How to study addiction

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How to study addiction
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Types of Cocaine and Routes of Administration

• Type Street Cocaine(White Powder)
• Administration Intranasal injection
• Type Crack
• Smokable (Inhalation)
• Type Freebase Cocaine
• Inhaled
• injected
• Type Coca Leaf
• Administration Oral

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1980s Cocaine Epidemic

• The Champagne of Stimulants
• Very expensive and difficult to obtain
• Crack - 1985
• produced by mixing cocaine HCl with baking
• soda and water. The solution is
• then heated, resulting in brittle
• sheets of cocaine that are cracked
• into small, smokable chunks or rocks.

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Duration of Action

• The duration of action of cocaine differs greatly
  from other stimulants such as amphetamines.
• Effects of cocaine are much shorter-lived
• The effects of cocaine are diminished 20-80
  minutes after administration
• One Hour Half-Life

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Metabolism Excretion

• Cocaine is metabolized through the kidneys
• Cocaine is present in the urine up until 12 hours
  after administration
• Metabolites present in urine for 2-3 days
  post-administration
• Chronic users possible for metabolites to be
  detected in urine for up to 2 weeks
  post-administration

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Acute Chronic Effects

• Hyperactivity
• Restlessness
• Increased blood pressure
• Increased heart rate
• Euphoria
• Alertness
• Cocaines primary acute effect is when used it
  raises the amount dopamine and serotonin in the
  nucleus accumbens
• As the drug is being eliminated from the body
• feelings of depression, a crash after the high
• No physical withdrawal, only mental

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The Addiction Cycle
Drug addiction and relapse
Exposure to
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Drug Self-Administration
Rat in Operant Chamber
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Cocaine Self-Administration Reinstatement Model
Cue
Active Lever Presses
Stress
Drug Prime
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• Reinstatement ?
• RELAPSE

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Cocaine Self-Administration Reinstatement Model
Cue
Active Lever Presses
Stress
Drug Prime
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Endpoint 1 Circuitry

• Can inactivate a brain area
• TTX (no action potentials)
• Lidocaine (numbing)
• Look at changes in behavior
• Acquisition
• Maintenance
• Extinction
• Relapse

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Stereotaxic Surgery

• Stereotaxis solid arrangement
• Stereotaxic apparatus

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The Stereotaxic atlas

• Way to navigate through the brain
• Relies on two landmarks
• Lambda bregma
• Brain areas are located by their coordinates

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Endpoint 2 Measuring Brain Secretions

• Can measure the amount of neurotransmitter
  released
• Microdialysis
• Used in experimental animals
• Use stereotaxic surgery to implant cannulae in a
  brain region of interest
• Can measure amount what kind of
  neurotransmitter is released during certain
  behaviors (acquisition, maintenance, relapse)

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Endpoint 3 Changes in behavior

• Apply treatment which is usually a drug
• Does this affect
• self-administration
• Acquisition
• Maintenance
• Sensitization
• Relapse

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Endpoint 4 Genetic Methods

• Protein Expression
• Western blots
• Immunohistochemistry
• mRNA expression
• In situ hibridization
• Gene chips (microarrays)
• Can then use targeted mutations or expressions
• knockout animals
• Viral overexpression

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Neuronatin
Arc
Sal
Coc
Sal
Coc
Expression Levels
Sal
Coc
Coc
Sal
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SEARCHING FOR NEW GENES ALTERED IN THE
ADDICTED BRAIN
- Gene expression profiling expression levels of
thousands of genes are simultaneously monitored
to study the effects of certain treatments /
diseases
- DNA microarray Gene chip
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Mesolimbic (Midbrain) DA System
REINFORCEMENT!
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STEP1 cDNA microarray -screening for changes in
gene expression caused by acute amphetamine
Gonzalez-Nicolini and McGinty- 2004
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STEP2 in situ hybridization - confirmation of
changes and anatomical distribution
1xAMPH (2.5mg/kg i.p.) 1h, 3h, 6h, 24h
dorsal STR
Downregulation of RGS4 levels by acute AMPH
Schwendt et al. J.Neurochem. 96 2006