The Neurobiology of Nicotine Dependence and CoMorbid Psychiatric Disorders

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

2
(No Transcript)
3
Criteria for Substance Dependence (DSM-IV)
From Koob GF and Le Moal M, Science, 1997,
27852-58.
4
(No Transcript)
5
Acute Nicotine Increases Brain Stimulation Reward
From Huston-Lyons D and Kornetsky C, Pharmacol
Bioch Behav, 1992, 41755-759.
6
(No Transcript)
7
Nicotine Self-Administration
Human data adapted from Henningfield JR,
Miyasato K and Jasinski DR, Pharmacol Biochem
Behav 1983, 19887-890.
8
From Watkins SS, Epping-Jordan MP, Koob GF and
Markou A, Pharmacol Biochem Behav, 1999,
62743-751.
9
Effects of DHbE 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,
62743-751
10
Key Neurochemical Systems Comprising Brain Drug
Reward Circuitry
11
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,
107285-289.
12
Mechanisms by which Nicotine Interacts with
Dopamine and Glutamate Transmission
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
From Kelley AE, Nature Med, 2002, 8477-479.
13
DependenceAn 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
Withdrawal from nicotine elicits an aversive
behavioral syndrome in humans

• Gastro-intestinal discomfort
• Bradycardia
• Increased appetite
• Anxiety
• Depressed Mood
• Craving
• Dysphoria
• Irritability
• Difficulty concentrating

15
(No Transcript)
16
ICSS Threshold Procedure
Adapted from Markou A and Koob GF, Physiol
Behav, 1992, 51111-119.
17
Spontaneous Nicotine Withdrawal
Adapted from Epping-Jordan MP, Watkins SS, Koob
GF and Markou A, Nature, 1998, 39376-79.
18
DH?E-precipitated Nicotine Withdrawal
From Epping-Jordan MP, Watkins SS, Koob GF and
Markou A, Nature, 1998, 39376-79.
19
Brain Reward Function During Acute
Withdrawal(0-72 hours)
20
Decreases in Extracellular Levels of
DopamineDuring Precipitated Nicotine Withdrawal
From Hildebrand BE, Nomikos GG, Hertel P,
Schilstrom B and Svensson TH, Brain Res, 1998,
779214-225.
From Panagis G, Hildebrand BE, Svensson TH and
Nomikos GG, Synapse, 2000, 3515-25.
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, 70491-496.
22
Nicotine Withdrawal
From Harrison AA, Liem YTB and Markou A,
Neuropsychopharmacology, 2001, 2555-71.
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
Adapted from Schoepp DD, J Pharmacol Exp Ther,
2001, 29912-20.
25
CNS Actions of Corticotropin Releasing Factor
(CRF)
26
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
27
Depression and Withdrawal from a Variety of
Drugsof Abuse are Associated with Altered
Function inSeveral Neurotransmitter Systems
Ach
DA
GABA
CRF
NPY
SS
Opioids
5-HT
NE or
Depression Drug withdrawal Psychostimulants O
piates Ethanol Nicotine
?
28
Hypothetical Anatomical Circuit Underlying
Melancholic Depression and Adversity
From Schulkin J, McEwen BS and Gold PW, Neurosci
Biobehav Rev, 1994, 18385-396.
29
Hypothetical Anatomical Circuit Underlying the
Dark Side of Drug Dependence
30
The Atypical Antidepressant Bupropion Reversed
Nicotine Withdrawal
Cryan, Bruijnzeel, Skjei Markou,
Psychopharmacology, 168347-358, 2003
31
Allostatic Change in Mood State associated with
Transition to Drug Addiction
From Koob GF and Le Moal M, Neuropsychopharmacolo
gy, 2001, 2497-129.
32
Potential Substrates in the Extended Amygdala for
the Motivational Effects of Drug Dependence
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.