1. The Disease Model of Opioid Addiction
Vincent Giannetti, PhD – Pharmacy
Benedict Kolber, PhD – Biological Sciences

2. Outline Giannetti Kolber Chemical dependency Abuse vs dependence
Evolutionary psychology of abuse
Disease process of abuse
Kolber
Biological mechanisms of abuse

3. Chemical Dependency
Periodic or chronic intoxication produced by the repeated consumption of a drug
Characteristics
Compulsion to use in spite of negative consequences
Tolerance and tendency to increase dose
Physical and or psychological dependence
Behavioral impairment

4. Abuse versus Dependence
Behavioral impairment
Continued use in spite of negative consequences
Dependence
Tolerance
Withdrawal
Loss of control
Preoccupation with use to the exclusion of other activities

5. Evolutionary Psychology I
Old brain
Brain stem, cerebellum and limbic system
Regulates respiration, heartbeat, body temperature, muscle movement,
Mediate emotions and cravings (anger, fear, thirst, pleasure)
Imprint survival memories (noxious and pleasurable experiences)
Old brain retains addiction memories
Adapted Uppers Downers and All Arounders: Inaba and Cohen, CNS Productions Inc

6. Evolutionary Psychology II
New Brain
Neocortex (cerebrum and cerebral cortex)
Information processing and reasoning
New brain is late in developing
Old brain predominates in stress and crisis (automatic tendency to revert to old brain functioning)
Adapted Uppers Downers and All Arounders: Inaba and Cohen, CNS Productions Inc.

7. Compulsion and Drug Dependence
On/Off Switches
Satiation Centers
When repetition of an action satisfies a drive, craving is turned off.
Healthy functioning person integrates drives of the old brain with reasoning ability of new brain.
Why can’t craving stop.
Repeated administration overrides and disrupts satiety
Repeated administration disrupts communication between the two brains
Repeated administration lays down powerful primitive memories that overwhelm the new brain
Physiological basis of superego, ego and Id
Adapted Uppers Downers and All Arounders: Inaba and Cohen, CNS Productions Inc.

8. Kosten and George, 2002 Sci Pract Perspect

9. Continuum of Drug Abuse
Experimental
Social-recreational
Circumstantial-situational
Intensified
Compulsive

10. The Disease Process Initiation Escalation Maintenance Experimentation
Social influence
Escalation
Preoccupation
Intoxication is normalized
Maintenance
Social fabric of life unravels
Use becomes compulsive

11. Etiology of Chemical Dependency
Social rebellion
Symptom relief
Learned behavior
Drive -cue-response -reinforcement
Tolerance-dependency-response -reinforcement
Personality traits
Disease

12. Dopamine and Addiction Molecular Psychiatry (2004) 9, 557–569. doi:10
Dopamine and Addiction Molecular Psychiatry (2004) 9, 557–569. doi: /sj.mp Published online 6 April 2004
The involvement of dopamine in drug reinforcement is well recognized but its role in drug addiction is much less clear. Imaging studies have shown that the reinforcing effects of drugs of abuse in humans are contingent upon large and fast increases in dopamine that mimic but exceed in the intensity and duration those induced by dopamine cell firing to environmental events. In addition, imaging studies have also documented a role of dopamine in motivation, which appears to be encoded both by fast as well as smooth DA increases. Since dopamine cells fire in response to salient stimuli, the supraphysiological activation by drugs is likely to be experienced as highly salient (driving attention, arousal conditioned learning and motivation) and may also reset the thresholds required for environmental events to activate dopamine cells. Indeed, imaging studies have shown that in drug-addicted subjects, dopamine function is markedly disrupted (decreases in dopamine release and in dopamine D2 receptors in striatum) and this is associated with reduced activity of the orbitofrontal cortex (neuroanatomical region involved with salience attribution and motivation and implicated in compulsive behaviors) and the cingulate gyrus (neuroanatomical region involved with inhibitory control and attention and implicated in impulsivity). However, when addicted subjects are exposed to drug-related stimuli, these hypoactive regions become hyperactive in proportion to the expressed desire for the drug. We postulate that decreased dopamine function in addicted subjects results in decreased sensitivity to nondrug-related stimuli (including natural reinforcers) and disrupts frontal inhibition, both of which contribute to compulsive drug intake and impaired inhibitory control. These findings suggest new strategies for pharmacological and behavioral treatments, which focus on enhancing DA function and restoring brain circuits disrupted by chronic drug use to help motivate the addicted subject in activities that provide alternative sources of reinforcement, counteract conditioned responses, enhance their ability to control their drive to take drugs and interfere with their compulsive administration.
Bottom line of dependency
Our brains are wired to ensure that we will repeat life-sustaining activities by associating those activities with pleasure or reward. Whenever this reward circuit is activated, the brain notes that something important is happening that needs to be remembered, and teaches us to do it again and again, without thinking about it. Because drugs of abuse stimulate the same circuit, we learn to abuse drugs in the same way. When some drugs of abuse are taken, they can release 2 to 10 times the amount of dopamine that natural rewards do. In some cases, this occurs almost immediately (as when drugs are smoked or injected), and the effects can last much longer than those produced by natural rewards. The resulting effects on the brain’s pleasure circuit dwarfs those produced by naturally rewarding behaviors such as eating and sex. The effect of such a powerful reward strongly motivates people to take drugs again and again. This is why scientists sometimes say that drug abuse is something we learn to do very, very well. National Institute of Drug Abuse

13. Treatment Process Intervention Assessment Treatment planning Aftercare
Confrontation and leveraging
Assessment
Degree of impairment
Dual diagnosis
Treatment planning
Detoxification
Residential / intensive day/ counseling
Aftercare
Relapse prevention/ AA, NA

14. Neurobiology of addiction
Addiction risk in chronic pain patients
Still controversial
1-5% of genes change with acute drug administration

15. Brain areas of addiction
Dopamine neurons in VTA project to ventral striatum, nucleus accumbens, amygdala, prefrontal
DA release signals reward/change in reward; acts as a reward prediction signal (learned associations); signals how much reward is wanted vs liked (incentive salience)
DA release is transferred from drug itself to learned associations and wanting
MOR activation in VTA is rewarding by inhibition of GABA neurons in the VTA which then causes DA to increase

16. Neurobiology of Addiction
Analgesia/addiction
Morphine tolerance – beta arrestin 2 mediates I think based on Bruchas review but he gives some contradictory information. Enhanced endocytosis with recycling reduces desensitization. But endocytosis without recycling would cause desensitization/tolerance.
Addiction
Al-Hasani & Bruchas, 2011 Anesthesiology

17. The High and The Low
The feelings of “low” after the “high” are hypothesized to be simply a return to homeostasis
Aversive state of withdrawal is strengthened by repeated drug taking – i.e. people take drugs to avoid withdrawal
This theory does not explain relapse (withdrawal symptoms go away but the patient relapses)
Biology of withdrawal
Rebound excitation of noradrenergic and serotonergic systems