the neurobiology of nicotine dependence and co-morbid psychiatric disorders george f. koob, ph.d....
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The Neurobiology of Nicotine Dependence and Co-Morbid Psychiatric Disorders
George F. Koob, Ph.D.Athina Markou, Ph.D.
Department of NeuropharmacologyThe Scripps Research Institute
La Jolla, California
Criteria for Substance Dependence (DSM-IV)
From: Koob GF and Le Moal M, Science, 1997, 278:52-58.
Acute Nicotine Increases Brain Stimulation Reward
From: Huston-Lyons D and Kornetsky C, Pharmacol Bioch Behav, 1992, 41:755-759.
Nicotine Self-Administration
Human data adapted from: Henningfield JR, Miyasato K and Jasinski DR, Pharmacol Biochem Behav1983, 19:887-890.
From: Watkins SS, Epping-Jordan MP, Koob GF and Markou A, Pharmacol Biochem Behav, 1999, 62:743-751.
Effects of DHE 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
Key Neurochemical Systems Comprising Brain Drug Reward Circuitry
Effects of 6-OHDA or Vehicle Infusions into theNucleus Accumbens on Nicotine Self-Administration in Rats
From: Corrigall WA, Franklin FBJ, Coen KM, and Clarke PBS, Psychopharmacology, 1992, 107:285-289.[
Nicotine activates nAChRs Nicotine activates nAChRs located on glutamate terminals located on glutamate terminals in the ventral tegmental area in the ventral tegmental area (VTA)(VTA)
Nicotine-stimulated glutamate Nicotine-stimulated glutamate release acts at glutamate release acts at glutamate receptors located on VTA receptors located on VTA dopamine neuronsdopamine neurons
Activation of glutamate Activation of glutamate receptors stimulates dopamine receptors stimulates dopamine release into terminal regions, release into terminal regions, such as the nucleus accumbenssuch as the nucleus accumbens
Mechanisms by which Nicotine Interacts with Dopamine and Glutamate Transmission
From: Kelley AE, Nature Med, 2002, 8:477-479.
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.
•Gastro-intestinal discomfort
•Bradycardia
•Increased appetite
•Anxiety
•Depressed Mood
•Craving
•Dysphoria
•Irritability
•Difficulty concentrating
Withdrawal from nicotine elicits an aversive behavioral syndrome in humans
ICSS Threshold Procedure
Adapted from: Markou A and Koob GF, Physiol Behav, 1992, 51:111-119.
Spontaneous Nicotine Withdrawal
Adapted from: Epping-Jordan MP, Watkins SS, Koob GF and Markou A, Nature, 1998, 393:76-79.
DHE-precipitated Nicotine Withdrawal
From: Epping-Jordan MP, Watkins SS, Koob GF and Markou A, Nature, 1998, 393:76-79.
Brain Reward Function During Acute Withdrawal(0-72 hours)
Decreases in Extracellular Levels of DopamineDuring 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.
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.
Nicotine Withdrawal
From: Harrison AA, Liem YTB and Markou A, Neuropsychopharmacology, 2001, 25:55-71.
The mGluII Receptor Antagonist LY341495 Reversed Spontaneous Nicotine Withdrawal
From: Kenny PJ, Gasparini F and Markou A, unpublished results.
Glutamatergic and GABAergic regulation of dopamine transmission in the VTA
Pre-synaptic ModulationPre-synaptic Modulation Post-synaptic ModulationPost-synaptic Modulation
GlutamateTerminal VTA
Dopamine Neuron
Adapted from: Schoepp DD, J Pharmacol Exp Ther, 2001, 299:12-20.
CNS Actions of Corticotropin Releasing Factor (CRF)
Neurotransmitter Systems Hypothesized to be Involved in the Motivational Aspects of Nicotine Withdrawal
Acetylcholinepedunculopontine tegmental nucleus
Dopaminenucleus accumbens, amygdala
Opioid Peptidesnucleus accumbens, amygdala, ventral tegmental area
Serotoninmedian raphe
Glutamateventral tegmental area
Corticotropin-Releasing Factor (???)
Lanca et al., 2000
Hildebrand et al., 1999Pangis et al., 2000
Malin et al., 1993Ise et al., 2000Watkins et al., 2000
Harrison et al., 2001Cheeta et al., 2001
Kenny et al., 2001
Depression and Withdrawal from a Variety of Drugsof Abuse are Associated with Altered Function in
Several Neurotransmitter Systems
Depression
Drug withdrawal
Psychostimulants
Opiates
Ethanol
Nicotine
Ach DA GABA CRF NPY SS Opioids5-HT NE
or
?
Hypothetical Anatomical Circuit Underlying Melancholic Depression and Adversity
From: Schulkin J, McEwen BS and Gold PW, Neurosci Biobehav Rev, 1994, 18:385-396.
Hypothetical Anatomical Circuit Underlying the “Dark Side” of Drug Dependence
The Atypical Antidepressant Bupropion Reversed Nicotine Withdrawal
Cryan, Bruijnzeel, Skjei & Markou, Psychopharmacology, 168:347-358, 2003
Allostatic Change in Mood State associated with Transition to Drug Addiction
From: Koob GF and Le Moal M, Neuropsychopharmacology, 2001, 24:97-129.
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 ExperimentalMedicine and Biology, Vol. 295), Plenum Press, New York, 1991, pp. 1-42.
Modified from:
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
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
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.