Original definition of addiction

1. Original definition of addiction Under Roman law, a formal giving over of a debtor to a creditor by court sentence, hence a binding over of a person to a master. Later analogy: a person is bound over to drug use, as a slave is to a master. Implication: a loss of freedom of action of the person so addicted

2. Essential features of definition Addictionj is a strongly established pattern of repeated self-administration of a drug in doses that reliably produce reinforcing psychoactive effects great difficulty in achieving long-term cessation of use despite adverse effects and strong motivation to stop

3. Addiction is a disorder of drug- taking, not of drug action. Passive exposure to a drug can cause tolerance and physical dependence, but these are not the same as addiction.

4. Neurobiological concept of addiction as proposed by NIDA, NIAAA and others: “Addiction is a chronic relapsing brain disease related to the chronic heavy use of a mind-altering drug” Objectives: to identify the locus and nature of the brain disorder, and develop rationally based medications to correct it - identify predisposing biological factors for targeting early prevention, including biological measures (e.g., gene therapy)

5. Winger, Woods, et al. (2005): “ Neuroscientific approaches to drug addiction [are] based on the premise that addiction…results from brain changes that in turn result from chronic administration of drugs of abuse. Alternative approach views drug addiction as a behavioral disorder in which drugs function as preeminent reinforcers. [T]here is a fundamental discrepancy between these two approaches.”

6. Basic neurobiological concepts: • People use drugs because they derive some benefit or pleasure [“reward”] from them, at least initially. • “Opponent processes” produce “anti-reward”, e.g., depression, craving, etc., even in acute use • Chronic heavy use leads to prolonged adaptation that can produce tolerance and physical dependence. • Neuroplasticity [“allostasis”] somehow removes reward system from normal controls

7. Fig.?1 (A) Dysphoric feelings followed the initial euphoria in experimental subjects who smoked cocaine paste, even though the concentration of cocaine in the plasma of the blood remained relatively high. The dysphoria is characterized by anxiety, depression. (B) Average behavioral ratings after an intravenous infusion of cocaine, 0.6 mg/kg over 30 sec George F. Koob : Neuropharmacology Volume 56, Supplement 1 2009 18 - 31

8. What is the “reward” mechanism? Repeatedly demonstrated that all drugs capable of causing dependence can stimulate dopamine (DA)-releasing cells in a midbrain area (the VTA) that sends fibres to the nucleus accumbens (NAcc) and the medial forebrain. Extent of DA stimulation is proportional to the dose, and to the speed with which the drug concentration rises in the brain.

9. Rat brain Pathways involved in reinforcement/”reward” system Dopaminergic GABAergic GlutamatergicOrexinergic (not shown: opioid, serotonin, noradrenergic, cholinergic, endocannabinoid, others)

10. Common assumption: the increased release of DA either causes or initiates the “rewarding effect” of these drugs The same DA pathway is stimulated by food-related cues, sexual cues, other natural reinforcers Assumption: drugs “highjack” normal reward mechanisms

11. Fig.?6 Neurocircuitry associated with the acute positive reinforcing effects of drugs of abuse and the negative reinforcement of dependence and how it changes in the transition from non-dependent drug taking to dependent drug taking. Key elements... George F. Koob: Neurobiological substrates for the dark side of compulsivity in addiction. Neuropharmacology Volume 56, Supplement 1 2009 18 - 31

12. Apparent support for this concept: DAR agonists (e.g., pramipexole) used in treating Parkinson disease can cause compulsive behaviors: - compulsive gambling - compulsive eating - compulsive sex - compulsive use of the drugs themselves (Ambermoon et al., 2011)

13. Alternative hypothesis: VTA-NAcc DA path is not a “reward” system, but an arousal system that alerts the brain to important novel stimuli ● DA response occurs to rewarding, punishing, or even motivationally neutral but intense stimuli ● DA neurons in VTA put out different patterns of response to different kinds of stimuli (Schulz) ● with repeated exposure to same stimulus, DA response fades, or shifts from actual “reward” to cues that predict delivery of reward ● suggestion: DA system monitors match between predicted reward and actual reward, serving as basis for experience-based learning

14. Genetic factors in addiction ● clinical observations in alcoholism: family trees, twin studies, adoption studies all demonstrate role of genetic factors separate from “copy-cat” behavior. ● some evidence for genetic influence in other addictions, but not yet explored as well as in alcoholism ● is clearly multigenic, not monogenic in nature ● not strict causality, but increase in degree of risk (child with high genetic load is at greater risk, but may choose to abstain)

15. But a huge number of different genes (more than 2,000 at present) are statistically linked to alcoholism, that determine very different traits in the offspring • Some relate to sensitivity of the individual to drug effects • Some govern rate of metabolism of the drug • Some relate to ability to develop adaptive changes in response to drug actions personality traits that somehow modify readiness to use the drug

16. The genes involved encode for virtually all parts of cell signalling systems. Implication: the genes and their products represent the cell machinery that enables nerve cells to respond to all kinds of stimuli, and thus permit all types of adaptive change, both beneficial (e.g., learning, memory) and harmful (e.g., tolerance, physical dependence)

17. [Li et al., 2008]

18. More recently, emphasis has been on genes governing personality traits that somehow modify readiness to use the drug, such as:  impulsivity  novelty-seeking  psychosis  mood disorders

19. ● “Impulsivity” = inability to postpone a response even when it would be advantageous to do so ● accompanied by genetically determined reduction of D2/3 receptors in N Acc ● predicts easier acquisition of drug-taking: alcohol, cocaine, opioids, etc.

20. ● High impulsivity ○ Low impulsivity

21. 0crit, 3crit – number of criteria of addiction; LI, HI – low/high impulsivity; LR, HR – low/high reactivity to novelty

22. But correlation between impulsivity and cocaine use was not very striking. Impulsivity also predicts other behavioral changes unrelated to drug self-administration (e.g., gambling) Conclusion: Can not assume direct causal link between impulsivity and drug addiction

23. Competing systems models of addiction(Bechara, Bickel, Jentsch) • Competition between impulsive system (limbic system, concerned with immediate outcomes) and executive system (prefrontal cortex, concerned with rational weighing of future outcomes) • Addiction = dominance of impulsive system over executive system

24. Examples of impaired executive functions found in addicts:   working memory ( recall of past experience)   risk evaluation   response inhibition   future discounting   cognitive flexibility Accompanied by  activation of prefrontal cortex,  activation of N. accumbens, in imaging studies

25. Future discounting in addicted Ss Future discounting (giving lesser value to delayed reward than to immediate reward) is another example of impaired executive function Greater future discounting is found in Ss dependent on cocaine, tobacco, alcohol, gambling, than in controls (Bickel et al)

26. Age-related change (from age 13 to age 16) in cortical activation response during visual memory task in adolescents who acquired heavy drinking during that time, compared with those who remained abstinent. [Those who became heavy drinkers had smaller improvements in visual memory accuracy and speed]

27. Squeglia et al., 2012

28. Factors influencing executive functioning in parallel with PFC activity: • Developmental stage: progressive increase with age • Cultural norms and demands • Educational and work demands • Brain injuries (traumatic, toxic, tumor, radiation, etc. [but do these lead to addiction ? Some evidence, but scanty]

29. Important omission of all biological theories: their failure to take into account environmental influences that affect drug use without changing genes or neuronal pathways: - environmental novelty - expectancies - other closely similar behaviors when no drugs are involved

30. Effect of novel environment on drug-related dopaminergic activity

31. Novel environment (N) facilitates acquisition of cocaine self-administration compared to home environment (H) (Capriani et al. , 2007)

32. Effect ofnovel environment on drinking of alcohol by rats

33. Effect of priming of expectancies and mood on alcohol consumption Stein, Goldman, Del Boca (2000)

34. Defining criteria of pathological gambling: • Preoccupation with gambling • Unsuccessful attempts to reduce or stop • Need to gamble larger sums over time • Attempts to recoup losses by gambling even more • Restlessness and irritability when trying to reduce or stop • Lying, stealing, etc., to cover losses • Other forms of personal and family harm

35. “Binging” on sucrose by rat on restricted access

36. Rats that binged on sucrose or chow show Nx-precipitable withdrawal signs

37. Habitual over-eating (palatable food binging) shares same neurobiological adaptations: • acutely, positive reinforcement via DA activation • withdrawal elicits anxiety, craving, depression • changes in DA, ACh, enkephalin release in N. accumbens • claimed treatment with naltrexone

38. Effect of Naltrexone with and without behavioral therapy Anton et al., JAMA, 2006

39. Percentage abstinence (clean urine) at six months in heroin addicts on extended-release Ntx(adapted from Reece, 2012) Study___Ntx inj Ntx oralPlacebo Kunoe 38 19 Hulse 63 26 Krupitsky #1 36 23 Krupitsky #2 53 16 11

40. Influence of Mu receptor variant on effect of Naltrexone in alcoholism (Oslin et al., 2003)

41. Major review of Mu receptor variants and Ntx in alcoholism (Ray et al., 2012) Many existing problems: • conflicting results of large-scale trials • effect size of receptor variant too small • multiple genes contribute to overall effect • different effects in treatment seekers and non-seekers • findings met with “considerable enthusiasm as well as a healthy level of skepticism”

42. What is the added (or subtracted) value of the neuroscience contribution to the concept of addiction? We have to consider several aspects: • Considerable gain in knowledge of the neurobiological mechanisms, including drug-related and other behaviors • Hence, some mechanistic basis for broadening the definition to include pathological gambling, eating, etc,

43. 3) Modest gain in treatment by drugs based on knowledge of mechanisms 4) Substantial loss through narrowing basis of research: great overemphasis on drug actions at expense of behavioral and social influences known to be important 5) Possible future gain through beginnings of research on environmental modification of genetic and neurobiological processes

44. Overall conclusion Neurobiological studies have added only a small extra value so far to the understanding of addiction But they offer hope of a larger “value added” in the reasonably near future, if they direct much more effort to studying brain interactions with environmental influences