MOA - PK Overview

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MOA - PK Overview

• George F. Koob, Ph.D.
• Professor, Department of Neuropharmacology
• Director, Division of Psychopharmacology
• The Scripps Research Institute

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Acamprosate
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(No Transcript)
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Stages of Alcoholism Important for the
Development of Animal Models
Acute Reinforcement/Social Drinking
Escalating/Compulsive Use Binge Drinking
Genetic variables Environmental
factors Stress Conditioning effects
Dependence
Relapse
Withdrawal
Protracted Withdrawal
Recovery?
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Effects of Acamprosate on Animal Models of
Excessive Drinking

• Acamprosate decreases alcohol drinking in rats
  selected for excessive drinking (Boismare et al.,
  1984)
• Acamprosate decreases alcohol intake in dependent
  rats(Le Magnen, Tran, Durlach and Martin, 1987)
• Acamprosate reverses the preference for alcohol
  and the increase in drinking in dependent rats
  during withdrawal (Geiss, Heidbreder, Opsomer,
  Durbin and De Witte, 1991 Morse and Koob,
  unpublished results)
• Acamprosate eliminates the alcohol deprivation
  effect in rats under free-drinking continuous
  access or operant limited access conditions
  (Spanagel, Holter, Allingham, Landgraf and
  Zieglgansberger, 1996 Holter, Landgraf,
  Zieglgansberger and Spanagel, 1997 Heyser,
  Schulteis, Durbin and Koob, 1998)

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Protocol for Initiation of Lever Pressing for
Oral Ethanol Self-Administration in the Rat
Training
Saccharin (w/v)
EtOH (w/v)
1-3 4-9 10 11-12 13 14 15-16 17 18
Days Days Day Days Day Day Days Day Day
0.2 0.2 - 0.2 - 0.2 - 0.2 -
0 5 5 5 5 8 8 10 10
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Blood Alcohol Levels in a Free-Choice Operant
Task for Ethanol (10) and Water Following the
Saccharin Fade Out Procedure
From Rassnick S, Pulvirenti L and Koob GF,
Alcohol, 1993, 10127-132.
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Effects of Abstinence Intervalon Alcohol
Self-Administration
From Heyser CJ, Schulteis G, Durbin P and Koob
GF, Neuropsychopharmacology, 1998, 18125-133.
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Chronic Acamprosate on Responding for Ethanol
Following 5 Days Abstinence
From Heyser CJ, Schulteis G, Durbin P and Koob
GF,Neuropsychopharmacology, 1998, 18125-133.
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What Acamprosate Does Not Do in Animal Models

• Acamprosate does not produce anti-conflict
  effects in an animal model of anxiety (Koob and
  Britton, unpublished results)
• Acamprosate does not substitute for alcohol in
  drug discrimination (Spanagel, Zieglgansberger
  and Hundt, 1996)
• Acamprosate does not block the discriminative
  stimulus properties of alcohol (Spanagel,
  Zieglgansberger and Hundt, 1996)
• Acamprosate does not have any reinforcing effects
  or aversive effects on its own (Grant and
  Woolverton, 1989 Morse and Koob, unpublished
  results)
• Acamprosate does not antagonize the
  discriminative stimulus effects of amphetamine or
  morphine, or the reinforcing effects of heroin
  (Pascucci et al., 1999 Spanagel et al., 1998)

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Schematic Neuron Showing the Possible Mode of
Action of Acamprosate onAlcohol-Related Effects
From Spanagel R and Zieglgansberger W, Trends
Pharmacol Sci, 1997, 1854-59.
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Neuropharmacological Effects of Acamprosate

• Acamprosate inhibits neuronal hyperexcitatability
  by decreasing presynaptic release of the
  excitatory neurotransmitter glutamate and by
  decreasing post-synaptic excitability of
  glutamate receptors (Zeise, Kaparaov, Capogna and
  Ziegelgansberger, 1993 Dahchour et al., 1998
  Koob, Mason, De Witte, Littleton and Siggins,
  2002)
• Acamprosate inhibits calcium influx through NMDA
  glutamate receptors through an interaction with
  polyamines on the NMDA receptor (Naassila,
  Hammoumi, Legrand, Durbin and Daoust, 1998
  al-Qatari, Bouchenafa and Littleton, 1998 Popp
  and Lovinger, 2000)
• Acamprosate inhibits calcium influx through
  voltage-dependent calcium channels (al-Qatari and
  Littleton, 1995 Allgaier, Franke, Dobottka and
  Scheibler, 2000)
• Acamprosate increases synaptic availability of
  the inhibitory neurotransmitter taurine
  (Dahchour, Quertemont and De Witte, 1996)

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Functional Significance of the Neuropharmacologica
l Mechanism of Action of Acamprosate

• Acamprosate acts as a partial co-agonist at the
  glutamate receptor through an allosteric
  interaction with the polyamine binding site on
  the NMDA glutamate receptor complex
• Neuropharmacological consequences are to enhance
  activation of the glutamate receptor when levels
  of endogenous activators are low, but inhibit
  activation when levels of endogenous activators
  are high (such as during alcohol withdrawal)

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Neuroprotective Effects of Acamprosate

• Acamprosate is neuroprotective against
  glutamate-induced neurotoxicity when enhanced by
  alcohol withdrawal in neocortical cultures of
  fetal rat brain (al Qatari, Khan, Harris and
  Littleton, 2001)
• Acamprosate reduces excitatory postsynaptic field
  potentials in the hippocampus which may lead to
  protection against hyperexcitability such as
  epileptiform activity and seizures (Koob, Mason,
  De Witte, Littleton and Siggins, 2002)
• Acamprosate decreases neurological deficits
  associated with cerebral ischemia in the rat
  (Engelhard, Werner, Lu, Mollenberg and
  Zieglgansberger, 2000)
• Acamprosate decreases the severe mortality
  associated with alcohol withdrawal in the rat
  (Dahchour, Landron and De Witte, 2001)
• Acamprosate normalizes sleep changes induced by
  alcohol and produces some cognitive-enhancing
  effects in healthy human volunteers (Koob, Mason,
  De Witte, Littleton and Siggins, 2002)

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Pre-Clinical and Clinical Pharmacokinetics of
Acamprosate

• Animal Human
• Bioavailability 16 - rats 11
• Elimination Half-life 23-31 hours - rats 18 hours
• Time to Steady State 5-7 days 5-7 daysPlasma
  Levels
• Protein Binding None None
• Elimination Not metabolized Not
  metabolized Renal excretion Renal excretion
• Lethality 6 grams/kg No known lethality

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Drug Interactions with Acamprosate

• Animal Human
• Alcohol None None
• Disulfiram None None
• Anticonvulsants None N/A
• Anxiolytics None None
• Antipsychotics None N/A
• Antidepressants None None
• Naltrexone N/A Plasma acamprosate

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Schematic Neuron Showing the Possible Mode of
Action of Acamprosate onAlcohol-Related Effects
From Spanagel R and Zieglgansberger W, Trends
Pharmacol Sci, 1997, 1854-59.