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Yavin Shaham Behavioral Neuroscience Branch IRP/NIDA/NIH/DHHS, Baltimore

Incubation of cocaine craving: behavioral and neuronal mechanisms. Yavin Shaham Behavioral Neuroscience Branch IRP/NIDA/NIH/DHHS, Baltimore. Special thanks: The Waletzky family SfN committee Jane Stewart Roy Wise Lin Lu Bruce Hope. Ongoing research projects.

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Yavin Shaham Behavioral Neuroscience Branch IRP/NIDA/NIH/DHHS, Baltimore

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  1. Incubation of cocaine craving: behavioral and neuronal mechanisms Yavin Shaham Behavioral Neuroscience Branch IRP/NIDA/NIH/DHHS, Baltimore Special thanks: The Waletzky family SfN committee Jane Stewart Roy Wise Lin Lu Bruce Hope

  2. Ongoing research projects 1. Stress-induced reinstatement of drug and palatable food seeking (Sunila Nair, Udi Ghitza) 2. Context-induced reinstatement of heroin seeking (Jennifer Bossert) 3. Developing a new model to assess relapse to cocaine seeking (Abraham Zangen, Weizmann Institute, Israel) 4. Time-dependent increases in cocaine seeking after withdrawal (incubation of cocaine craving)

  3. Outline • 1. The clinical problem • 2. Behavioral studies • 3. Neurobiological studies • 4. Conclusions and a brief summary of recent results on incubation of craving • 5. Acknowledgements

  4. Background The clinical problem:Relapse to cocaine use after prolonged abstinence This relapse can be provoked by re-exposure to cocaine-associated cues that also induce drug craving Based on anecdotal evidence, Gawin and Kleber (1986) suggested that cue-induced cocaine craving increases over the first several weeks of abstinence and remains high over extended abstinence periods Research question: how do we study this “incubation” phenomenon in the laboratory rat?

  5. Cocaine self-administration: 10 days Withdrawal (abstinence) period: 1 to 180 days 60 1 2 4 7 15 30 180 90 X Extinction tests for cocaine seeking in a drug-free state An experimental procedure to study time-dependent changes in cue-induced cocaine seeking

  6. Time-dependent increases in cue-induced cocaine-seeking after withdrawal from drug self-administration * * 300 300 * 225 225 * * * Lever presses (6 h) Lever presses (6 h) 150 150 * 75 75 0 0 1 30 90 180 Withdrawal day Withdrawal day 1 2 4 7 15 30 60 Extinction tests for cocaine seeking in a drug-free state Cocaine self-administration (10 days) Withdrawal period (1 to 180 days) 60 1 2 4 7 15 30 180 90 180 days in rats ~ 15-18 years in humans 60 days in rats ~ 5-6 years in humans Grimm et al. Incubation of cocaine craving after withdrawal.Nature, 2001

  7. Heroin Methamphetamine Sucrose * 400 200 150 * * * 120 * 300 150 1 6 12 25 66 * 90 Lever presses (3 h) Lever presses (6 h) 200 100 Lever presses (5 h) 60 50 100 30 0 0 0 1 7 30 60 90 180 1 21 51 Withdrawal day Withdrawal day Withdrawal day Generality of the incubation phenomenon to other drug and non-drug rewards Reward self-administration (10 days) Withdrawal period (1 to 180 days) Extinction tests Shalev et al. Psychopharmacology, 2001 Lu et al. Neuropharmacology, 2004 Shepard et al. Biol Psychiatry, 2004

  8. More evidence for incubation of reward craving Cocaine 1 Neisewander et al. 2000 Cocaine 3 Sorge and Stewart, 2005 Cocaine 2 Conrad, Marinelli, Wolf, 2005 * * 40 200 30 150 * Nose pokes (30 min) 20 Lever presses 100 10 50 0 0 1 21 1 45 1 10 60 Withdrawal day Withdrawal day Withdrawal day Alcohol Bienkowski et al. 2004 60 * 45 Lever presses (20 min) 30 15 0 1 28 56 Withdrawal day Heroin Di Ciano and Everitt 2004 Sucrose Di Ciano and Everitt 2004 120 70 * * * * 60 100 * * 50 * 80 40 * Lever presses (30 min) * Lever presses (30 min) 60 30 40 20 20 10 0 0 1 2 3 10 17 24 31 59 1 2 3 10 17 24 31 59 Withdrawal day Withdrawal day

  9. Summary of behavioral findings Incubation of reward craving: • Long-lasting, but not permanent • Observed with several drugs of abuse • Observed with non-drug reinforcers • Not evident after acute re-exposure to cocaine priming injections Lu L, Grimm JW, Hope BT, Shaham Y (2004) Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47S1: 214-227 (NIDA special issue)

  10. The neuronal mechanisms of incubation of craving

  11. Training phase Withdrawal phase 100 80 The mesocorticolimbic dopamine system 1 day 30 days 90 days 60 Rewards (6 h) Cortex 40 Sucrose (n=26) 20 Cocaine (n=25) 0 1 2 3 4 5 6 7 8 9 10 Day Nucleus accumbens Ventral tegmental area (VTA) From Nestler. Nat. Rev. Neurosci. 2001 Amygdala Initial molecular findings The neuroadaptation hypothesis of addiction Chronic drug exposure causes long-lasting molecular, cellular, and neurochemical adaptations in the mesocorticolimbic dopamine system that underlie compulsive drug use and prolonged relapse vulnerability during abstinence (Karler et al., 1989; Wolf and Khansa, 1991 ; Nestler et al. 1990; Kalivas and Stewart 1991)

  12. Summary of initial molecular findings Incubation of cocaine craving: Associated with increases in peptide levels of brain-derived neurotrophic factor (BDNF) in VTA, accumbens and amygdala Not associated with increases in protein levels of AMPA and NMDA glutamate receptor subunits in VTA, accumbens and amygdala Not associated with increases in protein levels of cyclin-dependent kinase 5 (cdk5) and tyrosine hydroxylase (TH) in VTA and accumbens Not associated with increases in the activity of cAMP-dependent protein kinase (PKA) and adenylate cyclase (AC) in VTA and accumbens Grimm et al. J Neurosci 2003 Lu et al. J Neurochem 2003, 2005 Lu et al. J Neurosci 2004

  13. NMDA/AP-5 ERK (extracellular signal-regulated kinase) A key regulator of synaptic plasticity and learning and memory (Sweatt 2001) Amygdala ERK is involved in conditioned fear responses (Schaffe et al. 2000) Mesolimbic ERK is activated by cocaine (Licata and Pierce 2003; Valjent et al. 2000) U0126 Role of central amygdala ERK in incubation of cocaine cravingLin LuCollaborator: Bruce Hope NMDA receptor Raf MEK ERK Also: the human amygdala is activated by cocaine cues (Grant et al. 1996; Childress et al. 1999) From Thomas and Huganir. Nature Neuroscience, 2004

  14. Behavioral data: Training and extinction tests Cocaine/saline self-administration training (10 days) Withdrawal period (1 or 30 Days) Extinction test Day 1 Extinction test Day 30 Training Extinction test 60 100 * 80 45 60 Lever presses (30 min) 30 Infusions (6 h) Cocaine (n=34) 40 Saline (n=34) 15 20 0 0 1 2 3 4 5 6 7 8 9 10 1 30 Withdrawal day Training day Saline-trained rats Cocaine-trained rats Lu, Hope et al. Nature Neuroscience, 2005

  15. Central amygdala Basolateral amygdala 200 * No test 150 Extinction test 100 % of naive rats 50 CeA 0 DAY 1 DAY 30 DAY 30 DAY 30 DAY 1 DAY 30 DAY 1 DAY 1 BLA Saline Cocaine Saline Cocaine pERK1 pERK2 Exposure to cocaine cues increases ERK phosphorylation in the central amygdala after 30 days of withdrawal No changes in total ERK

  16. Extinction responding Phosphorylated ERK 80 150 Vehicle U0126 60 100 * Lever presses (30 min) 40 % of vehicle values * 50 20 0 0 Vehicle U0126 Basolateral amygdala Central amygdala Raf MEK CeA ERK U0126 Inhibition of ERK phosphorylation in the central amygdala attenuates cocaine seeking after 30 daysof withdrawal NMDA receptor

  17. Inhibition of ERK phosphorylation in the basolateral amygdala has no effect on cocaine seeking after 30 daysof withdrawal Phosphorylated ERK Extinction responding 80 150 60 100 * % of vehicle values Lever presses (30 min) 40 50 20 0 0 Basolateral amygdala Central amygdala U0126 Vehicle Vehicle U0126 Raf MEK ERK U0126 BLA NMDA receptor

  18. Phosphorylated ERK Extinction responding 80 200 * 60 150 NMDA * Lever presses (30 min) 40 100 % of vehicle values 20 50 0 0 0 25 250 Basolateral amygdala Central amygdala NMDA dose (ng/site) NMDA receptor Vehicle NMDA (25 ng) NMDA (250 ng) CeA Induction of ERK phosphorylation in the central amygdala restores cocaine seeking after 1 dayof withdrawal Raf MEK ERK

  19. Phosphorylated ERK Extinction responding 200 80 Vehicle AP-5 60 150 % of vehicle values Lever presses (30 min) 100 40 * * 20 50 0 0 Central amygdala Basolateral amygdala AP-5 Vehicle CeA Blockade of NMDA receptors in the central amygdala attenuates cocaine seeking after 30 days of withdrawal AP-5 NMDA receptor Raf MEK ERK

  20. Glutamate mGluR2 mGluR3 Courtesy of Carl Lupica GABA Day 21 withdrawal Day 3 withdrawal Systemic injections Central amygdala injections Basolateral amygdala injections * * 200 150 Lever presses (3 h) 100 50 0 0 1.5 3.0 0 0.5 1.0 0 1.0 LY379268 dose (µg/site) LY379268 dose (µg/site) LY379268 dose (mg/kg, i.p) More evidence for a role of central amygdala glutamate in incubation of craving LY379268: a selective agonist of mGluR2/3 receptors that decreases evoked glutamate release Lu et al. Biological Psychiatry 2006

  21. Conclusions Implications for treatment Drug addicts may be highly vulnerable to relapse at time periods that are far beyond the acute drug withdrawal phase Time away from drug (e.g., incarceration) is not a good method for relapse prevention Our studies suggest that mGluR2/3 agonists should be considered in the treatment of relapse to cocaine and other drugs Incubation of reward craving is a general phenomenon that occurs with both drug and non-drug rewards Time-dependent increases in the responsiveness of central amygdala ERK and glutamate to cocaine cues mediate the incubation of craving

  22. An update on incubation of cocaine craving (1) Exposure to cocaine cues increases ERK phosphorylation in the medial prefrontal cortex after 30 days of withdrawal Extinction test Dorsal mPFC Ventral mPFC 80 100 * * 60 75 * 40 p-ERK positive cells/mm2 Lever presses (30 min) 50 20 25 No test 0 0 1 30 1 30 1 30 Withdrawal day Withdrawal day Withdrawal day dmPFC Extinction test vmPFC Koya, Uejima et al. SFN 2006

  23. An update on incubation of cocaine craving (2) Extinction tests GluR1 surface expression * * 40 300 30 200 20 Nose pokes % of control 100 10 0 0 1 45 1 45 Withdrawal day Withdrawal day Incubation of cocaine craving: • Enhanced in GluR1 knockout mice (Mead et al. Neuropsychopharmacol. 2006) • Attenuated by inhibition of protein synthesis in the amygdala following cue exposure during early withdrawal (Lee et al. J. Neurosci. 2006) • Associated with increases in neuronal activity in the accumbens (Hollander & Carelli. Neuropsychopharmacol. 2006) • Associated with greater total production and surface expression of GluR1 in the accumbens (Conrad et al. SFN 2006) Incubation of cocaine craving in humans: Incubation of cocaine relapse during a disulfiram clinical trial (Kosten et al. CPDD 2005). “In support of human ‘incubation’, only 3% of cocaine dependent subjects who stopped cocaine use for at least 2 weeks relapsed before week 4, and relapse peaked after 6.6 weeks of abstinence”

  24. Acknowledgements • Present post-doctoral fellows: Jennifer Bossert, Sunila Nair • Present students: Jamie Uejima, Gabriela Poles, Sam Golden • Former post-doctoral fellows:Yvona Buczek, David Highfield, Jeff Grimm, Hans Crombag, Uri Shalev, Lin Lu • Former students: Shirley Leung, Alison Clements, Jasmine Yap, Kelly Badger, Polly Robarts, Shirley Liu, Jack Dempsey, David Chuang, Robert Busch, Deepti Nagarkar, Sean Sheffler-Collins, Sarah Gray • Intramural collaborators: Bruce Hope, Marisela Morales, Eisuke Koya, Udi Ghitza, Jack Shepard, Tsung-Ping Su, Teruo Hayashi, Brandon Harvey, Michael Baumann, George Uhl, Tim Liu, Kenzie Preston, David Epstein, Zhi-Bing You, Roy Wise, Barry Hoffer • Extramural collaborators: Jane Stewart, AD Le, Doug Funk, Geoff Schoenbaum, Taco de Vries, Paul Fletcher, Diane Lattemann, Gal Yadid, Abraham Zangen, Suzanne Erb, Micky Marinelli • Final thanks: Pier-Vincenzo Piazza, Barry Everitt, Neil Grunberg, Klaus Miczek

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