Neuro,

6 Dialysis Probe Glutamate Homeostasis - balance between nonsynaptic and synaptic glutamate that regulates synaptic plasticity - Presynaptic Terminal iglur Dendrite Patch Recordings mglur2/3 mglur1/5 Cys/Glu Exchange Glu Transport Glia Cystine Cystine Glutathione

7 Self-administered Cocaine, Heroin and Nicotine Alter Glutamate Homeostasis Presynaptic Terminal Dendrite iglur mglur2/3 mglur1/5 N-acetylcysteine Lori Knackstedt Cy s Cys/Glu Exchange Glu Transport CeftriaxoneGlia Knackstedt et al., Biol Psychiat, 2009

8 Cocaine N-acetylcysteine Cys/Glu and exchange Nicotine restores regulates reducecystine-glutamate synaptic glutamate exchange release Baker et al, and by NatNeuro, providing stimulate 2003; Madayag tone release et al., JNeurosci, on regulating presynaptic 2007; Knackstedt mglur2/3 et al., BiolPsychiat, 2009 Baker et al, Nat Neurosci, Baker 2003; et al, JNeurosci, Moran et al., 2002; JNeurosci, Moran 2005; et al., Moussawi JNeurosci, et 2005 al., NatNeuro, 2009 N-acetylcysteine Cys Glu Glutamate outside the synapse Cys Glutathione

9 Cocaine Extinction Reinstatement Self-administration ± NAC ± NAC Days Withdrawal Reinstatement No NAC No NAC * Wenhua Zhou Chronic NAC augments extinction learning and inhibits retrieval of cocaine- and heroin-seeking Zhou and Kalivas, Biol Psychiat, 2008

10 Chronic NAC Ameliorates Cocaine-induced induced Prefrontal- Accumbens Neuropathology Glial glutamate transport (largely submitted for publication **shown for both heroin and cocaine) **Normalizes cystine-glutamate exchange and glutamate uptake- Knackstedt et al., BiolPsych, 2009 Presynaptic Restores glutamate release probability Restores mglur2/3 signaling Postsynaptic Normalizes AMPA:NMDA ratio Normalizes spine diameter and density Metaplasticity **Restores LTP and LTD-Moussawi et al., Nat Neuro, 2009

11 Using Glutamate Homeostasis to Treat Addiction In double-blind blind pilot clinical studies N-acetylcysteineN reduced: 1. Cue reactivity (craving) in cocaine addicts- LaRowe et al., Am J Psychiat, Number of cigarettes smoked- Knackstedt et al., Biol Psychiat,, Marijuana Scores on use obsessive in adolescents- compulsive Gray scale et al., Am modified J Addict, 2009 for pathological gambling- Grant et al., BiolPsychiat, Hair pulling in trchotillomania- Grant et al., Arch Gen Psychiat, 2009

12 Using Glutamate Homeostasis to Treat Addiction Robert Malcolm and Steve LaRowe Double blind trial in 111 randomized subjects with cocaine dependence. Tri-weekly urine measurements to verify NAC and cocaine use Increase dose of NAC, use a pro-cysteine drug with greater brain bioavailability. Biomarker for effectiveness I. PET mglur ligand. Better in vivo measures of glutamate homeostasis in animal models may reveal superior interventions I. Accurate estimates of extracellular glutamate (electrochemical biosensor combined with fepscs). II.. Combined in vivo Increase multiphoton number spine measure of subjects and and fepsc. compliance. More controlled testing environment Give NAC plus other drugs affecting glutamate homeostasis

13 New Pharmacotherapies Based on Glutamate Homeostasis Ceftriaxone NAC NAC mglur5 antagonist mglur2/3 agonist

14 The People Who Did the Work Kate Ryan Reisner LaLumiere Lori Knackstedt Armina Wiggins Haowei Shen Joachim Uys Khaled Moussawi Phelipe Hurt NARC Gary Aston-Jones Antonieta Lavin Jakie McGinty Ron See Others Karl Deisseroth, Stanford Steve LaRowe, MUSC Scott Mackler, UPenn Robert Malcolm, MUSC Athina Markou, UCSD Satish Nair, UMissouri Foster Olive, Ariz St U Susan Sesack, UPitt Paul Worley, Hopkins