The Neurobiology of Addiction

1. The Neurobiology of Addiction Kim Edward Light, Ph.D. Professor, College of Pharmacy University of Arkansas for Medical Sciences

2. Objectives • Review definitions for abuse, dependance, and addiction. • Outline the brain areas involved in drug use and drug seeking including the limbic, hypothalamic, prefrontal cortex, orbitofrontal cortex, and anterior cingulate gyrus. • Delineate the meaning of reward and how neuronal pathways are involved in signaling reward. • Identify the neurotransmitter mediating the reward signal and how various behaviors and substances trigger reward neurotransmission. • Outline the current neural interconnections involved in reward neurotransmission. • Identify how motivation controls behavior and impacts drug abuse and addiction.

3. Definitions • DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, ed 4. American Psychiatric Association, Washington, 1994. • The American Society of Addiction Medicine (ASAM). • The American Academy of Pain Medicine (AAPM). • The American Pain Society (APS).

4. Alcohol or Drug Abuse DSM-IV Definitions • one (or more) of the following, occurring within a 12-month period • recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home • recurrent substance use in situations in which it is physically hazardous • recurrent substance-related legal problems • continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance

5. Alcohol or Drug Dependence DSM-IV Definitions • three (or more) of the following, occurring at any time in the same 12-month period: • Tolerance • Withdrawal • Relapse • A great deal of time is spent in activities necessary to obtain, use or recover from the substance • Important social, occupational, or recreational activities are given up or reduced because of substance use • Continued use despite adverse consequences

6. Addiction The American Society of Addiction Medicine (ASAM), the American Academy of Pain Medicine (AAPM), and the American Pain Society (APS) Addiction is a primary, chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations.

7. Addiction Characterized by: • Impaired control over drug use, • Craving and/or compulsive use, • Continued use despite harm, • Relapse.

8. Addiction Neurobiology • Animal models • Must demonstrate these behaviors • Neuronal substrates and basis can be investigated. Slide image from NIDA

9. Reward Pathway • Intracranial self-stimulation identifies neural pathways • Reinforcement or “reward” involves • the acquisition of pleasure (positive) • the avoidance of pain (negative). • Several important brain areas

10. Cingulate gyrus Hippocampus Amygdala Dentate Gyrus “Reward Pathway” Limbic System • Several structures contained in both hemispheres • Linkages to the hypothalamus and other portions of the mid-brain. • Concerned with feelings and emotions. • Critical to memory processing and reward

11. Hypothalamus Pituitary Gland Hypothalamic Structures • Controls hunger, thirst, reproductive drive, temperature, blood pressure • Maintains hormonal balance Stress Response Center

12. Prefrontal & Orbitofrontal Cortex Prefrontal Orbitofrontal Cortex Cognition, Judgment, Planning, Inhibitions, Personality, Right/wrong Decision making

13. Why Rewards? • Natural Rewards or Instinctive Behaviors promote survival • Food acquisition • Water intake • Procreation (sex) • Nurturing / protection • Activities that “feel good” are noticed and repeated

14. ACG PFC NcA VTA OFC Brain Structures of Reward ACG - Anterior Cingulate Gyrus PFC - Pre-frontal cortex OFC - Orbitofrontal cortex NcA - Nucleus Accumbens VTA - Ventral Tegmental Area

15. Reward Signaling Mediated by Dopamine Neurotransmission

16. Glu Op DA GABA GABA Op Neurotransmitters and Reward Nucleus Accumbens Frontal Cortex ACG (+) (-) (+) Saliency (-) (-) Ventral Tegmental Area Op – opiate pathway Glu – glutamate pathway GABA – GABA pathway DA – dopamine pathway (-)

17. Pre-frontal Cortex Functions • Limit or reducing consumptive behavior • Inhibition of the amygdala (fear) and the stress response • Shifting attention • Balancing several inputs at once (multi-tasking) • Focusing short term memory for processing to long term

18. Orbitofrontal Cortex Function • Processing emotional behavior • Interpretation of emotional behavior • Information for planning • Linking an actions with a negative consequence

19. Anterior Cingulate Gyrus Functions • Emotion and awareness • Mediates conflict between emotional desires and intellectual values • “wanting” - and - “likely harm or wrongness” • Intellect control of emotion

20. Motivation • Important process that drives human behavior • Appetitive - desire or “appetite”; commonly associated with “hedonic” or the seeking of pleasure • Aversive – avoidance of pain or unpleasant experiences

21. Motivation • Pleasure and pain are the principle aspects of motivational processes; • Arise in the Limbic areas of the brain • Meaning or interpretation provided by the PFC, OFC, ACG. • Two states of stress -Hypothalamus • Eustress (positive) • Distress (negative)

22. Addiction Neurobiology • On a neurobiological basis then addiction can be viewed as: • a disruption or dysfunction of these pathways that may involve inadequate reward signaling from the limbic areas associated with certain behaviors, and/or • a diminished ability of the prefrontal cortex and anterior cingulate gyrus to properly formulate responses to emotional information delivered by the limbic and hypothalamic areas.

23. Intellect Intellect Emotional Emotional

24. Addiction Current hypothesis • Pathology of addiction involves inherent (genetic) and/or drug-induced alterations in the ability of the PFC, OFC, ACG to process and appropriately respond to information identified as important by DA neurotransmission from the reward pathway.

25. Review • Definition of abuse, dependance, and addiction. • Brain pathways that mediate and govern behaviors. • Neurobiology of reward and its interpretation • Activation of the reward pathway by drugs of abuse. • Alterations in the higher brain areas that receive the reward pathway communication. • Role of motivation in behavioral control and the hypothesized pathology of addiction.