1. MOA - PK Overview George F. Koob, Ph.D.
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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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4. Stages of Alcoholism Important for the Development of Animal Models
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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?

5. Effects of Acamprosate on Animal Models of Excessive Drinking
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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in drinking in dependent rats during withdrawal (Geiss, Heidbreder, Opsomer, Durbin and De Witte, 1991; Morse and Koob, unpublished results)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)
Days
Day
1-3
4-9 10
11-12 13 14
15-16 17
18+
0.2% - 0% 5% 8%
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, 10:

8. Effects of Abstinence Interval on Alcohol Self-Administration
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Effects of Abstinence Interval on Alcohol Self-Administration
From: Heyser CJ, Schulteis G, Durbin P and Koob GF, Neuropsychopharmacology, 1998, 18:

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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, 18:

10. What Acamprosate Does Not Do in Animal Models
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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 on Alcohol-Related Effects
From: Spanagel R and Zieglgansberger W, Trends Pharmacol Sci, 1997, 18:54-59.

12. Neuropharmacological Effects of Acamprosate
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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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13. Functional Significance of the Neuropharmacological 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)

14. Neuroprotective Effects of Acamprosate
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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)

15. Pre-Clinical and Clinical Pharmacokinetics of Acamprosate
Animal Human
Bioavailability 16% - rats 11%
Elimination Half-life hours - rats 18 hours
Time to Steady State 5-7 days 5-7 days Plasma Levels
Protein Binding None None
Elimination Not metabolized Not metabolized Renal excretion Renal excretion
Lethality 6 grams/kg No known lethality

16. 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 on Alcohol-Related Effects
From: Spanagel R and Zieglgansberger W, Trends Pharmacol Sci, 1997, 18:54-59.