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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.

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Presentation on theme: "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."— Presentation transcript:

1 Lecture 4 - Dopamine

2 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

3 Dopaminergic systems

4 The dorsal (upper) dopamine system the nigrostriatal system is involved in control of movement neural degeneration causes Parkinsons disease

5 Parkinsons 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 Parkinsons Disease Society:

6 Parkinsons disease

7 no cure, but dopamine replacement therapy is used to treat symptoms levodopa (L-dopa) can be converted into dopamine in the brain


9 Parkinsons disease 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

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

11 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

12 Executive functions: Towers of Hanoi Get from start position to goal in fewest possible moves (cant place a larger disc on top of a smaller one)

13 Tower of London task (Shallice, 1982) – task difficulty (number of moves) depends on Start and Goal positions

14 Tower of London task performance in patients with Parkinsons disease on & off L-dopa (Lange et al, 1992, Psychopharmacology 107, ) initial thinking time % perfect solutions

15 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

16 nucleus accumbens = the pleasure centre of the brain

17 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


19 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

20 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

21 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

22 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

23 Potency of antipsychotic effect correlates with a drugs affinity for dopamine receptors

24 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,

25 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)

26 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)

27 Drugs that increase DA levels in the brain L-dopa - DA precursor used to treat symptoms of Parkinsons disease monoamine oxidase inhibitors (MAOIs) prevent breakdown of DA (& other monoamine NTs – noradrenaline & serotonin) by enzyme MAO psychostimulants - amphetamine & cocaine

28 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

29 The dopaminergic neuron

30 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

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

32 Mechanisms of cocaine dependence (Dackis & OBrien, 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

33 Dopamine (DA) - summary dorsal (upper) dopaminergic pathway involved in control of movement & is damaged in Parkinsons 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

34 Learning outcomes 1)Understand how the motor, cognitive and mood symptoms of Parkinsons 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.

35 Recommended reading RA Bressan & JA Crippa (2005) The role of dopamine in reward and pleasure behaviour. Acta Psychiatrica Scandinavica 111, CA Dackis & CP OBrien (2001) Cocaine dependence. Journal of Substance Abuse Treatment 21, J Gerlach & EB Larsen (1999) Subjective experience and mental side-effects of antipsychotic treatment. Acta Psychiatrica Scandinavica 99 (Suppl. 395), S Kapur (2003) Psychosis as a state of aberrant salience. American Journal of Psychiatry 160, S Kapur (2004) How antipsychotics become anti-psychotic. Trends in Pharmacological Sciences 25, R Tandon & MD Jibson (2002) Extrapyramidal side effects of antipsychotic treatment. Annals of Clinical Psychiatry 14,

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