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Slide 70 -
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The Neurobiology of
Drug Addiction Glen R. Hanson, Ph.D., D.D.S.
Director, Utah Addiction Center
Professor of Pharmacology and Toxicology, U of U
Senior Advisor, NIDA
Drug Abuse and Addiction
are Among the Most Serious
Public HealthProblems Facing
Our Society and Frequently Coexist
with Other Mental and
Physical Disorders Drug abuse Smoking HIV/AIDS Child abuse Violence Stress Cancer Drunk driving Heart disease Alcohol abuse Two Decades of Neurobiological
Research Have
Brought Us A New Understanding of
Drug Abuse and Addiction, Their
Complexity and their Solutions
We Know That Despite
Their Many Differences, Virtually
All Abused Substances Enhance
Dopamine (neurotransmitter) Activity
(particularly related to pleasure,
motor, and cognitive function For Example… Other pathways also involved! Dopamine Pathways Functions
reward (motivation)
pleasure,euphoria
motor function
(fine tuning)
compulsion
perserveration
decision making Serotonin Pathways Functions
mood
memory
processing
sleep
cognition nucleus
accumbens hippocampus striatum frontal
cortex substantia
nigra/VTA raphe Neuronal structure (receiving) (sending) /serotonin Vmat transporter DA/5HT How some drugs of abuse cause dopamine release:
opioids narcotics (activate opioid receptors)
nicotine (activate nicotine receptors)
marijuana (activate cannabinoid receptors)
caffeine
alcohol (activate GABA receptors; an inhibitory transmitter) Drug :
cocaine
ritalin vesicle Neuronal terminal Release DA from vesicles and reverse
transporter Drug Types:
Amphetamines
-methamphetamine
-MDMA (Ecstasy) Vmat transporter serotonin/ DA/5HT Source: Di Chiara and Imperato Effects of Drugs on Dopamine Release Much greater
Activity than any
Other drug of abuse
-causes neurotoxicity Natural Rewards Elevate Dopamine Levels Implication: Elucidation of the mechanism of
drug addiction will help to
understand other addictive and
motivational behaviors/disorders OFC SCC MOTIVATION/
DRIVE
(saliency) Brain Circuits Involved in
Drug Addiction HOW DOES ADDICTION
OCCUR? Principles of Behavior Dynamics Behavior Tracts Compete for Expression Expression is Determined by (i) Dominance of Tracts,
(ii) Strength of Prefrontal Cortex to Select, (iii) Relevance or
saliency (orbitofrontal cortex) Activation of Dopamine reward pathway initiates a behavior
track dopamine initiated (Miller & Cohen, Annu. Rev. Neurosci. 24 [2001] 167) Principles of Behavior Dynamics How does a behavior become
an addiction? Prolonged Drug Use Changes
the Brain and
In Fundamental
and Long-Lasting Ways We Have Generated A Lot of
Evidence Showing That… We Have Evidence That
These Changes Can Be Both
Structural and Functional AND… Positron Emission Tomography BRAIN IMAGING Magnetic Resonance Imaging control cocaine abuser Decreases in Metabolism
in Orbito Frontal Cortex (OFC) Volkow et al. Am. J. Psychiatry 148, 621 Compromise assigning appropriate
Value Source: McCann U.D. et al., The Journal of Neuroscience, 18(20), pp. 8417-8422, October 15, 1998. METH Suppresses Expression of DAT (note: duration of use/3-20 yrs; abstinent/ 1-4 yrs) Comparison Subject METH Abuser Dopamine Transporter Loss After
Heavy Methamphetamine Use
(PET analysis) Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001. Dependence of Verbal Memory on Striatal DAT R = 0.70
p < 0.005 R = 0.64
p < 0.01 Interference recall Delayed recall Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001. Compromises Cognitive Functions MOTOR FUNCTION Slowed gait Impaired balance Impairment correlates with damage
to dopamine system Implication: Brain changes resulting from
prolonged use of psychostimulants,
such as methamphetamine
may be reflected in compromised
cognitive and motor functioning Is There Recovery? Good News: After 2 years some
of the dopamine deficits are
recovering Bad News: Functional deficits
persist What does this mean??? Reward System in Addiction Cocaine Food Activity of Reward System METH Alcohol controls treated More Less INHERITED FACTORS
(genetic vulnerability-not
inevitability) Common strategy to investigate
are Twin Studies In General: Inheritability for Drug
Abuse Ranges From 40-60% Some Variability Between Drugs Some Gender Variability Complex genetics Complex phenotypes (expressions) (Relation to Risk Factors?) VULNERABILITY to What? For Example-
Contribution of Genetic Factors to: Nicotine- Liability to initiate=56% Transition to dependence=70% Smoking persistence= >50% (Lerman & Berrettine, Amer. J. Med. Gen. 54 (2003) 48) Genetics May Influence How
Neurobiology Interacts With
Environment PET Images:
Dopamine Receptor Density More
likely
to self-
administer
Cocaine Addictive Disorders Often Co-Exist with or Predispose to Mental Disorders (Note: can we have parity for mental health with-
out considering drug abuse?) Common Underlying Neurobiological
Factors Can Be: Because of this overlap, drugs of abuse
can cause symptoms that mimic
most forms of mental illness Some drugs of abuse have a
mechanism of action similar to
that of drugs used as
psychotherapeutic agents
Significance: rationale for
self-administration Serotonin/dopamine synaptic
terminal Synaptic vesicle Postsynaptic
target transporter Prozac,
Ritalin, &
Cocaine
block Chronic use of some of these drugs of
abuse may alter the way the brain
functions, making persons particularly
susceptible to mental illness Double People With Comorbid
Mental and Addictive Disorders
Have a Brain Disease Double Mental
Disorder Addictive
Disorder Comorbid
Disorders Role of Stress and Trauma The Stress Hormone Cycle Hypothalamus Pituitary
Gland Adrenal
Glands Kidneys CRF ACTH Stress Responses Stress Responses Stress Responses Stress Responses CRF:
Corticotropin
Releasing
Factor DRUG USE(Self-Medication) STRESS CRF Anxiety CRF Anxiety What Role Does Stress Play
In Initiating Drug Use? Abstinence RELAPSE CRF Anxiety What Happens When A Person
Stops Taking A Drug? Stress Reliably Reinstates Drug Seeking in Rats Saline Nicotine Nicotine-trained rats Footshock Saline Cocaine Footshock Water Alcohol Footshock Cocaine-trained rats Alcohol-trained rats 0 20 40 60 80 100 Responses Inactive Lever Active Lever Saline Heroin Footshock Heroin-trained rats * * * * * * * * 0 20 40 60 80 100 Responses From: Psychopharmacology, 1996, 1998, 1999 ; J. Neurosci. 1996 CRF1 Receptor Antagonist Attenuates
Stress-Induced Reinstatement
of Drug Seeking Alcohol-trained rats From: Shaham et al. Psychopharmacology 1998; Le et al. Psychopharmacology, 2000 CP-154,526 Dose (mg/kg, SC) Intermittent Footshock No stress Heroin-trained rats Cocaine-trained rats 0 15 * 30 * 0 15 30 45 60 Responses (3 hr) * * 0 15 30 * 0 15 30 45 60 Responses (1 hr) 0 15 30 That was then . . . We Are Capitalizing on
Basic Science Discoveries in the Design
Of Behavior Therapies and
Medications
To Treat Addiction Objectives of Intervention: Rearrange dominance of behavior tracks contingency management (vouchers) motivational enhancement therapeutic communities Principles of Behavior Dynamics A B C Prefrontal
Cortex C B dopamine initiated Strengthen prefrontal cortex influence
(change thinking process) cognitive and cognitive behavioral tx
(unlearn old habits-suppress; learn
new skills) assertiveness training (suppress and
express) Principles of Behavior Dynamics A B C Prefrontal
Cortex C B dopamine initiated Alter function of orbitofrontal
(saliency) cortex motivational therapy family therapies Principles of Behavior Dynamics A B C Prefrontal
Cortex C B dopamine initiated Recovery of function (frontal and obito-
frontal cortex) all treatments that keep brain away
from drugs for extended time Principles of Behavior Dynamics A B C Prefrontal
Cortex C B dopamine initiated Alleviate underlying psychiatric
disorder administer: Antidepressants for depression
Ritalin for ADHD
Sedatives for anxiety Targets of Medication Methadone, LAAM and Buprenorphine Nicotine gum/patch Naloxone Vmat transporter stimulation DA How some drugs of abuse cause dopamine release:
opioids narcotics (activate opioid receptors)
nicotine (activate nicotine receptors) vesicle Neuronal terminal Psychostimulants Principles of Behavior Dynamics A B C Prefrontal
Cortex C B dopamine initiated GABA and cannabinoid
systems critical for
function Relieve stress-related drug abuse CRF antagonist Abstinence RELAPSE CRF Anxiety Science is helping to improve
our strategies and successes To be successful, treatment is a
Lifetime Process Consequence: There is no
“cure”…
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