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Kim Edward Light, Ph.D.Professor, College of PharmacyUniversity of Arkansas for Medical Sciences

The Neurobiology of Addiction

Objectives

1. Review definitions for abuse, dependance, and addiction.

2. Outline the brain areas involved in drug use and drug seeking including the limbic, hypothalamic, prefrontal cortex, orbitofrontal cortex, and anterior cingulate gyrus.

3. Delineate the meaning of reward and how neuronal pathways are involved in signaling reward.

4. Identify the neurotransmitter mediating the reward signal and how various behaviors and substances trigger reward neurotransmission.

5. Outline the current neural interconnections involved in reward neurotransmission.

6. Identify how motivation controls behavior and impacts drug abuse and addiction.

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).

Alcohol or Drug Abuse DSM-IV Definitions one (or more) of the following, occurring within a 12-

month period1. recurrent substance use resulting in a failure to fulfill

major role obligations at work, school, or home

2. recurrent substance use in situations in which it is physically hazardous

3. recurrent substance-related legal problems

4. continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance

Alcohol or Drug DependenceDSM-IV Definitions

three (or more) of the following, occurring at any time in the same 12-month period:

1. Tolerance

2. Withdrawal

3. Relapse

4. A great deal of time is spent in activities necessary to obtain, use or recover from the substance

5. Important social, occupational, or recreational activities are given up or reduced because of substance use

6. Continued use despite adverse consequences

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.

Addiction

Characterized by:

1. Impaired control over drug use,

2. Craving and/or compulsive use,

3. Continued use despite harm,

4. Relapse.

Addiction Neurobiology

Animal models Must demonstrate these behaviors Neuronal substrates and basis can be

investigated.

Slide image from NIDA

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

Cingulate gyrus

Amygdala

Hippocampus

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

Hypothalamus

Pituitary Gland

Hypothalamic Structures Controls hunger, thirst, reproductive drive,

temperature, blood pressure Maintains hormonal balance

Stress Response Center

Prefrontal Orbitofrontal

Cortex

Cognition, Judgment, Planning,

Inhibitions, Personality,Right/wrong

Decision making

Prefrontal & Orbitofrontal Cortex

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

VTA

NcA

PFC

ACG

OFC

ACG - Anterior Cingulate Gyrus

PFC - Pre-frontal cortex

OFC - Orbitofrontal cortex

NcA - Nucleus Accumbens

VTA - Ventral Tegmental Area

Brain Structures of Reward

Reward Signaling Mediated by Dopamine Neurotransmission

ActivityIncrease in DA

release NcA

Food or sexual activity 50 – 100%

Alcohol, MJ, Nicotine 125 – 225%

Morphine, Heroin 150 - 300%

Cocaine 400%

Methamphetamine 1000%

Frontal Cortex

ACG

Ventral Ventral Tegmental Tegmental

AreaArea

Nucleus Nucleus AccumbensAccumbens

DADAGABA

GABA

Glu

Op

Op

Op – opiate pathwayGlu – glutamate pathwayGABA – GABA pathwayDA – dopamine pathway

(-)

(-)

(-)(-)

(+)

(+)

Saliency

Neurotransmitters and Reward

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

Orbitofrontal Cortex Function

Processing emotional behavior Interpretation of emotional behavior Information for planning Linking an actions with a negative

consequence

Emotion and awarenessMediates conflict between emotional

desires and intellectual values “wanting” - and - “likely harm or

wrongness” Intellect control of emotion

Anterior Cingulate Gyrus Functions

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

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)

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.

Intellect

Emotional

EmotionalEmotionalIntellectIntellect

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.

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.