Neurobiology of Addiction

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Neurobiology of Addiction

• Principles of Primary Care
• Block 4
• March 28, 2006
• Martha Wunsch MD
• Discipline Chair, Addiction Medicine

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Learning Objectives

• Identify the anatomical areas of the brain
  involved in the reward pathway.
  
• List the neurotransmitter systems which activate
  the reward pathway
  
• List the receptors activated by psychoactive
  drugs
  
• Identify the anatomical areas of the brain
  involved in withdrawal from psychoactive drugs.
  

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Dedicated to the mice
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rats..
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And monkeys
For their contribution to our knowledge in this
area of science
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(No Transcript)
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Evolution of Theories of Addiction

• Spiritual/possession
• Rum and spirits
• Sometimes behavior of someone with addiction
  seems more like an animal than a human
  
• Violence associated with intoxication
• Moral failing
• Weakness or lack of moral fiber
• Drunk drivers
• Inability to handle stress except with use
• Demonization of addicts
• Chronic Health Condition
• People with addiction may engage in behavior that
  is morally unjustified
  
• Attention to spiritual health is a key to
  recovery from addiction

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• King Saul, King in the Bible (around 1050 - 1000
  B.C.)"Choli nophel" (falling sickness), was the
  ancient Hebrew term for epilepsy "nophel" (
  Hebrew verb "naphal" to fall), 'the falling
  person', was a popular term in ancient Hebrew for
  someone with epilepsy.The first book of Samuel
  mentions Saul's uncontrolled violent behavior
  several times. In Chapter 10, it is written "And
  the spirit of God came mightily upon him, and he
  prophesied among them." (1 Samuel, 1010).
  Elsewhere in Samuel, an evil spirit from God is
  talked about which takes possession of Saul from
  time to time "Behold now, an evil spirit from
  God is tormenting you." (1 Samuel 1615) and two
  chapters later "And on the morrow an evil spirit
  from God rushed upon Saul, and he raved within
  his house." (1 Samuel 18 10).
•                 Saul and David   

Saul
 (Rembrandt, 1630)
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Epilepsy the Sacred Disease

• It is thus with regard to the disease called
  sacred it appears to me to be in no way more
  divine nor more sacred than other diseases...
  
• The brain is the cause of this affliction...
• When the surplus phlegm from the brain runs
  down through the veins, the patient loses his
  speech and foams at the mouth, his hands are
  contracted, the eyes contorted, he becomes
  insensible, and in some cases the bowels are
  emptied...
• The patient kicks with his feet ... The patient
  must endure all these symptoms when the cold
  phlegm flows into the warm blood.

Hippocrates
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Current Theory Reward Pathway

• There is reward pathway in the brain which is
  activated by
  
• Food, water and sex
• Nurturing and caring for others
• Thrills (hang gliding, merry go rounds)
• Exercise
• This reward pathway is also activated by
• Drugs, including alcohol
• Gambling

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Neuropeptides which activate receptors and act on
the reward pathway

• Serotonin
• Affects Mood
• Receptor 5HT3
• Dopamine
• Affects Mood
• D1, D2
• Cannibinoids
• Pain
• Multiple cannibinoids receptors identified
• Endorphins, Enkephalins, Dynorphins
• Mood, pain
• 5 types of Mu, Delta, Kappa

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Prefrontal cortex
Thalamus
Ventral tegmental area
Nucleus accumbens
Locus coeruleus
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Will work for stimulation of the VTA or NA
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Will work for morphine or cocaine
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Neurobiology of addiction

• Disease model
• 1930 AA is founded by a physician and business
  man
  
• 1956 to AOA and AMA released formal statements
  supporting the definition of alcoholism as a
  disease
  
• Reward center of brain (Olds and Milner, 1954)
• Identified from work performed in animals
• Further Experimental results
• Stimulation
• Ablation
• Blockade studies
• Neuroimaging studies (PET Scans, SPECT scans)

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Brain areas involved in the reward pathway, and
in addiction

• Ventral tegmental area (VTA)
• Nucleus accumbens (NA)
• Prefrontal cortex (PC)
• Locus coeruleus (LC)
• Thalamus

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Reward pathway
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Stimulation of nucleus accumbens
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Stimulation of VTA
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Reward pathway
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Reward pathway
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Evidence for reward pathway

• Stimulation (electrical or chemical) of NA VTA
  is intrinsically rewarding.
  
• Stimulation elsewhere is not
• Reward can be interrupted by
• Severing NA-FC fibers
• Using dopamine blocker
• Blocking can interrupt naturally rewarded
  behaviors
  
• Patients on drugs that block dopamine look flat
  to us and experience decreased emotions

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Reward pathway blocked
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Reward pathway

• Dopamine is the primary transmitter that is the
  final activation chemical in all rewards
  
• Activates D1 receptors
• D2 receptors are also activated
• Responsible for reinforcing behavior

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All drugs act via dopaminergic pathways
Dopamine
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Development of addiction

• Increasing use of the substance to feel high
• Gradual increase in number of receptors
• Gradual decrease in amount of normal transmitter
  by depletion and feedback inhibition
  
• Gradual decrease in reinforcing properties of
  drug (loss of high or rush)
  
• Increase in need for drug to maintain normalcy
• Beginning of dependence

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Direct action

• Some of the actions of drugs of abuse are due to
  direct action on a psychoactive receptor
  
• Example opioid (pain medications) binding to mu
  or endorphin receptors
  
• Effect limited by the number of receptors
  present
  
• Direct action continues as long as drug is present

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Indirect action Mechanisms

• Indirect action on a given transmitter system
• Serotonergic effect of alcohol via G coupled
  protein receptors
  
• Use of secondary messenger systems
• Indirect action via a neurotransmitter which in
  turn modulates another transmitter system

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Indirect action multiple systems

• Alcohol as an example
• Binds to receptors
• GABAA , NMDA, endorphin
• Activates receptor-coupled adenyl cyclase
  systems.
  
• Downstream effects on dopamine from above
  systems
  
• In high doses affects membrane lipid

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Indirect action Cocaine

• Act via reuptake inhibition of dopamine
• Promote dopamine release via dopamine transporter
  (DAT)
  
• Because indirect action depends on existing
  neurotransmitter, effect of drug attenuates as
  this is depleted
  

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Cocaine inhibiting reuptake of Dopamine
Normal Re-Uptake of Dopamine
D1 Receptor
Dopamine
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Drugs which act via the GABA receptor system

• Alcohol and other drugs (Valium)
• GABA major inhibitory neurotransmitter
• Use of alcohol and valium makes the individual
  feel calmer, sleepier, less anxious via
  activation of this receptor system
  
• Binds to sub-receptors GABAA or GABAB
• Activates secondary messages and eventually
  causes release of dopamine
  

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Withdrawal from alcohol and drugs

• Tolerance a physiologic adaptation of the
  organism to the presence of a drug. Upon abrupt
  discontinuation of the drug, a recognizable
  syndrome develops
• Always involves autonomic disturbance
• Activation of thalamus
• Activates the Locus coeruleus
• LC has projections to frontal cortex, limbic
  cortex, and amygdala
  
• Individual feels dysphoric, depressed, angry, and
  irritable

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Withdrawal
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Withdrawal
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Withdrawal
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Withdrawal
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Case example Asian-American male age 23

• Started tobacco age 13, cannabis age 15
• Never liked alcohol because of flushing
• On weekends started snorting heroin, gradual
  increase to three nights/week
  
• Added crack cocaine, rapid deterioration
• Increasing cost led to switch to opioid pills,
  crack, low grade dealing
  
• Increasing availability led to escalating use
• Began injecting opioids/ cocaine
• Admitted for treatment

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Case example Neurotransmitter issues

• Depletion of dopamine
• Anergic, anhedonic, irritable
• Depletion of endorphins
• Poor sleep, anhedonic, decreased pain tolerance
• Apparent depletion of serotonin
• Depression, increased impulsivity

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• Questions?