Biological Psychology

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Biological Psychology
Reward and addiction
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Olds and Milner, 1954
Journal of Comparative and Physiological
Psychology, 47, 419-427
Observed that a single animal appeared to enjoy
brain stimulation By the time the third
electrical stimulus had been applied the animal
seemed indubitably to be coming back for more

• Subsequently showed that animals would press a
  lever repeatedly in order to receive electrical
  stimulation of specific brain areas.
• effect was region specific
• dependent on stimulus strength

This is self-stimulation
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Self-stimulation
Animals will work (e.g. press a lever) in order
to receive electrical stimulation of certain
brain areas.

• Best areas
• median forebrain bundle
• ventral tegmental area

• Also (but less effective)
• prefrontal cortex
• nucleus accumbens

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Factors affecting self-stimulation

• Effects of stimulation current on press rate
• Not supported below a certain current (threshold)
• As the current increases the press rate increases

• Effects of drugs/lesions on press rate
• Threshold current is increased by dopamine
  antagonists
• Press-rate is decreased by low doses of dopamine
  antagonists
• Pressing abolished by lesions of MFB

• Self-stimulation and dopamine release
• Causes an incresse in dopamine release in nucleus
  accumbens

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Dopamine and natural reward

• Animals will work (e.g. press a lever) to receive
  reward
• e.g. food, water, sex

• Work rates are affected by dopaminergic drugs,
  given either systemically or locally into n.
  accumbens
• e.g. dopamine antagonists decrease lever
  pressing for food reward

Dopamine release is increased during lever
pressing to receive reward (or a stimulus
associated with reward)
Dopamine release is increased during naturally
rewarding behaviours (e.g. feeding, drinking,
sex), and during neutral stimuli predictive of
either
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Drug self-administration

• Animals will work (e.g. press a lever) in order
  to receive drug infusions intra-venously, or
  intracerebrally, particularly
• Nucleus accumbens
• Ventral tegmantal area

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Drugs which support self-administration

• Drugs which animals will self-administer
  intravenously
• amphetamine, cocaine
• morphine, nicotine, ethanol

• Drugs which animals will self-administer locally
• amphetamine (into NAc)
• morphine (into VTA)

• Pharmacological actions of drugs which support
  self administration
• Amphetamine increases dopamine release, blocks
  reuptake and inhibits enzymatic breakdown
• Cocaine blocks dopamine reuptake
• Morphine agonist at opiate receptors
• Nicotine agonist at acetylcholine receptors
• Ethanol mechanism of action uncertain

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Effects of dopaminergic manipulations on
self-administration

• Systemic self-administration of amphetamine or
  cocaine is
• Potentiated by dopamine antagonists
• Press rate increases in order to receive more
  drug to overcome the effect of the antagonist
• Blocked by 6-OHDA lesions of nucleus accumbens
• Lesion removes all dopamine neurones, therefore
  abolishing the mechanism by which the drugs are
  reinforcing

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Reward or reinforcement?

• Reward
• A pleasurable experience
• May or may not increase the likelihood of
  repeating the behaviour

• Subjective
• Objective

• Positive reinforcement
• Presentation of a stimulus which increases the
  likelihood of eliciting a behaviour
• Does not necessarily imply pleasure

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Conditioned place preference

• Training
• The rat is placed in the central chamber of a
  three chamber cage
• R rewarded chamber (e.g. food)
• C control chamber

C
R
Test The rat is again placed in the central
chamber, but there is no reward present. Measure
time spent in CR (conditioned reward) chamber
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Data from DiChiara Imperato (1988)
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Drugs which increase dopamine release

• Brain microdialysis studies have shown a number
  of drugs which increase dopamine release in
  nucleus accumbens
• (DiChiara Imperato, 1988)
• Amphetamine
• Cocaine
• Nicotine
• Morphine
• Ethanol
• Larger responses in nucleus accumbens than
  striatum

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Dopamine and reward is it that simple?

• Evidence that dopamine release in nucleus
  accumbens signals reward
• self-stimulation and effects of dopaminergic
  drugs
• drug self-administration (systemic and local)
• conditioned place preference
• dopamine release in nucleus accumbens during
  rewarded behaviour
• drugs which enhance these behaviours, all evoke
  dopamine release in nucleus accumbens when given
  alone

• BUT
• aversive stimuli also evoke dopamine release in
  nucleus accumbens

Therefore dopamine release in nucleus accumbens
signals more than just reward
Is it perhaps salience ?
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A link with addiction?

• Many drugs , when administered systemically, have
  been shown to enhance dopamine release in nucleus
  accumbens
• amphetamine, cocaine
• nicotine, ethanol, opiates (morphine heroine),
  barbiturates
• Release is relatively specific to nucleus
  accumbens

• These are the same drugs which
• enhance self-stimulation
• support self-administration
• show conditioned place preference
• enhance reinforced behaviours

• have addictive potential in humans

Therefore there is believed to be a link between
dopamine release in nucleus accumbens, reward and
addiction
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Addictive drugs and dopamine

• Addictive drugs have several different
  behavioural effects
• CNS Stimulants amphetamine, cocaine, nicotine,
  caffeine
• CNS depressants alcohol, opioids, barbiturates,
  benzodiazipines, volatile solvents
• Hallucinogens LSD, ecstacy, ketamine, cannabis
• Act via several different neuronal/pharmacological
  mechanisms
• Therefore addictive potential is unlikely to be
  related to primary pharmacology
• All these drugs have in common the ability to
  increase dopamine release in the mesolimbic
  pathway
• Why are direct dopamine agonists not addictive?

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Interactions of addictive drugs with dopamine (1)
Amphetamine Increases dopamine release,
decreases uptake and breakdown Cocaine
Decreases dopamine uptake Nicotine Stimulates
dopamine neurones, by activating nicotinic Ach
receptors on VTA cell bodies Caffeine
Antagonist action on adenosine receptors.
Unclear whether stimulation of dopamine neurones
is through this mechanism. Alcohol Has
effects on opioid, GABA and glutamate systems.
Stimulation of dopamine neurones may be direct or
may be through one of these. Opioids Stimulates
dopamine neurones, by inhibiting GABAergic
neurones in VTA, which inhibit VTA dopamine
neurones (disinhibition) Barbiturates
benzodiazipines Stimulates dopamine neurones,
by enhancing GABAergic inhibition of inhibitory
neurones in VTA (i.e. disinhibition) Volatile
solvents Stimulates dopamine neurones, by
unknown
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Interactions of addictive drugs with dopamine (2)
LSD Stimulates dopamine neurones, by via 5HT
receptors, probably in VTA. Ecstacy Stimulates
dopamine neurones, possibly by a direct
amphetamine-like effect or via 5HT
mechanisms Ketamine Stimulates dopamine
neurones, by activating glutamatergic input to
VTA Cannabis Acts through cannabanoid
receptors. May interact with opioid systems to
increase mesolimbic dopamine release.
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Addictive behaviour

• Many behaviours and/or stimuli associated with
  drug taking become reinforced
• Promote drug taking
• Induce craving for drugs
• Induce physical symptoms similar to withdrawal
  symptoms
• This implies a link with conditioning
• Behaviours associated with reward (actual or
  potential) may also become addictive
• Gambling (addiction of impulse-control disorder)
• Exercise
• Eating disorders
• Can this explain psychological dependence?
• Behaviours which activate dopamine systems

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Further reading
Joseph MH, Young AMJ and Gray JA (1996) Are
neurochemistry and reinforcement enough Can the
abuse potential of drugs be explained by common
actions on a dopamine reward system in the brain?
Human Psychopharm 11, S55-S63. Robbins TW
Everitt BJ (1999) Drug addiction bad habits add
up. Nature 398, 567-570. Wise RA (1996)
Neurobiology of addiction. Current Opinion in
Neurobiology, 6, 243-251
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Models of drug addiction

• Incentive salience model
• Incentive salience is a distinct component of
  motivation and reward, and is distinguishable
  from hedonic impact and reward learning.
• Dopamine provides the driving force to perform a
  behaviour
• Dopamine systems drive wanting incentives, but
  not liking them nor do they drive learning new
  likes and dislikes.
• Drugs which increase dopamine tap into this
  innate mechanism, and thus reinforce the drug
  taking behaviour
• The behaviour is not necessarily pleasurable
• May also lead to physiological changes in
  neurotransmitter systems, leading to a state
  where normal function requires the presence of
  the drug.

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Recommended Reading

• General reviews on Neurochemical basis of
  addiction
• Di Chiara, G. (1999) Drug addiction as
  dopamine-dependent associative learning disorder.
  European Journal of Pharmacology 375 13?30
• Everitt BJ, Dickinson A and Robbins TW
  (2001)The neuropsychological basis of addictive
  behaviour,Brain Research Reviews, Volume 36,
  Pages 129-138 
• Koob, G.F., Sanna P.P., and Bloom F.E. (1998).
  Neuroscience of addiction. Neuron, 21, 467-476.
• Wise, R.A. (1996) Neurobiology of addiction.
  Current Opinion in Neurobiology, 6243-251
• There are also some papers at this link, if you
  want to follow up on specific aspects (Do not be
  overwhelmed by this list I only suggest these
  papers if you want further depth I am not
  suggesting you read them all! http//www.le.ac.uk
  /pc/amjy1\Tutorials\Addiction_papers.htm

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Summary of action of drugs affecting reinforced
behaviour