1. The Neurobiology of Nicotine Dependence and Co-Morbid Psychiatric Disorders George F. Koob, Ph.D. Athina Markou, Ph.D. Department of Neuropharmacology The Scripps Research Institute La Jolla, California

3. Criteria for Substance Dependence (DSM-IV) From: Koob GF and Le Moal M, Science, 1997, 278:52-58.

5. Acute Nicotine Increases Brain Stimulation Reward From: Huston-Lyons D and Kornetsky C, Pharmacol Bioch Behav, 1992, 41:755-759.

7. Nicotine Self-Administration Human data adapted from:Henningfield JR, Miyasato K and Jasinski DR, Pharmacol Biochem Behav 1983, 19:887-890.

8. From:Watkins SS, Epping-Jordan MP, Koob GF and Markou A, Pharmacol Biochem Behav, 1999, 62:743-751.

9. Effects of DH  E on Nicotine Self-Administration in Rats (0.03 mg/injection) From:Watkins SS, Epping-Jordan MP, Koob GF and Markou A, Pharmacol Biochem Behav, 1999, 62:743-751

10. Key Neurochemical Systems Comprising Brain Drug Reward Circuitry

11. Effects of 6-OHDA or Vehicle Infusions into the Nucleus Accumbens on Nicotine Self-Administration in Rats From: Corrigall WA, Franklin FBJ, Coen KM, and Clarke PBS, Psychopharmacology, 1992, 107:285-289.[

12. Nicotine activates nAChRs located on glutamate terminals in the ventral tegmental area (VTA) Nicotine-stimulated glutamate release acts at glutamate receptors located on VTA dopamine neurons Activation of glutamate receptors stimulates dopamine release into terminal regions, such as the nucleus accumbens Mechanisms by which Nicotine Interacts with Dopamine and Glutamate Transmission From:Kelley AE, Nature Med, 2002, 8:477-479.

13. Dependence: An Affective Definition “The notion of dependence on a drug, object, role, activity or any other stimulus-source requires the crucial feature of negative affect experienced in its absence. The degree of dependence can be equated with the amount of this negative affect, which may range from mild discomfort to extreme distress, or it may be equated with the amount of difficulty or effort required to do without the drug, object, etc.” From: Russell MAH, What is dependence? In Edwards G (ed), Drugs and Drug Dependence, Lexington Books, Lexington, MA, 1976, pp. 182-187.

14. Gastro-intestinal discomfort Bradycardia Increased appetite Anxiety Depressed Mood Craving Dysphoria Irritability Difficulty concentrating Withdrawal from nicotine elicits an aversive behavioral syndrome in humans

16. ICSS Threshold Procedure Adapted from: Markou A and Koob GF, Physiol Behav, 1992, 51:111-119.

17. Spontaneous Nicotine Withdrawal Adapted from: Epping-Jordan MP, Watkins SS, Koob GF and Markou A, Nature, 1998, 393:76-79.

18. DH  E-precipitated Nicotine Withdrawal From: Epping-Jordan MP, Watkins SS, Koob GF and Markou A, Nature, 1998, 393:76-79.

19. Brain Reward Function During Acute Withdrawal (0-72 hours)

20. Decreases in Extracellular Levels of Dopamine During Precipitated Nicotine Withdrawal From:Hildebrand BE, Nomikos GG, Hertel P, Schilstrom B and Svensson TH, Brain Res, 1998, 779:214-225. From:Panagis G, Hildebrand BE, Svensson TH and Nomikos GG, Synapse, 2000, 35:15-25.

21. Effects of Nicotine and a Nicotinic Antagonist Injected into the Dorsal Raphe Nucleus on the Social Interaction Test From: Cheeta S, Tucci S and File SE, Pharmacol Biochem Behav, 2001, 70:491-496.

22. Nicotine Withdrawal From:Harrison AA, Liem YTB and Markou A, Neuropsychopharmacology, 2001, 25:55-71.

23. The mGluII Receptor Antagonist LY341495 Reversed Spontaneous Nicotine Withdrawal From: Kenny PJ, Gasparini F and Markou A, unpublished results.

24. Glutamatergic and GABAergic regulation of dopamine transmission in the VTA Pre-synaptic Modulation Post-synaptic Modulation Glutamate Terminal VTA Dopamine Neuron Adapted from: Schoepp DD, J Pharmacol Exp Ther, 2001, 299:12-20.

25. CNS Actions of Corticotropin Releasing Factor (CRF)

26. Neurotransmitter Systems Hypothesized to be Involved in the Motivational Aspects of Nicotine Withdrawal Acetylcholine pedunculopontine tegmental nucleus Dopamine nucleus accumbens, amygdala Opioid Peptides nucleus accumbens, amygdala, ventral tegmental area Serotonin median raphe Glutamate ventral tegmental area Corticotropin-Releasing Factor (???) Lanca et al., 2000 Hildebrand et al., 1999 Pangis et al., 2000 Malin et al., 1993 Ise et al., 2000 Watkins et al., 2000 Harrison et al., 2001 Cheeta et al., 2001 Kenny et al., 2001

27. Depression and Withdrawal from a Variety of Drugs of Abuse are Associated with Altered Function in Several Neurotransmitter Systems Depression Drug withdrawal Psychostimulants Opiates Ethanol Nicotine AchDAGABACRFNPYSSOpioids5-HTNE or ?

28. Hypothetical Anatomical Circuit Underlying Melancholic Depression and Adversity From: Schulkin J, McEwen BS and Gold PW, Neurosci Biobehav Rev, 1994, 18:385-396.

29. Hypothetical Anatomical Circuit Underlying the “Dark Side” of Drug Dependence

30. The Atypical Antidepressant Bupropion Reversed Nicotine Withdrawal Cryan, Bruijnzeel, Skjei & Markou, Psychopharmacology, 168:347-358, 2003

31. Allostatic Change in Mood State associated with Transition to Drug Addiction From: Koob GF and Le Moal M, Neuropsychopharmacology, 2001, 24:97-129.

32. Potential Substrates in the Extended Amygdala for the Motivational Effects of Drug Dependence Heimer L and Alheid G, Piecing together the puzzle of basal forebrain anatomy. In: Napier TC, Kalivas PW and Hanin I (Eds), The Basal Forebrain: Anatomy to Function (series title: Advances in Experimental Medicine and Biology, Vol. 295), Plenum Press, New York, 1991, pp. 1-42. Modified from:

33. Summary and Conclusions Nicotine is readily self-administered by animals and enhances brain reward Neurochemical substrates important for the acute reinforcing effects of nicotine include dopamine, GABA, opioid peptides, serotonin, and glutamate systems in the basal forebrain. The focus of research to date on the acute reinforcing effects of nicotine has been on specific nicotinic receptor dynamics in the context of glutamate/GABA interactions with dopamine neurons in the ventral tegmental area. Development of “motivational” dependence to nicotine is associated with dysregulation of the brain reward system and decreased function in some of the same neurochemical systems involved in negative affect associated with co-morbid psychiatric disorders

34. Collaborators Athina Markou John Cryan Mark Epping-Jordan Amanda Harrison Paul Kenny Laura O’ Dell Neil Paterson Svetlana Semenova Luis Stinus Shelly Watkins Support from the National Institute on Drug Abuse and National Institute on Mental Health Research Grant from Novartis Support from the Tobacco Etiology Research Network of the Robert Wood Johnson Foundation Support from the Tobacco-Related Disease Research Program, State of California

35. Summary and Conclusions (What is unknown) The reward dysregulation of early and late withdrawal from nicotine is hypothesized to result from “allostatic”, rather than homeostatic, changes in the brain reward circuitry. The “dark side” of dependence to nicotine may also involve the recruitment of changes in the brain stress systems including corticotropin releasing factor and/or norepinephrine. The subdivisions of the extended amygdala provide a heuristic framework for integrating the hypothesis that normal motivational function is usurped by chronic drugs of abuse to produce a deficit emotional state associated with addiction. Neuropharmacological changes in the circuits of the extended amygdala may persist during protracted withdrawal and provide a motivational basis for vulnerability to co-morbid psychiatric disorders.