The Future of Treating Alcoholism: Framing the Key Research Questions

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1 The Future of Treating Alcoholism: Framing the Key Research Questions Kathleen A. Grant, Ph.D. President, Research Society on Alcoholism A Society of basic, clinical and translation researchers committed to addressing public health concerns related to alcohol abuse and dependence

2 RSA lecture series: 2006 Module #1 Module #2 Basics of Alcohol Action: Pharmacodynamics & Etiology of Alcohol Abuse & Alcoholism Metabolism Who becomes alcohol dependent & why? Arthur Cederbaum, Ph.D. Mount Sinai School of Medicine Cardiovascular Effects of Alcohol Sam Zakhari, Ph.D. NIAAA/NIH Effects of Alcohol on the Endocrine System Catherine Rivier, Ph.D. The Salk Institute Alcohol & Stress Stress & Drinking: What is the link? Rajita Sinha, Ph.D. Yale University Neurobiology of Alcoholism: Insights from the dark side of reward neurocircuitry George Koob, Ph.D. The Scripps Research Institute Diagnosis & Assessment of Alcohol Dependence Deborah Hasin, Ph.D. Columbia University Behavioral Treatments for Alcohol Dependence Allen Zweben, Ph.D. Columbia University Medications to Treat Alcoholism: Where WeÕve Been and Where WeÕreGoing Henry Kranzler, M.D. University of Connecticut Kenneth Sher, Ph.D. University of Missouri Alcohol & Genetics: Is your child at risk? Tamara Phillips, Ph.D. Oregon Health and Science University Alcohol-Related Brain Pathology If you drink your brain will shrink! Clive Harper, M.D. University of Sydney Effects of Alcohol on Cognitive Function Sara Jo Nixon, Ph.D. University of Kentucky Fetal Alcohol Spectrum Disorders Edward Riley, Ph.D. San Diego State University Alcohol and Adolescence Linda Spear, Ph.D. Binghamton University College Drinking Mark Goldman, Ph.D. NIAAA/NIH Alcohol Policy Thomas Greenfield, Ph.D. University of California, Berkeley

3 Key Questions in Alcohol Research Why do some people drink more than others? What are individual differences in drinking quantity and pattern? What contributes to problem drinking and dependence? Prevalence of Past-year DSM-IV Alcohol Dependence by Age - U.S. Drinkers 18 and older 14% 12% 10% 8% 6% 4% 2% 0% Age Grant and Dawson, NIAAA

4 Prevalence of DSM-IV Alcohol Use Disorder Diagnoses by sex and age Abuse Dependence Percent Men Women

5 DSM-IV Dependence Criteria Tolerance* Withdrawal* Using in larger amounts/over a longer time period than intended Persistent desire to cut down/control Great deal of time spent obtaining/using/recovering* Important activities given up/reduced* Continued drinking despite physical/psychological problems that are caused/exacerbated by alcohol* * These criteria are modeled well in animals, whereas terms in red text are human constructs

6 DSM-IV Abuse Criteria Failure to fulfill major role obligations Recurrent use in physically hazardous situations Recurrent alcohol-related legal problems Continued drinking despite social/interpersonal problems that are caused/exacerbated by alcohol Criteria for alcohol dependence not met

7 Comprehensive models of why people drink to excess and dependence Pharmacological Vulnerability Affect (mood) Regulation Negative affect regulation ( self-medication ) Positive affect regulation ( reward seeking ) Deviance/Disinhibition

8 Animal models help address the biological basis of traits found in human alcohol abuse and alcoholism Eventual Binger (16 drinks/day) Eventual non-binger Drinking behavior gulping drinks Brain imaging Sex differences Genetics

9 Selective breeding for high and low alcohol drinking preference Drinking preferences transfer across environments: An example of salience Water (ml/day) Ethanol intake (g/kg/day) Ethanol ( ml/day) g/kg/day Generations of breeding Ethanol concentration

10 Patterns of drinking show tolerance and attempts to cut down on alcohol consumption Tolerance (increased intake) over 4 months of drinking pellet etoh water One day out of 4 showing volitional cutting down on drinking drinks/day MONKEY 6888 BEC=181 mg/dl (3.42 g/kg) Session Time (hr) etoh water pellets Session Time (hr) Session Time (hr) 16-Jan 17-Jan 18-Jan 19-Jan

11 Alcohol co-opts normal brain processes that compel behaviors linked to survival Reinforcement Ventral pallidum Nucleus Accumbens Core Prefontal Cortex Impulsivity Ventral Tegmental Area Pleasure/ Positive Reinforcement Ventral Tegmental Area Basolateral amygdala Rats bred to prefer alcohol will inject alcohol directly into the brain (Posterior VTA) Raphe nucleus Hippocampus Extended amydala Central nucleus amydala Bed nucleus stria terminalis Nucleus Accumbens shell Anxiety/ Negative Reinforcement Dopamine Glutamate GABA GABA/CRF/NPY Dopamine/GABA/Opioid 5HT Adapted from Kalivas and Volkow (2005) Am J Psychiatry 162:

12 Potential molecular and neural pathways involved in excessive alcohol drinking have been identified and can be the target of new drug therapies Cholinergic Excitatory Input GLU Excitatory Input CB1-R AMPA NMDA Serotonin Modulatory Input CRF? DOPAMINE (D1, D2) Prefrontal cortex Amygdala Lateral septum Hippocampus GLU Excitatory Input CB1-R Enkephalin Inhibitory Input NIC-R GABA Inhib Input NIC-R Dopamine Neuron GABA Neuron Mu Opioid Receptors GABA Inhibitory feedback GABA Neuron CB1-R REINFORCEMENT Ventral Tegmental Area (VTA) Nucleus Accumbens (nacc)

13 Genes Contributing to Alcohol-Related Behaviors in both Rodents and Humans Gene a-synuclein BDNF Rodent QTG for alcohol preference (Liang et al., PNAS 2003) BDNF levels in the NAc are lower in P rats than NP rats (Yan et al., Brain Res. 2005) Human associated with alcohol dependence (Bonsch et al., Hum Mol Genet. 2005) association of val66met polymorphism with alcohol dependence & violence in males (Tsai et al., Neurosci Lett. 2005) NMDA NR1 CB1 CCK-AR 5-HTT Mutant mice show attenuated alcohol effects on behavior (Kiefer et al., Biol Psychiatry 2003) KO showed alcohol consumption (Hungund et al., J Neurochem 2003) KO showed alcohol consumption (Miyasaka et al., Alcohol & Alcohol 2005) Alcohol intake in KO mice (Kelai et al., Alcohol Alcohol 2003) the A allele is associated with type I alcohol dependence (Wernicke et al., Biol Psychiatry. 2003) 1359G/A polymorphism confers vulnerability to alcohol withdrawal (Schmidt et al., Drug Alc Dep. 2002) -81A/G polymorphism is Associated with alcohol dependence in a Japanese population (Miyasaka et al., Alcohol & Alcohol 2004) Associated with lower risk of binge drinking (Olsson et al., Mol Psychiatry 2005)

14 Alcohol has both stimulant and sedative effects: possible risk factor and drug therapy target The stimulant effects of alcohol are at lower doses than the sedative effects Light drinkers and alcohol non-prefering rats do not show stimulation after 2-3 drinks Arousal Index Light drinkers 2-4 drinks/week N=9 Heavy drinkers drinks/week N=9 0 Pre Pre Time (mins) DA GABA NMDA Activity (counts above/below saline control) * * * * P MALES (n=10) * p<0.05 * NP MALES (n=10) * * * Ethanol, g/kg body weight

15 Naloxone, over a wide range of doses, decreases alcohol but not water consumption in rats Naloxone Dose (mg/kg)

16 Stress is likely involved in relapse to drinking after a period of abstinence. Negative Mood-Induced Alcohol Craving Predicts Time to First Drink After Inpatient Treatment

17 Stress is likely involved in relapse to drinking after a period of abstinence. Animal Models are being developed to help understand this link and suggest possible therapeutic interventions Brain serotonin systems are involved stimulation of serotonin release blockade of serotonin receptors Brain Areas related to anxiety and conflict are involved nucleus accumbens bed nucleus of the stria terminalis

18 Stress Management is a Key Component of Effective Behavioral Treatments for Alcoholism Cognitive Behavioral Treatment focuses on stress management training Cognitive restructuring, problem solving skills 12-Step Facilitation targets increases social support AA, NA or other peer support programs Enlist family and friends Case management services - housing, employment, medical care New Approaches Gaining Attention: Mindfulness Meditation Desensitization techniques to decrease craving-related distress state. Enhancing attentional/memory abilities to increase prefrontal functioning. Increasing emotional distress tolerance skills.

19 Conclusion: Research can identify molecular and behavioral aspects of alcoholism for the development of drug and behavioral treatments Brain pathways and candidate genes for: Specific features of alcohol use disorder modeled in animals Transition from voluntary to involuntary drinking Importance of gene-environment interactions Access to alcohol Early childhood experiences Current stressful environments Sex Age relapse

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