Dr. Abdullah AbuAdas Presented by dr abdullah abuadas http://medicsindex.ning.

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Experimental Drug Use

Casual Drug Use

Intensive Drug Use

Compulsi ve Drug Use

Addiction

Circumstanti al Drug Use

Motivational Strength Motivational Toxicity

From Bozarth (1990); terms described on the continuum were suggested by Jaffe (1975).

Intoxication Accidents / injury Poisoning / hangovers Absenteeism High-risk behaviour

I D

Regular / excessive Use Health Finances Relationships Child neglect

Dependence Impaired control Drug-centred behaviour Isolation / social problems Withdrawal symptoms and psychiatric problems Health problems

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 .

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 individuals response to drugs and the propensity for the development of dependence

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

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.

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 cant talk herself out of the compulsion any more than someone can talk herself out of depression.

Schick Shadel Hospital, 2009

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.

Positive Hedonic Effects Dopamine Opioid peptides

Negative Hedonic Effects of Withdrawal Dopamine dysphoria Opioid peptides ... pain

Serotonin
GABA

Serotonin dysphoria
GABA anxiety, panic attacks

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 ).

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 .

Imagining the brain on drugs

Reduced D2R availability & blood flow correlate with addiction

Volkow (2004) Nat Rev.

Natural rewards elevate dopamine levels

NAc shell
DA Concentration (% Baseline) 200

FOOD

200

SEX

% of Basal DA Output

150

150

100 Empty Box Feeding

100

15 10 5

Copulation Frequency

50

0
0 60 120 180

Time (min)

ScrScr BasFemale 1 Present Sample 1 2 3 4 5 6 7 8 Number

Scr

Scr

Female 2 Present

9 10 11 12 13 14 15 1617 Mounts Intromissions Ejaculations

Source: Di Chiara et al.

Source: Fiorino and Phillips

Non-Addicted Brain
Control CG

Addicted Brain
Control

STOP
Saliency NAc

Drive OFC

Saliency

Drive

GO
Memory

Memory
Amygdala

Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.

Dopamine D-2 receptor binding- decreased in human imaging studies in dependent subjects CREB ( cyclic adenosine monophosphate response element binding protein) transcription factordecreased in nucleus accumbens and extended amygdala during the development of dependence

Delta-FosB transcription factor-changed during protracted abstinence to drugs of abuse

Effects of Drugs on Dopamine Release

1500

METHAMPHETAMINE
% of Basal Release Accumbens

400 300 200 100 0

Accumbens

COCAINE
DA DOPAC HVA

% Basal Release

1000

500

0 0 1 2 3hr Time After Methamphetamine 250 % of Basal Release 200 150 100 Time After Cocaine 250 Accumbens

NICOTINE
% of Basal Release Accumbens Caudate

ETHANOL
Dose (g/kg ip) 0.25 0.5 1 2.5

200

150

100

3 hr

Time After Nicotine

1 2 3 Time After Ethanol

4hr

Source: Shoblock and Sullivan; Di Chiara and Imperato

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 nd satisfaction in living.

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.

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.

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.

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 .

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 .

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.

Motivational Toxicity Dependent Relapse Chronic hypodopaminergic activity Transitory hyperdopaminergic activity

anhedonia

craving

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.

The Most Effective Treatment Strategies Will Attend to All Aspects of Addiction:

Biology

Behavior
Social Context

31

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

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 .

Dr. Abdullah AbuAdas Presented by dr abdullah abuadas http://medicsindex.ning.com/profile/drabdul lahabuadas JOIN Free at www.myliveclinic.com to stay updated