ADDICTION IS A CONFLICT BETWEEN DESIRE AND WILL

1. ADDICTION IS A CONFLICT BETWEEN DESIRE AND WILL Dr. Abdullah AbuAdas Presemted by drabdullahabuadas

2. Addiction Intensive Drug Use Casual Drug Use Compulsive Drug Use Motivational Strength Motivational Toxicity Continuum of Drug Use Experimental Drug Use Circumstantial Drug Use From Bozarth (1990); terms described on the continuum were suggested by Jaffe (1975).

3. I R D Types of problems: Thorley’s Model • Intoxication • Accidents / injury • Poisoning / hangovers • Absenteeism • High-risk behaviour • Regular / excessive Use • Health • Finances • Relationships • Child neglect • Dependence • Impaired control • Drug-centred behaviour • Isolation / social problems • Withdrawal symptoms and psychiatric problems • Health problems

4. Stages of the Addiction Cycle

5. Drugs of abuse (including alcohol) are inherently rewarding, which is why they are consumed by humans or self-administered by laboratory animals . Only a small percentage of individuals exposed to drugs will become addicted, that is, shift from controlled drug use to compulsive drug use with loss of control over intake despite adverse consequences, however . Factors that determine who becomes addicted include genetic (50% of risk), developmental (risk is higher in adolescence), and environmental (e.g., drug access, stress) factors .

6. Drugs and genes • While psychological theories account for a large proportion of the behaviours related to drug use, other factors are also important • It is increasingly recognised that genes play an important role in an individual’s response to drugs and the propensity for the development of dependence

7. Environmental factors • A range of environmental factors impact on drug use, including price and availability of both licit and illicit drugs • Other environmental factors include prenatal problems, early childhood experiences, family relationship and bonding, and early educational opportunities. • Cultural norms around drug use also act as powerful determinants of the use of both licit and illicit substances

8. How the reward system works

10. A HEALTHY PATHWAY: The ‘reward pathway ‘ produces feelings of pleasure in response to naturally enjoyable stimuli, such as food and sex. • Connected to other brain regions, including memory storage, the pathway motivates us to repeat activities that perpetuate the species.

11. AN ADDICTED PATHWAY: Drinking or doing drugs hijacks the reward pathway. • But in genetically vulnerable people, this altered state leads to an addiction that they are, on their own, powerless to overcome. • Someone with an addiction can’t talk herself out of the compulsion any more than someone can talk herself out of depression.

12. Reward System Schick Shadel Hospital, 2009

13. We once held the simplistic view of dopamine as the “pleasure chemical”; when you did something that felt good, the increase in dopamine was the reason. • Experimental psychologists now make clear distinctions between “wanting” something and “liking” something, and dopamine seems to be important for the “wanting” but not necessary for the “liking.”

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

15. All drugs that can lead to addiction increase DA in NAc, which is achieved through their interaction with different molecular targets by the various drug classes . In humans, PET studies have shown that several drugs [stimulants , nicotine , alcohol , and marijuana increase DA in dorsal and ventral striatum (where NAc is located). These studies used a radiotracer that binds to DA D2 receptors (D2Rs) but only when these are not occupied by DA . By comparing binding after placebo and after the drug, these studies estimate the decreases in D2R availability induced by the drug, which are proportional to DA increases. Most studies have reported that participants who display the greatest DA increases with the drug also report the most intense “high” or “euphoria” ).

16. PET studies have also shown that the speed with which a drug enters and leaves the brain (pharmacokinetic profile) is crucial for its reinforcing effects. Specifically, PET studies of brain pharmacokinetics of drugs labeled with positron emitters show that peak levels in human brain are reached within 10 min after i.v. administration and that this fast drug uptake is associated with the high . Indeed, for an equivalent level of cocaine reaching the brain (assessed as equivalent level of DA transporter blockade), when cocaine entered the brain rapidly (smoked and i.v. administration), it elicited a more intense high than when it entered the brain more slowly (snorted) . This is consistent with preclinical studies showing that the faster the drug's entry into the brain, the stronger are its reinforcing effects . This probably reflects the fact that abrupt and large DA increases triggered by drugs mimic the fast and large DA increases associated with phasic DA firing that are associated in the brain with conveying information about reward and saliency .

17. Imagining the brain on drugs Reduced D2R availability & blood flow correlate with addiction Volkow (2004) Nat Rev.

18. FOOD SEX 200 200 NAc shell 150 150 DA Concentration (% Baseline) 100 100 15 % of Basal DA Output 10 Empty Copulation Frequency 50 Box Feeding 5 0 0 Scr Scr Scr Scr 0 60 120 180 Bas Female 1 Present Female 2 Present Mounts Time (min) Sample Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Intromissions Ejaculations Source: Di Chiara et al. Source: Fiorino and Phillips Natural rewards elevate dopamine levels

19. Control Control CG STOP Saliency Saliency Drive Drive Drive OFC GO Saliency NAc Memory Memory Memory Amygdala Non-Addicted Brain Addicted Brain Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.

20. Common Molecular Changes Associated with Dependence • Dopamine D-2 receptor binding-decreased in human imaging studies in dependent subjects • CREB ( cyclic adenosine monophosphate response element binding protein) transcription factor-decreased in nucleus accumbens and extended amygdala during the development of dependence • Delta-FosBtranscription factor-changed during protracted abstinence to drugs of abuse

21. Effects of Drugs on Dopamine Release COCAINE Accumbens 400 DA 300 DOPAC HVA % of Basal Release 200 100 0 Time After Cocaine 250 NICOTINE ETHANOL 250 Accumbens Dose (g/kg ip) 200 Accumbens 200 Caudate 0.25 0.5 150 % of Basal Release 1 % of Basal Release 2.5 150 100 0 1 2 3 hr 100 0 0 0 1 2 3 4hr Time After Nicotine Time After Ethanol 1500 1000 500 0 METHAMPHETAMINE Accumbens % Basal Release 0 1 2 3hr Time After Methamphetamine Source: Shoblock and Sullivan; Di Chiara and Imperato

22. Why not use a drug that blocks the effects of all addictive drugs, an abstinence-based approach that appeals to some people? • The problem with such a drug is that it would also prevent all the normal rewards through which people need to find satisfaction in living.

23. Treatment Implications of the Brain Reward System • Operating through different mechanisms drugs of abuse have a final common pathway by which they increase dopamine levels within the core structures of the so called “brain reward system” which includes the VTA and NA. A balance between the negative effects of the drug and positive feelings associated with stimulation of the brain reward system determine if an individual will enjoy and continue using the substance or not. Generally the positive effects or “high” of using a drug occur immediately or shortly after use, by the action of increasing dopamine.

24. The closer positive and negative effects are to the actual time of drug use, the more likely we are to associate these effects with the drug. Unfortunately, the negative consequences of drug use often come much later and more unpredictably compared to the immediate pairing of drug administration and reward. For example, the later potential negative consequences of chronic drinking (such as liver disease) may not be as important as the immediate rewarding positive effects of drinking.

25. Some approaches to treatment attempt to consistently pair the negative consequences of drug administration with drug administration. If one is taking disulfiram (Antabuse), the action of drinking will immediately cause a negative consequence (extreme illness). The immediate negative consequence of drinking now competes with the normally immediate positive reward of drinking to combat illness. By changing the time course of positive and negative drug effects through behavioral interventions or pharmaceutical interventions, we may be able to better treat addictions in the future.

26. Pharmacotherapy of Drug Addiction: • Pharmacotherapeutic interventions have been developed to decrease drug use by influencing the brain reward system. General strategies for pharmacological treatment of drug addiction include creating aversion to the addicted drug, bringing consequences or punishment closer to the reinforcement of drug use, modification of neurotransmitters to decrease drug intake, and long-term substitution with a less addictive and cross-tolerant medication .

27. 1-Aversive Conditioning • Increasing the negative or aversive effects of a drug is one effective treatment used for alcohol addiction. Disulfiram (Antabuse), metronidazole, or calcium carbimide is used to create negative effects with the ingestion of alcohol . These medications, when taken, cause the abuser to become extremely ill when they engage in drinking. Instead of experiencing the negative effects of alcohol the next day (hangover) or years later (liver disease), they experience unpleasant effects such as nausea, vomiting, and flushing in closer proximity to ingestion which opposes the normally immediate positive reward of the drug .

28. 2-Neurotransmitter Manipulation • By manipulating neurotransmitters in the reward pathway, we can potentially modify cravings for drugs of abuse. This can be accomplished , by giving drug antagonists, or drugs that block the addicting effects of the dopamine reward system. For example, dopamine blocking agents have been shown to diminish intake of all drugs of abuse in animal studies . However, application in humans has been less promising. In humans, the euphoria induced by amphetamine administration is attenuated by dopamine blocking agents. Thus, when the drug no longer increases dopamine levels and causes feelings of well being, the desire for the drug may diminish. Bupropion, a dopamine agonist, has been shown in nicotine addiction but has not been shown to be effective in cocaine addiction.

29. Relapse to Drug Use Motivational ToxicityDependent Relapse Transitory hyperdopaminergic activity Chronic hypodopaminergic activity anhedonia craving

30. 3-Pharmacological Substitution • By substituting one substance that stimulates the brain reward pathway with another less addictive/ less harmful substance, we may aid in relapse prevention. One example is the use of methadone to treat heroin addiction. Methadone does not have the euphoric effects that heroin does; however, it does adequately stimulate the brain reward system and provides a safer alternative to heroin use.

31. The Most Effective Treatment Strategies Will Attend to All Aspects of Addiction: • Biology • Behavior • Social Context

32. We Need to Treat the Whole Person and the Whole Village! In the Social Context Educate the Community, the Children, the Healthcare Providers Increased Prescription Monitoring Working in Conjunction with Law Enforcement

33. Ongoing Funded Projects Development of immunotherapies using: Active and passive immunization using anti-cocaine antibodies and anti-cocaine catalytic antibodies Passive immunization using anti-cocaine monoclonal antibodies. Passive immunization using anti-PCP monoclonal Antibodies. Passive immunization using anti-methamphetamine monoclonal antibodies . Cocaine vaccine (Xenova, UK) Nicotine vaccine .

34. Thank you