알코올 의존, 질병의 경과와 항갈망제의 사용 Industry-sponsored lecture 알코올 의존, 질병의 경과와 항갈망제의 사용 Ki, Seon Wan M.D., Ph. D. Incheon St. Mary’s Hospital Incheon, Korea

template "Absinthe Drinker" Pablo Picasso (1910)

Alcoholism is a Brain a Brain Disease. New Paradigm of Alcoholism

Drug Addiction (and Alcoholism) is conceptualized as a chronic relapsing syndrome that moves from an impulse control disorder involving positive reinforcement to a compulsive disorder involving negative reinforcement Drug Addiction

Addiction, presented in 2005 APA meeting, Koob Acute stage Positive affective state Pleasure seeking Impulse control Positive reinforcement HPA axis change Chronic stage Negative affective state Anxiety relief Compulsive behavior Negative reinforcement CNS change

From: Koob GF, Alcohol Clin Exp Res, 2003, 27:

Stages of the Addiction Cycle

Protocol for Initiation of Lever Pressing for Oral Ethanol Self-Administration in the Rat Initiation of the free-choice operant task: ethanol (10%) and water Rats trained to lever press on a FR-1 schedule Ethanol added to the saccharin solution Access to ethanol and water or ethanol + saccharin and water Days Day Days Day Days Day 0.2% - 0.2% - 0.2% - 0.2% - 0% 5% 8% 10% ******** TrainingSaccharin (w/v)EtOH (w/v) From: Rassnick S, Pulvirenti L and Koob GF, Alcohol, 1993, 10:

Neurochemical Circuitry in Drug Reward

‘Reward’ pathway (mesolimbic dopamine system) ‘Withdrawal’ pathway (locus coeruleus) The addiction pathways

Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus Accumbens From: Nestler EJ, Nat Neurosci, 2005, 8:

NA VTA Prefrontal cortex

How alcohol affect the brain

Alcohol & Neurotransmitters

Reward Transmitters Implicated in the Motivational Effects of Drugs of Abuse Dopamine … “dysphoria” Opioid peptides... pain Serotonin … “dysphoria” GABA … anxiety, panic attacks Dopamine Opioid peptides Serotonin GABA Positive Hedonic EffectsNegative Hedonic Effects of Withdrawal

Neurochemical Changes Associated with the Transition from Drug Use to Dependence From:Roberts AJ and Koob GF, Alcohol: ethanol antagonists/amethystic agents. in Adelman G and Smith BH (Eds.), Encyclopedia of Neuroscience, 3rd edn, Elsevier, New York, 2003 [

Pharmacotherapy to treat addictive disorders Disrupting the acute reinforcing and conditioning effects (Positive Reinforcement and Learning) Disrupting the acute reinforcing and conditioning effects (Positive Reinforcement and Learning) –Agonist substitution or Replacement therapy –Agents that will diminish DA increase in NA mu opioid, CB 1 antagonist Specific D1 D3 antagonist GABAergic agents 5HT3 antagonist –Agents that can trigger aversive responses Compensation for neuroplastic brain changes related to chronic substance use Compensation for neuroplastic brain changes related to chronic substance use –Glutamate transmission Glutamate blocking agent Agent that serves to activate the mGlu2/3 autoreceptors – ↓ DA release in the amygdala and PFC and not blocking DA release in the NA –CRF 1 antagonist

Withdrawal from chronic drugs of abuse produces a reward (motivational) dysregulation as measured by thresholds for intracranial self-stimulation Drug Withdrawal

Mechanism of Action in Treating Alcohol Withdrawal : A Hypothesis Alcohol withdrawal is also associated with hypersensitivity of the locus caeruleus and liberation of norepinephrine –an effect associated with increased symptoms of anxiety during alcohol withdrawal The locus caeruleus is under dual excitatory and inhibitory control –from the nucleus paragigantocellularis & from the nucleus prepositus hypoglossi Therefore, an agent, by blocking glutaminergic input and facilitating GABA A currents, might serve to quell locus caeruleus-associated increases in norepinephrine during alcohol withdrawal

Neurotoxicity and Neuroprotection De Witte P et al, CNS drugs, 2005; 19(6) glutamate receptor subtype 5 (mGluR5)an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5) in particular surge in glutamic acid attenuated by acamprosate.For example, during chronic exposure to alcohol, the glutamatergic system becomes upregulated, leaving the brain exposed to excessive glutamatergic activity when alcohol is abruptly withdrawn. The surge in glutamic acid release that occurs following alcohol withdrawal can be attenuated by acamprosate. neuronal lossThe elevated extracellular levels of glutamic acid observed in withdrawal, together with supersensitivity of NMDA receptors, may expose vulnerable neurons to excitotoxicity, possibly contributing to the neuronal loss sometimes observed in chronic alcohol dependence. excitotoxicity produced by ethanol can effectively be blocked by acamprosate.In vitro studies suggest that the excitotoxicity produced by ethanol can effectively be blocked by acamprosate.

Acamprosate Disrupting the acute reinforcing and conditioning effects (Positive Reinforcement and Learning) Disrupting the acute reinforcing and conditioning effects (Positive Reinforcement and Learning) –Agonist substitution or Replacement therapy –Agents that will diminish DA increase in NA mu opioid, CB 1 antagonist Specific D1 D3 antagonist GABAergic agents 5HT3 antagonist –Agents that can trigger aversive responses Compensation for neuroplastic brain changes related to chronic substance use Compensation for neuroplastic brain changes related to chronic substance use –Glutamate transmission Glutamate blocking agent Agent that serves to activate the mGlu2/3 autoreceptors – ↓ DA release in the amygdala and PFC and not blocking DA release in the NA –CRF 1 antagonist Neuroprotection

Relevant Pharmacological Characteristics for Human Laboratory Model Construction Naltrexone NaltrexoneAcamprosate Onset of action RapidSlow Hypothesized underlying mechanism decreased positive reinforcement O decreased negative reinforcement O Population affected non dependent O dependent OO Primary outcomes decreased heavy drinking O increased abstinence O decreased craving O effects on post treatment periodLimitedLong-term

Mechanism of Medication Treating Alcohol Dependence