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

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

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.

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)

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.”

Basic neurobiological concepts:

1. People use drugs because they derive some benefit or pleasure [“reward”] from them, at least initially.

2. “Opponent processes” produce “anti-reward”, e.g., depression, craving, etc., even in acute use

3. Chronic heavy use leads to prolonged adaptation that can produce tolerance and physical dependence.

4. Neuroplasticity [“allostasis”] somehow removes reward system from normal controls

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.

George F. Koob : Neuropharmacology Volume 56, Supplement 1 2009 18 - 31

(B) Average behavioral ratings after an intravenous infusion of cocaine, 0.6 mg/kg over 30 sec

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.

Pathways involved in reinforcement/”reward” system

Dopaminergic GABAergic Glutamatergic Orexinergic

(not shown: opioid, serotonin, noradrenergic, cholinergic, endocannabinoid, others)

Rat brain

• 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

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

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)

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

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)

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

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)

[Li et al., 2008]

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

●“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.

● High impulsivity ○ Low impulsivity

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

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

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

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

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)

Future discounting in addicted Ss

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]

Squeglia et al., 2012

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]

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

Effect of novel environment on drug-related dopaminergic activity

Novel environment (N) facilitates acquisition of cocaine self-administration compared to home environment (H)

(Capriani et al. , 2007)

Effect of novel environment on drinking of alcohol by rats

Effect of priming of expectancies and mood on alcohol consumption

Stein, Goldman, Del Boca (2000)

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

“Binging” on sucrose by rat on restricted access

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

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

Effect of Naltrexone with and without behavioral therapy

Anton et al., JAMA, 2006

Percentage abstinence (clean urine) at six months in heroin addicts on extended-release Ntx

(adapted from Reece, 2012)

Study___ Ntx inj Ntx oral Placebo

Kunoe 38 19

Hulse 63 26

Krupitsky #1 36 23

Krupitsky #2 53 16 11

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

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”

What is the added (or subtracted) value of the neuroscience contribution to the concept

of addiction?We have to consider several aspects:

1)Considerable gain in knowledge of the neurobiological mechanisms, including drug-related and other behaviors

2)Hence, some mechanistic basis for broadening the definition to include pathological gambling, eating, etc,

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

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