Lecture 4 - Dopamine. Dopamine (DA) systems 2 major neural pathways: (1) a dorsal (upper) pathway...

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Lecture 4 - Dopamine

Dopamine (DA) systems

• 2 major neural pathways:

(1) a dorsal (upper) pathway from the substantia nigra (in the brain stem) to the basal ganglia and striatum – also called the nigrostriatal system

(2) a ventral (lower) pathway from the ventral tegmental area of the brain stem to the basal forebrain and frontal & prefrontal cortex – also called the mesolimbic system

Dopaminergic systems

The dorsal (upper) dopamine system

• the nigrostriatal system

• is involved in control of movement

• neural degeneration causes Parkinson’s disease

Parkinson’s disease

• progressive brain disease affecting movement• symptoms – tremor, slowness of movement

(bradykinesia), muscle rigidity, stooped posture

• about 120,000 people (1 in 500) in the UK have PD• about 10,000 new cases diagnosed each year - 1 in 20

of these under 40 years old

• Parkinson’s Disease Society: www.parkinsons.org.uk

Parkinson’s disease• no cure, but dopamine replacement therapy is used

to treat symptoms• levodopa (L-dopa) can be converted into dopamine

in the brain

• patients also show a distinctive pattern of cognitive impairments affecting ‘executive functions’ (planning, working memory)

• and high rates of co-morbid depression (40-50% of patients)

• these symptoms are linked to reduced dopaminergic activity in the ventral pathway

The ventral (lower) dopamine system(or mesolimbic system)

Prefrontal cortex (PFC)

• the PFC is particularly rich in dopaminergic neurons

• frontal executive functions =‘high level’ cognitive abilities involved in planning, monitoring & control of behaviour

Executive functions: Towers of HanoiGet from start position to goal in fewest possible moves

(can’t place a larger disc on top of a smaller one)

‘Tower of London’ task (Shallice, 1982) – task difficulty (number of moves) depends

on ‘Start’ and ‘Goal’ positions

Tower of London task performance in patients with Parkinson’s disease on & off L-dopa (Lange et al, 1992,

Psychopharmacology 107, 394-404)

initial thinking time % ‘perfect’ solutions

2 move 3 move 4 move 5 move

difficulty

Off L-dopaOn L-dopa

2 move 3 move 4 move 5 move

difficulty

Dopamine & reward

• naturally pleasurable and rewarding stimuli (food, sex, etc.) increase DA release in the nucleus accumbens area of the basal (‘deep’) forebrain

• drugs with a high potential for abuse and addiction also increase DA release in this part of the brain

nucleus accumbens = the ‘pleasure centre’ of the brain

Dopamine & reward• the ventral dopaminergic system normally mediates

responses to naturally rewarding stimuli• addictive drugs ‘hijack’ this reward system by

inducing DA release, particularly in the nucleus accumbens

• some drugs (e.g. amphetamine, cocaine) increase DA by acting directly on dopaminergic neurons within the reward system

• others (e.g. alcohol, opiates) increase DA indirectly, via effects on other NT systems

Amphetamine Cocaine Nicotine Morphine Ethanol0

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.

DiChiara G. & Imperato A.Proc. Natl. Acad. Sci. USA (1988), 85; 5274-5278

Dopamine release in the caudate nucleus (CN : dorsal striatum) and nucleus accumbens (NAc : ventral striatum) was measured in conscious freely moving rats using brain microdialysis. Figures (redrawn from the original paper) represent the maximum increases in dopamine (expressed as a percentage of the basal level) in response to systemic administration of drugs.

Schizophrenia

• schizophrenia = ‘split mind’

• not a ‘split personality’, but a ‘splitting-off’ or disconnection between experience & reality, or thoughts & feelings

• 1-2% of people will have at least one ‘psychotic episode’ in their lifetimes

• onset is usually between 15 and 35 years old

Dopamine & schizophrenia

• ‘Positive’ (or ‘florid’) symptoms - presence of abnormal experiences & behaviour - disordered thought & speech, hallucinations (usually auditory), delusions (often paranoid) - linked to increased DA, especially in basal forebrain areas

• ‘Negative’ (or ‘deficit’) symptoms - absence of normal experiences & behaviour - emotional blunting, anhedonia, apathy, social withdrawal, poverty of speech - linked to reduced DA, especially in frontal & prefrontal cortex

The ‘salience hypothesis’ (Kapur 2003)

• normally, the occurrence of a motivationally salient (or significant) stimulus or event is signalled by release of DA in the basal forebrain

• in psychosis, this process is disrupted so that increased DA coincides with stimuli or events that have no intrinsic significance

• this leads to the formation of delusional beliefs to account for subjective experiences of ‘significance’

• similarly, hallucinations are internally generated representations (thoughts, mental images) that have been assigned inappropriate significance

Drugs that reduce DA activity in the brain

• antipsychotics: used to treat ‘positive’ symptoms of schizophrenia

– chlorpromazine ( = Thorazine), the first anti-psychotic drug (1950)

– haloperidol (1957), about 50 times more potent (by weight) than chlorpromazine

– originally described as neuroleptics (‘taking hold of nerves’), because reduction in DA produced difficulty in moving

– work by blocking dopamine receptors

Potency of antipsychotic effect correlates with a drug’s affinity for dopamine receptors

Mean improvement in symptoms over time in patients taking antipsychotics (combined data from 42 double-blind, placebo-

controlled studies; n = 7450) – from Agid et al 2003, Archives of General Psychiatry 60, 1228-1235

Kapur (2004)• neuroleptic drugs are effective in treating the

positive symptoms of schizophrenia because, by blocking the actions of DA, they are able to ‘dampen’ the inappropriate experience of salience

• but, side-effects can include reduced feelings of salience/motivation for stimuli and experiences in general

• referred to as neuroleptic induced dysphoria – feelings of emptiness, apathy, inability to feel pleasure (anhedonia)

Drug “side effects”

• neuroleptic antipsychotics– can cause Parkinson-like side-effects– problems with movement: tremor, rigidity, painful muscle

contractions (dystonia)– referred to as ‘motor side-effects’ or ‘extrapyramidal

symptoms’ (EPS); linked to reduced DA in the dorsal system– unpleasant subjective reactions to medication: feelings of

restlessness (akathisia), emptiness, anhedonia & apathy– referred to as ‘mental side-effects’ or ‘neuroleptic-induced

dysphoria’; linked to reduced DA in the ventral system

– major reasons for patients stopping medication– but newer ‘atypical’ antipsychotics (clozapine, olanzapine,

risperidone) have much reduced side-effects– see Gerlach & Larsen (1999), Tandon & Jibson (2002)

Drugs that increase DA levels in the brain

• L-dopa - DA precursor used to treat symptoms of Parkinson’s disease

• monoamine oxidase inhibitors (MAOIs) prevent breakdown of DA (& other monoamine NTs – noradrenaline & serotonin) by enzyme MAO

• psychostimulants - amphetamine & cocaine

Drug “side effects”

• L-dopa– increases levels of DA– can cause schizophrenia-like symptoms in patients

• amphetamine & cocaine– increase levels of DA– increase ‘positive’ symptoms in schizophrenia– chronic abuse can cause schizophrenia-like

symptoms (paranoia, delusions, hallucinations, stereotyped repetitive & compulsive behaviours) in non-schizophrenics

The dopaminergic neuron

Amphetamine & Cocaine

• these drugs increase levels of both DA & NA

• acute effects are similar - reduced fatigue; increased energy, alertness & confidence; increased motor activity & speech

• effects of cocaine are more intense and have shorter duration (30-45 mins) than amphetamine

• euphoric ‘high’ (due to raised levels of DA in the limbic forebrain - especially nucleus accumbens) means these drugs have a high potential for abuse & dependence

Cocaine blocks reuptake of dopamine, leading to increased concentration in synaptic cleft

Mechanisms of cocaine dependence (Dackis & O’Brien, 2001)

• positive reinforcement – acute subjective effects of cocaine are intensely pleasurable

• negative reinforcement – unpleasant rebound effects due to dopamine depletion (depressed mood, anhedonia, apathy, lethargy) are reversed by further drug use

• classical conditioning – stimuli (including places & people) associated with drug use trigger drug craving

Dopamine (DA) - summary

• dorsal (upper) dopaminergic pathway involved in control of movement & is damaged in Parkinson’s disease

• ventral (lower) dopaminergic pathway involved in frontal executive functions & pleasure/reward

• abnormalities in dopaminergic neurotransmission are implicated in schizophrenia – ‘positive’ symptoms are associated with increased levels of DA, ‘negative’ symptoms with reduced DA

• neuroleptics = antipsychotic drugs that reduce dopaminergic activity by blocking DA receptors (but can cause Parkinsonian side-effects & dysphoria)

• drugs that increase dopaminergic activity (amphetamine, cocaine) have a high potential for abuse/addiction because of effects in brain ‘reward’ pathways, and can also precipitate psychotic symptoms

Learning outcomes

1) Understand how the motor, cognitive and mood symptoms of Parkinson’s disease are related to abnormalities in dopaminergic neurotransmitter systems.

2) Understand how the ‘positive’ and ‘negative’ symptoms of schizophrenia are related to abnormalities in dopaminergic neurotransmission.

3) Understand the psychopharmacological basis for the therapeutic effects and side-effects of neuroleptic anti-psychotics.

4) Understand the evidence for the involvement of dopamine in pleasure/reward behaviour.

5) Understand the role of dopamine in the acute effects of cocaine intoxication and the mechanisms involved in the development of cocaine dependence.

Lecture 4 - Dopamine. Dopamine (DA) systems 2 major neural pathways: (1) a dorsal (upper) pathway...

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