Addiction in the Brain/Latest Research

Addiction in the Brain Latest Research
Gary M. Henschen, MD, LFAPA
Chief Behavioral Health Officer
Magellan Healthcare, Inc.
The Neurobiology of Addiction
About the speaker
Gary M. Henschen, M.D. is Chief Behavioral Health Officer for Magellan Healthcare, Inc. He has been employed by
Magellan since 2001, and has been in his current position since 2008.
In his current role, he directs a team that develops medical necessity criteria, new technology assessments, and
clinical practice guidelines for behavioral health. He provides clinical expertise in new product development and
the quality improvement program of Magellan. He oversees medical management for Magellan’s behavioral
health programs.
Prior to joining Magellan, Dr. Henschen was Chief Medical Officer of Charter Behavioral Health Systems, LLC. He
was previously in private practice for psychiatry and psychoanalysis in Greensboro, North Carolina for 15 years.
Dr. Henschen is a graduate of Davidson College. He received the M.D. degree from the University of North
Carolina at Chapel Hill. He completed his internship in medicine at Letterman Army Medical Center, San Francisco,
and completed military service with the U.S. Army in Germany where he was flight surgeon and commander of
the 536th General Dispensary.
Dr. Henschen completed his residency and chief residency in psychiatry at Duke Medical Center, and completed
psychoanalytic training at the UNC-Duke Psychoanalytic Institute. His research interests have included the
assessment and prevention of suicide; psychiatric consultation-liaison with primary care physicians; the
development of quality metrics; addressing the needs of individuals diagnosed with both serious mental illness
and substance use disorders; and providing consultation to behavioral special investigation units.
Dr. Henschen is licensed to practice medicine in Georgia, North Carolina, Tennessee, New Jersey, Pennsylvania and
Iowa.
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Disclosure
Gary Henschen, M.D. has no relevant financial relationship or commercial
interest that could be reasonably construed as a conflict of interest.
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Learning objectives
Upon completion of this activity, participants should be able to:
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Demonstrate the neurologic basis of addiction
Discuss how treatment alters the neurological addictive patterns
Outline the difference between tolerance and addiction
Engage in discussions about the risks and benefits of medication-assisted treatment
for opiate use disorder
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Opiate abuse in the headlines
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Slippery slope to addiction
Over-prescribing
Unknowingly risking
addiction
Improper use to abuse
• Pharmaceutical marketing
• Pain as a symptom, not a
disease
• Little consideration for
patient's substance use
history, assessing for risk of
addiction
• No consensus about who
should receive how much
opioid and for how long
• Opioids suppress pain
• Painkillers can create a
euphoric, relaxed sensation
• Can provide a release from
stress
• Significant adverse side
effects, overdose deaths
• 2 million Americans met
the criteria for an opioid
use disorder
• Taking someone else’s
medication to self-medicate
• Taking opioids in a way
other than prescribed
• Taking medication to get
high
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The impact of prescription drug abuse
Prescription drug abuse has become a public health crisis, and appropriate
interventions to prevent addiction are crucial. Prescription and nonprescription opioid users of all ages can quickly become addicted.
2015 CDC. National Vital Statistics System mortality data. http://www.cdc.gov/nchs/deaths.htm(2013) SAMHSA, Results from the 2012 National Survey
on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: SAMHSA
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How does this problem occur in the brain?
Graphics courtesy of Institute on Drug Abuse; National Institutes of Health; U.S. Department of Health and Human Services
The central nervous system
Comprises brain and spinal cord
Brain is a functional unit
Comprises billions of nerve cells that
communicate with each other
They use electrical and chemical signals
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Brain regions and neuronal pathways
Parts of the brain govern
specific functions:
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sensory-blue
motor-orange
visual cortex-yellow
cerebellum-pink
hippocampus-green
reward pathway-orange
thalamus-magenta
Pathway for sensation of pain and reaction to pain
When the finger is injured— nerve
endings in finger:
• sense injury
• send impulses along spinal cord
• neurons in spinal cord connect to
thalamus, part of mid-brain
• information organized, sent to sensory
cortex
• directs motor cortex to send
information back to thalamus
• thalamus organizes information
• sends information down spinal cord
• motor neurons react to pain
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Neuronal structure
Pathways made up of neurons
Cell body-soma
Dendrites
Axon
Terminal at end of axon
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Impulse flow
Information flow is electrical and
chemical
Impulse flows down axon toward
terminal-connects to dendrite of
adjacent neuron
Passes on chemical information
Synapses can occur between terminal,
soma, or axon
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The synapse & synaptic neurotransmission
Electrical impulse arrives at terminal
Triggers vesicles containing
neurotransmitter
Neurotransmitter binds with specific
proteins called receptors
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Dopamine neurotransmission & modulation by
endogenous opiates
Vesicle fuses with membrane
releases dopamine
Dopamine molecules bind to
dopamine receptor
After binding-removed by uptake
pumps
Neighboring neurons that release
neuromodulators
Endorphins-bind to opiate receptors
Endorphins destroyed by enzymes
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The reward pathway and addiction
Natural rewards: Allow organism to feel pleasure
when eating, drinking, procreating & being nurtured
Food
Water
Sex
Nurturing
There is a brain pathway responsible
for rewarding behaviors
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The reward pathway
The reward pathway
• ventral tegmental area
• nucleus accumbens
• prefrontal cortex
VTA sends information to
prefrontal cortex via neurons
These neurons contain DOPAMINE
Released in prefrontal cortex &
nucleus accumbens
Pathway activated by rewarding
stimulus
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Activation of reward pathway by an electrical
stimulus
Brain of rats is studied
Electrode placed in nucleus accumbens
Rat presses lever to receive small
electrical stimulus
Feels pleasurable
Does not press lever when electrode
placed in other areas
DOPAMINE released
If dopamine blocked-no pleasure
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Addiction
A state in which an organism engages in a compulsive behavior
The behavior is reinforcing (rewarding or pleasurable)
Loss of control in limiting intake
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Craving
Reward pathway even more
important in creating craving
Craving may be more important
than the reward itself
Clear that addiction is a brain
disease
Two examples of drugs that are
addictive and how they affect their
cellular targets in the brain and the
reward pathway
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The action of opiates:
morphine, heroin, oxycontin, hydrocodone
Opiate binding sites within brain and spinal cord
Heroin converted to morphine by
enzymes in the brain
Morphine binds to opiate receptors
REWARD PATHWAY
• Cerebral cortex
• VTA
• Nucleus accumbens
PAIN PATHWAY
• Thalamus
• Brainstem
• Spinal cord
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Morphine binding within the reward pathway
Morphine binds to receptors in
nucleus accumbens ventral
tegmental area (VTA)
Reward pathway is activated!
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Synapse in nucleus accumbens
Opiates bind to opiate receptors
Increase release of dopamine
3 types of neurons participate
• releases dopamine
• adjacent neuron with different
neurotranmitter (GABA)
• post-synaptic cell-contains dopamine
receptors
Sends signal to dopamine terminalreleases more dopamine
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Rats self-administer heroin in experiments
Rat presses a bar to receive heroin
Heroin injected into nucleus accumbens
Creates pleasure - rat presses bar repeatedly
to get heroin and pleasure
Heroin is positively reinforcing
If needle placed elsewhere in brain - no
pleasure, no pressing the bar
Dopamine is released in reward pathway
More dopamine in synaptic space dopamine-dependent neurotransmission
augmented
Reward pathway activated
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Tolerance
A state in which an organism no longer responds to
a drug
A higher dose is required to achieve the same
effect
With heroin or morphine - tolerance to analgesia
develops rapidly
Develops at level of the cellular targets
Morphine binds to opiate receptors - triggers
inhibition of adenyl cyclase - maintains firing of
impulses
Enzyme adapts quickly, so morphine no longer
causes changes in cell firing
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Brain regions in the development of morphine
tolerance
Tolerance-different areas of brain
separate from reward pathway
Thalamus
Spinal cord
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Dependence
A state in which an organism functions normally only in the presence of a drug
Manifested as a physical disturbance when the drug is removed
Neurons adapt to repeated drug exposure, function normally only in presence
of the drug
When drug withdrawn:
• withdrawal syndrome
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Brain regions mediating morphine dependence
Specific areas of the brain – separate
from reward pathway
Thalamus
Brain stem
Withdrawal symptoms occur when
opiate receptors in these areas are
deprived of morphine
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Addiction vs. dependence
Possible to be dependent on
morphine without being addicted
Especially true of patients with cancer
or chronic pain
Addiction = compulsive use
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The action of cocaine
Snorting vs. smoking cocaine: Different liabilities
Smoking freebased cocaine gets it
to the brain more quickly than
snorting
Route more direct to the brain
Time between taking the drug and
positive reinforcement, rewarding
effects can determine likelihood of
abuse
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Localization of cocaine binding sites
Cocaine binds to sites in specific
areas
• VTA
• Nucleus accumbens
• Caudate nucleus
Binds especially in the reward areas
Binding in caudate nucleus explains
stereotypical behaviors
• Pacing
• Nail-biting
• Scratching
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The action of cocaine: Dopamine binding
Cocaine binds in sites rich in dopamine
Dopamine released into synaptic space
Binds to dopamine receptors-then
taken back up by pumps back into
terminal
Cocaine binds to uptake pumps prevents reuptake of dopamine
Dopamine builds up
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Cocaine dependence: Activation of reward pathway
Cocaine binds within reward pathway
• VTA & nucleus accumbens
Increased impulses to activate reward
pathway
Pathway activated in absence of cocaine
craving!
With repeated use-body relies on cocaine
to maintain rewarding feelings
No longer able to feel natural rewards
In absence of cocaine-anhedonia,
depression
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Rats self-administer cocaine in experiments
Increased dopamine in synapses of
reward pathway in rats
Rats press a bar to receive injections of
cocaine into reward pathway
If needle not in reward pathway, will
not press bar
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Bibliography
Goldstein RZ, Volkow ND: Dysfunction of the prefrontal cortex in addiction:
neuroimaging findings and clinical implications. Nat Rev Neurosci 12:652-669,
2011
Koob GF: Allostatic view of motivation: implications for psychopathology in
Motivational Factors in the Etiology of Drug Abuse. Edited by Bevins RA, Bardo
MT. Lincoln, University of Nebraska Press, 2004, pp 1-18
Koob GF, LeMoal M: Drug addiction, dysregulation of reward, and allostasis.
Neuropsycopharmacology 24: 97-129, 2001
Koob GF, LeMoal M: Neurobiology of Addiction. London, Academic Press, 2006
Drugs, Brain and Behavior: The Science of Addiction. National Institute on
Drug Abuse. Washington, 2014.
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Questions and discussion