NEUROBIOLOGY

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NEUROBIOLOGY ASAM Review Course in Addiction
Medicine 26-28 October 2008 Westin OHare Hotel,
Rosemont, Illinois
Eliot L. Gardner, Ph.D. Chief, Neuropsychopharmaco
logy Section Intramural Research Program National
Institute on Drug Abuse National Institutes of
Health egardner_at_intra.nida.nih.gov 443.740.2516
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• The basic reward circuitry of the brain is a
  3-neuron in-series synaptic circuit
• Descending Link ABN ? VTA, via Medial Forebrain
  Bundle
• Ascending Link VTA ? NAcc, via Medial Forebrain
  Bundle
• Further Ascending Link NAcc ? VP

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HIPP
GLU
FCX
AMYG
CRF
GLU
5HT
GABA
OPIOID
OPIOID
ENK
GABA
GABA
VP
DYN
5HT
OFT
DA
GABA
BNST
NE
LC
ABN
PAG
Opiates
NE
END
HYPOTHAL
LAT-TEG
To dorsal horn
5HT
ICSS
Raphé
RETIC
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HIPP
GLU
FCX
AMYG
CRF
GLU
5HT
GABA
OPIOID
OPIOID
ENK
GABA
GABA
VP
DYN
5HT
OFT
DA
GABA
BNST
NE
LC
ABN
PAG
Opiates
NE
END
HYPOTHAL
LAT-TEG
To dorsal horn
5HT
ICSS
Raphé
RETIC
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• How Do We Know This?
• Electrical Brain-Stimulation Reward
• In Laboratory Animals
• In Human Patients

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• Also
• Conditioned Place Preference to Intracranial
  Microinjection of Rewarding Drugs
• Self-Administration of Rewarding Drugs Directly
  into Brain Sites

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The crucial reward neurotransmitter is dopamine
(DA)
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• How Do We Know This?
• Virtually all addictive drugs are DA agonists
• The one common feature they share
• Microinjections of DA agonists
• Conditioned place preference
• Intracranial self-administration
• Effects of DA antagonists
• Negative reinforcers in animals
• Subjective effects in humans (neuroleptics)
• Effects of DA antagonists on drug
  self-administration
• Compensatory increase in drug intake
• Extinction
• Nucleus Accumbens (NAcc) neurochemistry during
  self-administration
• In vivo brain microdialysis

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IV heroin self-administration
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PROPONENT AND OPPONENTBRAIN REWARD
PROCESSESIN ADDICTION
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DRUG WITHDRAWALBRAIN REWARD PROCESSESIN
ADDICTION
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REWARD DEFICIENCYAS A DRIVING FORCEIN
ADDICTION
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Addiction is not physical dependence

• Many drugs produce physical dependence without
  addiction
• Some drugs produce addiction without physical
  dependence
• Animals take addicting drugs in absence of
  physical dependence
• Pain significantly reduces addictive liability
• Brain sites of addiction differ from brain sites
  that mediate physical dependence

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Pert A, Yaksh T. Sites of morphine induced
analgesia in the primate brain relation to pain
pathways. Brain Research 80135-140,
1974.Bozarth MA, Wise RA. Anatomically
distinct opiate receptor fields mediate reward
and physical dependence. Science 224516-517,
1984.
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HIPP
GLU
FCX
AMYG
CRF
GLU
5HT
GABA
OPIOID
OPIOID
ENK
GABA
GABA
VP
DYN
5HT
OFT
DA
GABA
BNST
NE
LC
ABN
PAG
Opiates
NE
END
HYPOTHAL
LAT-TEG
To dorsal horn
5HT
ICSS
Raphé
RETIC
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Real problem in addiction medicine is relapse
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TRIGGERS TO RELAPSE

• Re-exposure to DRUG
• Cross-triggering between drug classes
• Exposure to STRESS
• Mild stress extremely effective
• Exposure to environmental CUES
• Sights, sounds, smells associated with drug use
• People, places, things Alcoholics Anonymous

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Animal Models of Relapse

• Reinstatement (Self-administration)
• Drug-triggered
• Stress-triggered
• Cue-triggered
• Reactivation (Conditioned Place Preference)
• Drug-triggered
• Stress-triggered
• Cue-triggered

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Saline No Cues
Cocaine Cues
Drug
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Saline No Cues
Cocaine Cues
Stress
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Saline No Cues
Cocaine Cues
Cues
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HIPP
GLU
FCX
AMYG
CRF
GLU
5HT
GABA
OPIOID
OPIOID
ENK
GABA
GABA
VP
DYN
5HT
OFT
DA
GABA
BNST
NE
LC
ABN
PAG
Opiates
NE
END
HYPOTHAL
LAT-TEG
To dorsal horn
5HT
ICSS
Raphé
RETIC
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HIPP
GLU
FCX
AMYG
CRF
GLU
5HT
GABA
OPIOID
OPIOID
ENK
GABA
GABA
VP
DYN
5HT
OFT
DA
GABA
BNST
NE
LC
ABN
PAG
Opiates
NE
END
HYPOTHAL
LAT-TEG
To dorsal horn
5HT
ICSS
Raphé
RETIC
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HIPP
GLU
FCX
AMYG
CRF
GLU
5HT
GABA
OPIOID
OPIOID
ENK
GABA
GABA
VP
DYN
5HT
OFT
DA
GABA
BNST
NE
LC
ABN
PAG
Opiates
NE
END
HYPOTHAL
LAT-TEG
To dorsal horn
5HT
ICSS
Raphé
RETIC
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Incubation of Relapse Propensity Over Time
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Mechanism-based, hypothesis-driven medication
development for treating addiction
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Early failures were based on blockade of reward
circuitry
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Current promising medication development
strategies

• Dopamine D3 receptor antagonists
• Gamma-vinyl-GABA (GABAb)
• Slow-onset, long-acting DAT inhibitors
• Drugs acting on endocannabinoid system
• Drugs acting on glutamate system
• Central CRF antagonists

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SB-277011A Blocks Nicotine-Enhanced
Brain-Reward
P lt 0.001
Plt0.025
Plt0.001
P lt 0.001
Plt0.025
P lt 0.001
Percent Enhancement of Brain Reward (Decrease in
q0)
beta-cyclodextrin saline (vehicle)
beta-cyclodextrin 0.25mg/kg nicotine
3 mg/kg SB277011A 0.25 mg/kg nicotine
6 mg/kg SB277011A 0.25 mg/kg nicotine
12 mg/kg SB277011A 0.25mg/kg nicotine
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Effect of SB-277011A By Itself On Brain-Reward
Percent Enhancement of Brain Reward (Decrease in
q0)
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Effect of NGB-2904 By Itself On Brain-Reward
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SB-277011A Blocks Expression of
Nicotine-Enhanced CPP
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SB-277011A Lowers Progressive-Ratio Break-Point
for Cocaine (0.5mg/kg/inf)
Self-Administration
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NGB-2904 Dose-Dependently Attenuates
Cocaine-Triggered Reinstatement

of Cocaine-Seeking Behavior
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SB-277011A (12mg/kg i.p.) Attenuates
Stress-Triggered
Reinstatement of Cocaine-Seeking Behavior
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SB-277011A Dose-Dependently Attenuates
Cue-Triggered Reinstatement of Cocaine-Seeking
Behavior
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SB-277011A inhibits D9-THC-induced increase
in extracellular
DA in the nucleus accumbens
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SB-277011A inhibits incubation of cocaine craving
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SB-277011A dose-dependently inhibits incubation
of cocaine craving
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CRUCIAL TAKE-HOME MESSAGEDISTINCTIONS BETWEEN

• Drug-Induced Reward (High Hit Blast)
• VTA-Accumbens Reward/Pleasure Circuit
• Craving and Relapse
• 3 Separate Craving and Relapse Circuits
• Drug-Triggered Craving and Relapse
• Stress-Triggered Craving and Relapse
• Cue-Triggered Craving and Relapse
• Physical Dependence and Withdrawal
• Locus Coeruleus and Dorsal Mesencephalon
• Analgesia
• Periaqueductal Gray Matter and Raphé Nuclei

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ACKNOWLEDGEMENTS
Saint Johns University Charles R. Ashby Jr.,
Ph.D. Brookhaven National Laboratory Nora D.
Volkow, M.D. Peter K. Thanos, Ph.D. Seth N.
Rivera, B.A. Centre of Excellence for Drug
Discovery, GlaxoSmithKline Pharmaceuticals
Christian A. Heidbreder, Ph.D. Jim J. Hagan,
Ph.D. Derek N. Middlemiss, Ph.D., D.Sc. Maria
Pilla, Ph.D. MegaPharma Pharmaceuticals
Ltd., Budapest, Hungary József Gaál, Ph.D.
NIDA-IRP Zheng-Xiong Xi, M.D., Ph.D. Amy H.
Newman, Ph.D. Xiao-Qing Peng, M.D., Ph.D. Xia Li,
M.D., Ph.D. Jie Li, M.D. Amanda Higley, B.S.,
M.S. Arlene C. Pak, B.A. Jeremy G. Gilbert,
B.A. Krista Spiller, B.A. Christopher Dillon,
B.A. Albert Einstein College of
Medicine Stanislav Robert Vorel, M.D.,
Ph.D. Robert J. Hayes, Ph.D. William Paredes,
M.Sc. Xinhe Liu, M.Ed.
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Neuropsychopharmacology SectionIntramural
Research Program, NIDA
Zheng-Xiong Xi, MD, PhD
Xiao-Qing Peng, MD, PhD
Christopher Dillon, BA
Jie Li, MD