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Time-Dependent Activity and Metabolic Markers A Novel Characterization of Ethanol WithdrawalAnant NaikIMPACT Program
Under the guidance of:Dr. Doo-Sup ChoiMolecular Pharmacology and Experimental Therapeutics TrackMayo Clinic, Rochester MN
Ethanol Withdrawal
Administration of Alcohol Acute
Alcohol Effects
Opposing Neuroadaptation
Alcohol tolerance
Removal of Alcohol
Withdrawal Syndrome
Recovery from Neuroadaptation
CNS Equilibrium
Alcohol-free state
Littleton (1998) National Institute on Alcohol Abuse and Alcoholism
Himmelsbach Hypothesis
Administration of Alcohol Acute
Alcohol Effects
Opposing Neuroadaptation
12
3
Various Models in Mice- Vapor Chamber- Oral Gavage- Two Bottle Choice
Administration of Alcohol Acute
Alcohol Effects
Opposing Neuroadaptation
12
3
Various Models in Mice- Vapor Chamber- Oral Gavage- Two Bottle Choice
- Drowsiness- Altered Mental Status
Administration of Alcohol Acute
Alcohol Effects
Opposing Neuroadaptation
12
3
Various Models in Mice- Vapor Chamber- Oral Gavage- Two Bottle Choice
- Drowsiness- Altered Mental Status
Molecular Changes
GlutamateAdenosine
Mitochondrial Changes in Astrocytes- Migration- Morphology- Functionality
Alcohol tolerance
Removal of Alcohol
Withdrawal Syndrome
4 New homeostasis- Decreased effect
of EtOH- Plasticity
56
Alcohol tolerance
Removal of Alcohol
Withdrawal Syndrome
4 New homeostasis- Decreased effect
of EtOH- Plasticity
56
Time
Beha
vior
al F
requ
ency
Extinction Phenomenon
Extinct
Spontaneous Relapse
Extinction Start
Extinction Burst
Alcohol tolerance
Removal of Alcohol
Withdrawal Syndrome
4 New homeostasis- Decreased effect
of EtOH- Plasticity
56
Time
Beha
vior
al F
requ
ency
Extinction Phenomenon
Extinct
Spontaneous Relapse
Extinction Start
Extinction Burst
Symptoms of Withdrawal• Sleep difficulty• Anxiety• Loss of Appetite• Nausea• Rapid Heart Rate• Lethargy
Medline, NIH
Can we identify objective time-dependent markers for metabolic activity for ethanol withdrawal?
Q
Lack of Metabolic Considerations
Limited Understanding of Time-dependent
Changes
Insufficient Biological Basis
MethodsEthanol Dependence Schedule
Acute Injection
• Long Term Exposure
• BAC Measurement
Chronic Exposure
Acute Re-administration
6:00
18:00
Dark CycleLight Cycle
10:00
Ethanol ExposureNo exposure
Outputs:• Oximetry• Activity• Food IntakeVapor Chamber
ResultsBlood Ethanol Concentration
ResultsLong-term vs. Chronic Withdrawal
𝑅𝑒𝑠𝑝𝑖𝑟𝑎𝑡𝑜𝑟𝑦 𝑄𝑢𝑜𝑡𝑖𝑒𝑛𝑡(𝑅𝑄)=𝐶𝑂2𝑒𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑒𝑑𝑂2𝑐𝑜𝑛𝑠𝑢𝑚𝑒𝑑A. B. Dark Cycle
ResultsLong-term vs. Chronic Withdrawal
Dark Cycle
A. B.
ResultsRe-administration of EtOH
A. B.
ResultsRe-administration of EtOH
A. B. C.
Future Directions
• Pre-clinical comparisons of genotype using paradigm
• Comparison of RQ and EE values with treatment with Taurine or Acamprosate during alcohol withdrawal
Metabolite-based Biomarkers of withdrawal, observing glutamine, adenosine, correlating with metabolic behavior. • Magnetic Resonance
Spectroscopy Imaging
• Micro-dialysis
Mitochondrial Dysfunction and regulation, size, density, orientation, location in neurons and astrocytes
Clinical monitoring of Respiratory Quotient and Energy expenditure and correlates with withdrawal of ethanol
1 2 3 4
Acknowledgements
Lab MembersSierra SladeDr. David Hinton, Ph.D.Phillip StarskiWayne OlsonDr. Ada HoAlfredo OliverosKatie WiningerSun ChoiDaniel LindbergDr. Yun-Fang JiaDr. Paul Croarkin, D.O, M.S.
Dr. Doo-Sup Choi, Ph.D.Summer StudentsBetsey DalyJoyce YangErin Nosco
IMPACT ProgramDr. Katie CampbellIMPACT Scholars
MPETDr. MaysMPET Summer Students
“If I have seen further than others, it is by standing upon the shoulders of giants.”
- Isaac Newton
