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.