Dr Jonathon Arnold

1. Dr Jonathon Arnold Room 211 c Bosch Building Department of Pharmacology Email: arnie@med.usyd.edu.au

2. Suggested readings • Chapters 42 from Pharmacology by Rang, Dale, Ritter and Moore (5th Edition) • Robbins, T. W., & Everitt, B. J. (1999). Drug addiction: bad habits add up. Nature, 398(6728), 567-570. For the keen beans only

3. Overview - science of addiction • Addiction is a disease that evolves through an individuals chronic use of drugs, such as heroin, alcohol, cocaine and cannabis. • Social stigma sometimes blocks sensible policy-making and strategies that may result in progress when dealing with the drug abuse problem. • There have been remarkable advances in our understanding of addiction in the last two decades. • Researchers have worked out the mechanism of action of nearly all drugs of abuse. • Neuroscientists have identified a common brain pathway that seems to be critically involved in addiction to most substances of abuse.

4. The politics of addiction • "The war on drugs" is waged by governments all over the world. • Drug addiction places a huge burden on society in terms of crime and health • It has been estimated that the Australian Government spent $1.5 billion on costs associated with drug addiction in 1987/88. • Drug addiction is viewed as a social problem, thus requiring social solutions such as dealing with it through the criminal justice system. • However, science has shown us that drug addiction is not only a social problem but a "health problem".

5. Double standards • In our tabloid press most addiction stories relate to the demon drug heroin, even though tobacco and alcohol use killed nearly 22,000 Australians in 1997 and heroin about 800. • In Australia, many more people are addicted to legal tranquillizers ("sleeping tablets") such as Valium than drugs such as heroin or cocaine.

6. DSM-4 Criteria - Drug Dependence (3 or more in a 12 month period) 1) Tolerance (diminished drug effect/use of greater doses to achieve desired effect) 2) Drug withdrawal 3) T he substance is often taken in larger amounts or over a longer period than was intended There is a persistent desire or unsuccessful efforts to cut down or control substance use 5) A great deal of time is spent in activities necessary to obtain the substance, use the substance or recover from its effects 6) Important social, occupational, or recreational activities are given up or reduced because of substance use 7) The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance

7. WHO definition of dependence “A state, psychic and sometimes also physical, resulting from the interaction between a living organism and a drug, characterised by behavioural and other responses that include a compulsion to take a drug on a continuous or periodic basis in order to experience its psychic effects, and sometimes to avoid the discomfort of its absence”.

8. "Physical" dependence • Some drugs such as heroin and alcohol produce "physical dependence" so that abstaining from use of these drugs produces physical withdrawal symptoms such as diarrhoea and convulsions. "Psychological" dependence • Other seemingly highly addictive drugs such as cocaine and amphetamine DO NOT produce physical dependence during withdrawal. • Signs of "psychological dependence" include agitation, depression and most importantly craving for the drug.

9. Learning theories of addiction • Drug dependence involves learning 1) Negative reinforcement theory. Process that strengthens behaviour that allows escape from a negative event. Example - taking aspirin. Limitations • individuals will continue to self-administer compounds in the absence of withdrawal symptoms. • An individual may be physically dependent on a drug without being addicted to it (e.g. opioids in pain management) • a lot of drugs do not produce a physical withdrawal syndrome. Eg. cocaine, amphetamine

10. Learning theories of addiction (continued.) 2) Positive reinforcement theory. Process that strengthens behaviour that leads to a satisfying outcome. That is, drug taking behaviour is strengthened by the pleasurable consequences of psychoactive drug use. Limitations • that not all drug use is associated with pleasure. Eg. cigarette smokers don't greatly enjoy the experience. • Also some experiments have documented addicts working for a drug that they claim they cannot subjectively experience as pleasurable.

11. How do addictive drugs work? • The primary mechanism of action of most psychoactive drugs have been characterized • They produce psychoactive effects by acting in the CNS • To do this they must be able to cross the blood brain barrier • They then act to disrupt neuronal communication at the level of the synapse.

13. Biological theory of addiction The mesolimbic dopamine theory • Studies have shown that the neurotransmitter dopamine in the mesolimbic pathway of the brain may play a crucial role in addiction

16. The mesolimbic dopamine theory of addiction • One idea is that natural rewards normally activate this system to direct behaviour towards stimuli in the environment that promote survival. • Drugs of addiction are able to “shortcircuit” this motivational system and take a strong hold over behaviour.

17. Evidence for the mesolimbic dopamine theory • Microdialysis all drugs of abuse (alcohol, cannabis, opiates, and cocaine) increase levels of dopamine in the nucleus accumbens. • Dopamine antagonists such as haloperidol modulate the i.v. self-administration of drugs such as cocaine in rats. • Intracranial drug self-administration. Rats will self-administer minute quantities of drugs directly into the VTA and nucleus accumbens.

18. Schematic of microdialysis probe

21. Some problems related to the mesolimbic dopamine theory • Mesolimbic dopamine mediates only pleasure BUT Nasty stimuli also increase dopamine levels. Aversive stimuli such as handling, electric shock, tailpinch and aggressive attacks also increase levels of dopamine in the nucleus accumbens. • Dopamine is the only transmitter involved BUT 5-HT, glutamate and GABA may also be involved

23. Biological theory: Summary • Mesolimbic DA system subserves natural rewards. • Chronic drug intake switch users to abusers through neuroadaptations. • Important pathway affected is the mesolimbic DA system (may be others/more research needed). • A “shortcircuit” in this system makes drugs take on biological significance like natural rewards. • These relatively hardwired changes in a key motivational circuit may be responsible for the obsessive and compulsive nature of drug addiction and craving.