acamprosate moa - pk overview george f. koob, ph.d. professor, department of neuropharmacology...

ACAMPROSATEACAMPROSATE

MOA - PK OverviewMOA - PK OverviewGeorge F. Koob, Ph.D.

Professor, Department of Neuropharmacology

Director, Division of Psychopharmacology

The Scripps Research Institute

George F. Koob, Ph.D.

Professor, Department of Neuropharmacology

Director, Division of Psychopharmacology

The Scripps Research Institute


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AcamprosateAcamprosate


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Stages of Alcoholism Important for the Development of Animal ModelsStages of Alcoholism Important for the Development of Animal Models

Acute Reinforcement/Social DrinkingAcute Reinforcement/Social Drinking

Escalating/Compulsive Use Binge Drinking

Escalating/Compulsive Use Binge Drinking

DependenceDependence

WithdrawalWithdrawal

Protracted WithdrawalProtracted Withdrawal

Recovery?Recovery?

Genetic variables

Environmental factors

Stress

Conditioning effects

Genetic variables

Environmental factors

Stress

Conditioning effectsRelapse


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Effects of Acamprosate on Animal Models of Excessive Drinking

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in drinking in dependent rats during withdrawal (Geiss, Heidbreder, Opsomer, Durbin and De Witte, 1991; Morse and Koob, unpublished results)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)

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in drinking in dependent rats during withdrawal (Geiss, Heidbreder, Opsomer, Durbin and De Witte, 1991; Morse and Koob, unpublished results)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

Protocol for Initiation of Lever Pressing for Oral Ethanol Self-Administration in

the Rat

1-3

4-9

10

11-12

13

14

15-16

17

18+

1-3

4-9

10

11-12

13

14

15-16

17

18+

Days

Days

Day

Days

Day

Day

Days

Day

Day

Days

Days

Day

Days

Day

Day

Days

Day

Day

0.2%

0.2%

-

0.2%

-

0.2%

-

0.2%

-

0.2%

0.2%

-

0.2%

-

0.2%

-

0.2%

-

0%

5%

5%

5%

5%

8%

8%

10%

10%

0%

5%

5%

5%

5%

8%

8%

10%

10%

TrainingTraining Saccharin (w/v)Saccharin (w/v) EtOH (w/v)EtOH (w/v)


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ACAMPROSATEACAMPROSATEFrom: Rassnick S, Pulvirenti L and Koob GF, Alcohol, 1993, 10:127-132.

Blood Alcohol Levels in a Free-Choice Operant Task for Ethanol (10%) and Water

Following the Saccharin Fade Out Procedure

Blood Alcohol Levels in a Free-Choice Operant Task for Ethanol (10%) and Water

Following the Saccharin Fade Out Procedure


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Effects of Abstinence Intervalon Alcohol Self-AdministrationEffects of Abstinence Interval

on Alcohol Self-Administration

From: Heyser CJ, Schulteis G, Durbin P and Koob GF, Neuropsychopharmacology, 1998, 18:125-133.


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Chronic Acamprosate on Responding for Ethanol Following 5 Days

Abstinence

Chronic Acamprosate on Responding for Ethanol Following 5 Days

Abstinence

From: Heyser CJ, Schulteis G, Durbin P and Koob GF,Neuropsychopharmacology, 1998, 18:125-133.


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What Acamprosate Does Not Do in Animal Models

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)

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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ACAMPROSATEACAMPROSATEFrom: Spanagel R and Zieglgansberger W, Trends Pharmacol Sci, 1997, 18:54-59.

Schematic Neuron Showing the Possible Mode of Action of Acamprosate on

Alcohol-Related Effects




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Neuropharmacological Effects of Acamprosate

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)

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 Neuropharmacological Mechanism of

Action of Acamprosate

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)

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

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)

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

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 metabolizedRenal excretion Renal excretion

Lethality 6 grams/kg No known lethality

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 metabolizedRenal excretion Renal excretion

Lethality 6 grams/kg No known lethality


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Drug Interactions with Acamprosate

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

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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ACAMPROSATEACAMPROSATEFrom: Spanagel R and Zieglgansberger W, Trends Pharmacol Sci, 1997, 18:54-59.





acamprosate moa - pk overview george f. koob, ph.d. professor, department of neuropharmacology...

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