Addiction

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Addiction?
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Structure
Drug use/abuse
Introduction to the acute neurobiological effects
of drugs of abuse
Introduction to the chronic neurobiological
effects of drugs of abuse
Video debate legalisation of drugs of abuse
PORTFOLIO ACTIVITY
Introduction to the psychobiology of addiction
Debate legalisation of drugs of abuse based on
neurobiological evidence
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What is addictive ?
Common (legal) substances Alcohol Nicotine
Caffeine
Illicit drugs Stimulants Cocaine,
Amphetamine Narcotics Heroin, Morphine
Hallucinogens LSD, Ketamine, PCP, MDMA
Depressants Benzodiazepines (valium)
Inhalants Solvents Anabolic steroids
Cannabis
Addictive behaviours Gambling Shopping
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Substance use in the UKAlcohol (2001-2002)
Men Women
Recommended weekly limits 21U 14U
Average weekly consumption of alcohol (U)
16.9 7.5
Averaging more than recommended 27
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Binge drinking (gt8U men/6U women) 21
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Substance use in the UKIllicit drugs (2002)
16 24 yr olds
Drug usage last year 30 Have used but not
in the last year 21 Never used 49
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What substances are we concerned about?
Clinical (health profession) (..probability of
harmful consequences) Nicotine Alcohol Tranquil
lisers and hypnotic Narcotics Stimulants
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Public health problems associated with substance
abuse
EXAMPLES OF SOME HEALTH PROBLEMS
SMOKING
Lung cancer, emphysema, cardiovascular
problems Heavy smoker 25 x more likely to
develop lung cancer Light smoker 10 x more
likely to develop lung cancer
Liver cirrhosis, internal haemorrhage Illegal
alcohol level in 6 of road traffic accident -
20,140 casualties per year in UK
ALCOHOL
Risks include HIV and hepatitis
ILLICIT DRUGS
Higher risk of fetal abnormalities, cognition
impairments, learning disabilities, low birth
weights, addiction in infants.
PREGNANCY
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Costs of substance abuse (UK)

Alcohol abuse NHS costs 3 billion / yr Illicit
drugs 4 billion / yr (1998) mainly spent
on drug related crime rather than prevention/
treatment 1 treatment save 3 crime
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Treatment

1. Substitution and Maintenance programs
Replace substance with a prescribed drug
Stabilise the user whilst other aspects of their
life (e.g. criminality) are sorted out and
other treatment can be arranged.
Methadone maintenance for heroin
abuse Synthetic opiate Can be taken orally
(decreased HIV risk) Prevents withdrawal
symptoms Doesnt produce a high Reduces
criminal activity
normal functioning
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Treatment

2. Drug-free treatment Abstinence based
programmes Concentrate on relapse
prevention Enter drug free or go through
detoxification (medicated) Programmes last 3
12 months Provide safe environment Provide
support (lectures, counselling, family
involvement) Behavioural cognitive therapy
Alcoholics Anonymous 12 step program Peer
support Once an addict, always an addict
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Treatment

3. Pharmacological treatment for relapse
prevention Patient takes a prescribed drugs
that will interact with the substance of
abuse. Antabuse (disulfiram)
alcohol Stops the complete breakdown of alcohol
leading to a build up of acetaldehyde. -
headache, nausea, vomiting, sweating, trouble
breathing. Naltrexone heroin Blocks the
action of heroin.
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What is addiction ?
Drug taking
Pleasurable effect
Drug wears off
Dysphoria/craving
Loss of control over limiting access
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Neurobiological processes
Mesocorticolimbic pathway ventral tegmentum area
? nucleus accumbens Neurotransmitter - dopamine
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Binding sites of cocaine following acute
administration
Striatum
Fowler et al (1989) Synapse 4 371-377
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How do we know that is pathway is involved in
reward ?

Dose self-administration lead to activation of
these brain areas?
Dopamine level ( baseline)
Time (min)
Increase in dopamine release in the nucleus
accumbens following morphine Activation of the
mesocorticolimbic pathway by morphine.
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How do we know that is pathway is involved in
reward ?

Dose damage to these brain areas alter drug
self-administration?
Control group
Damage to the nucleus accumbens decreases
self-administration of heroin. Mesocorticolimbic
pathway needed for drug self-administration.
Damage to nucleus accumbens
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Reward pathway
Drugs of abuse maintain dopamine release in the
nucleus accumbens shell after repeated exposure.
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Effects of chronic drug use on brain activity

Brain activity measured as glucose metabolism
Cocaine user
Control subject
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Effects of chronic drug use
Repeated exposure to a drug produces long term
changes in nervous system.   1. Tolerance
Drug-induced compensatory reaction, opposed to
acute drug effects, to enable normal functioning
in the presence of a drug. Results in a
diminished effect of a given dose of the drug
over repeated exposures, and withdrawal effects
when the drug is removed.

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Chronic drug use
acute drug effects

tolerance
drug effects
ve
-ve
increase in tolerance
tolerance
increase drug taking
drug effects
Dependence a state in which the organism
functions normally only in the presence of the
drug
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Removal of drug of abuse
increase in tolerance
tolerance
increase drug taking
drug effects
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Effects of chronic drug use
Repeated exposure to a drug produces long term
changes in nervous system.   2. Sensitisation
Drug-induced adaptation that enhances drug
responsiveness with repeated administration. Repea
ted exposure to the drug increases the effect of
the drug.

E.g. Repeated administration of amphetamine leads
to sensitisation to the locomotor stimulant
effects. Craving?
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cAMP and CREB
Activation of cAMP
Increase intracellular calcium
Stress-induced signalling cascades
Phosphorylation of PKA
CaMK
CREB
ERK
CRE-site in promoter TGACGTCA (palindromic
sequence)
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CRE-mediated transcription
CRE-mediated transcription following chronic
morphine treatment (CRE-LacZ reporter mice)
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CRE-mediated transcription
Rewarding effects of morphine in mice with
underactivity (m CREB) or overactivity (CREB) of
CREB, using conditioned place preference
Drug rewarding conditioned place preference
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Activation and inhibition of PKA and rewarding
effects of cocaine
Self-administration of cocaine following
activation (Sp) or inhibition (Rp) of PKA
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CRE-mediated transcription and withdrawal
CRE-mediated transcription increases in the
Nucleus Accumbens during morphine withdrawal
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?FosB
?FosB Immediate early gene Part of the
Fos family of immediate early genes (eg cFos,
FosB) Transcription factor
Fos member Jun member
AP-1
Promotes or suppresses gene expression (site
dependent)
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?FosB and addiction
Accumulation of ?FosB with chronic drug taking
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?FosB
Self-administration of cocaine in mice that
overexpress ?FosB (filled symbols)
Overexpression ?FosB ? increases the rewarding
value of cocaine
? increases the rate of acquisition of cocaine
self-
administration
? relapse?
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PORTFOLIO EXERCISE
Should drugs be decriminalised
Jeremy Paxman (Chair)
Emma Bonino (For)
Danny Kushlick (For)
Keith Hellawell (Against)
Andrew Johns (Against)