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MOA - PK Overview

MOA - PK Overview. George F. Koob, Ph.D. Professor, Department of Neuropharmacology Director, Division of Psychopharmacology The Scripps Research Institute. Acamprosate. Stages of Alcoholism Important for the Development of Animal Models. Acute Reinforcement/Social Drinking.

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MOA - PK Overview

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  1. MOA - PK Overview George F. Koob, Ph.D. Professor, Department of Neuropharmacology Director, Division of Psychopharmacology The Scripps Research Institute

  2. Acamprosate

  3. 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?

  4. 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in drinking in dependent rats during withdrawal (Geiss, Heidbreder, Opsomer, Durbin and De Witte, 1991; Morse and Koob, unpublished results) • Acamprosate eliminates the alcohol deprivation effect in rats under free-drinking continuous access or operant limited access conditions (Spanagel,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)

  5. Protocol for Initiation of Lever Pressing for Oral Ethanol Self-Administration in the Rat Training Saccharin (w/v) EtOH (w/v) Days Days Day Days Day Day Days Day Day 1-3 4-9 10 11-12 13 14 15-16 17 18+ 0.2% 0.2% - 0.2% - 0.2% - 0.2% - 0% 5% 5% 5% 5% 8% 8% 10% 10%

  6. 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, 10:127-132.

  7. Effects of Abstinence Intervalon Alcohol Self-Administration From: Heyser CJ, Schulteis G, Durbin P and Koob GF, Neuropsychopharmacology, 1998, 18:125-133.

  8. 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.

  9. 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)

  10. Schematic Neuron Showing the Possible Mode of Action of Acamprosate onAlcohol-Related Effects From: Spanagel R and Zieglgansberger W, Trends Pharmacol Sci, 1997, 18:54-59.

  11. 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)

  12. 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)

  13. 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)

  14. 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

  15. 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

  16. Schematic Neuron Showing the Possible Mode of Action of Acamprosate onAlcohol-Related Effects From: Spanagel R and Zieglgansberger W, Trends Pharmacol Sci, 1997, 18:54-59.

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