The neuroanatomy of dopamine and the effects of neuroleptics

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Med IV 2009 Neurosciences and psychopharmacology
Dr Brian Power B Med Sci (Hons) MB BS
PhDClinical lecturer UWA, Lundbeck teaching
fellow
One of the difficulties in understanding the
brain is that it is nothing so much as a lump of
porridge -RL Gregory, 1966-
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Causes of a raised CK
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The neuroanatomy of dopamine and the effects of
neuroleptics
DA
DA
DA
DA
DA
DA
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Direction of nerve impulse
Axon terminal of presynaptic neuron
Synthesis of neurotransmitter
Destruction
Neurotransmitter in vesicles
autoreceptor
Uptake
Release
Synapse
Destruction
receptors
Dendrite of postsynaptic neuron
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Dopamine (DA)

• an inhibitory monoamine
• distribution of dopaminergic cell bodies
• mesencephalon A8-A10
• diencephalon A11-A14
• telencephalon A15-A17
• many neurons in the brain use DA, and DA
  receptors are widespread, but there are several
  specific DA pathways in the brain

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Lifecycle of dopamine

• Tyrosine gt L DOPA gt Dopamine (DA)
• rate limiting enzyme TH (tyrosine hydroxylase)
• DDC (DOPA decarboxylase)
• DA diffuses across synapse post synaptic
  receptor (mediates action)
• 2nd messenger (not ligand gated ion channels)
• D1 and D5 post synaptic inhibition
• D2-D4 pre and post synaptic inhibition
• Reuptake into presynaptic neuron
• Degradation to HVA (which can be measured in
  blood/CSF)
• monoamine oxidase (MAO) in presynaptic
  mitochondria
• catechol-O-methyl transferase (COMT), outside
  neuron

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Tyrosine
MAO
DA
DA
DA
DA
DA
DA
DA
COMT
DA
DA
Release
Uptake
DA
DA
receptors
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Chemicals altering synaptic activity

• DA depletor (inhibit synthesis) reserpine,
  tetrabenzine, AMPT
• DA neurotoxin MPTP
• DA releaser amphetamine
• DA agonist bromocriptine, apomorphine
• DA antagonist neuroleptics
• DA uptake inhibitor cocaine, amphetamine
• DA degradation inhibitor (inhibit MAO)
  selegeline, pargyline, tranylcypromine

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toxin
MPTP
Depletor
TH
DDC
Tyr
LDOPA
Dopamine
pargyline
MAO
reserpine
destruction
DA
DA
DA
DA
DA
DA
Release
Uptake
amphetamine
DA
DA
cocaine
DA
DA
Agonist
Antagonist
bromocriptine
neuroleptic
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Major dopaminergic pathways

• mesolimbic
• mesocortical
• tubero- infundibular
• nigostriatal

Figure from Kaplan and Sadok, 1998
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(No Transcript)
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Psychosis

• problems with thought form
• problems with thought content
• perceptual abnormalities
• disorganised speech or behaviour

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Symptoms of schizophrenia

• Positive symptoms
• delusions, hallucinations, disorganised speech or
  behaviour, catatonic behaviour, agitation,
  distortions in language or communication
• Negative symptoms
• blunted affect, emotional withdrawal, poor
  rapport, passivity, apathetic social withdrawal,
  difficult in abstract thinking, lack of
  spontaneity, stereotyped thinking (the 5 as
  alogia, avolition, anhedonia, attentional
  impairment, affective bluntening)
• Neurocognitive symptoms
• impairments in attention, information processing,
  verbal fluency, serial learning, executive
  function

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Dopamine Hypothesis of Schizophrenia
Hypoactivity Negative symptoms Cognitive
impairment
Hyperactivity Positive symptoms
Borrowed from Shymko 2006 adapted from Inoue and
Nakata. Jpn J Pharmacol. 200186376.
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The ideal treatment

• there are four DA pathways
• blocking the hyperactive mesolimbic pathway is
  useful blocking the other 3 would be harmful
• the perfect treatment would
• decrease positive symptoms (decrease DA in
  mesolimbic pathway)
• improve negative and neurocognitive symptoms
  (increase DA in mesocortical pathway)
• have no effect on nigrostrital or
  tuberoinfundibular pathway

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Neuroleptics

• DA antagonists/ antipsychotics
• D1 and D5 most neuroleptics block these, but
  blockade correlates poorly with antipsychotic
  action
• D2, D3, D4 neuroleptic affinity for D2
  correlates with antipsychotic potency
• Effects
• 1. typicals (dopamine antagonists) decrease
  positive symptoms
• 2. atypicals (mostly DA serotonin antagonists)
  decrease positive symptoms, improve negative
  symptoms and neurocognitive symptoms

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Variable side effects depending on class and dose
of medication

• 3. nigrostriatal dopamine blockade motor SE
  (extrapyramidal side effects EPSE)
• 4. tuberoinfundibular dopamine blockade
  prolactin increase
• 5. anticholinergic effects (muscarinic
  cholinergic activity)
• 6. anti alpha adrenergic effects (adrenergic
  activity)
• 7. antihistamine effects (histamine activity)

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1. Typical antipsychotics

• block D2 receptors
• clinical effect essentially decrease
  hyperactivity of mesolimbic dopaminergic pathway
• side effects effectively block the hypoactive
  mesocortical pathway (increase negative
  symptoms), block effects of DA in nigrostriatal
  and tuberoinfundibular pathways (EPSE and
  hyperprolactinaemia)
• provide symptom relief in SCZ, but significant
  side effects
• inexpensive, have depot preparations, well
  established side effect profiles

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2. Atypical antipsychotics

• block D2, D4 and 5HT receptors
• newer
• DA and serotonin (5HT) blockade thought to
  account for action (decreased positive as well as
  improved negative and neurocognitive symptoms)
• some have fewer SE
• EPSE, especially TD
• hyperprolactinaemia
• more expensive, but cost effective
• less well established side effect profiles, only
  one kind of depot

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Unwanted effects of neuroleptics

• 3. EPSE
• 4. hyperprolactinaemia
• 5. anticholinergic, 6. antiadrenergic, 7.
  antihistaminergic

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3. EPSE

• from dopamine receptor blockade in nigrostriatal
  pathway, leading to a pro cholinergic effect
• ie anticholinergic benztropine can help with some
  EPSE
• motor side effects
• tremor
• dystonia sustained involuntary motor activity
• akasthisia motor restlessness
• parkinsonism bradykinesia, rigidity, tremor
• tardive dyskinesia permanent orofacial
  dyskinesia
• neuroleptic malignant syndrome (NMS) life
  threatening triad of change in muscle tone and
  mental state, and autonomic instability

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Substantia nigra is part of the extrapyramidal
nervous system

• Extrapyramidal (ie those cells involved in motor
  function that are not pyramidal cells of motor
  cortex

Figure from Haines, 1991
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Components of basal ganglia

• cortical linkers
• putamen (L husk)
• caudate nucleus
• globus pallidus (internal and external segments)
• regulators
• subthalamic nucleus
• substantia nigra
• putamen GP lentiform /lenticular nucleus (L
  lentil)
• caudate lenticular nucleus corpus striatum
  (striped appearance)
• caudate putamen striatum (embryologically
  related)

(Figure from Kandell, Schwartz and Jessell, 2001)
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Basal ganglia
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Simplified Circuitry

• Direct pathway
• ctx CP
• CP - GP
• GP - thalamus
• thalamus ctx
• net effect -- on ctx
• Indirect pathway
• ctx CP
• CP - GPe
• Gpe - STN
• STN GPi
• GPi - thalamus
• thalamus ctx
• net effect --- - on ctx

(Figure from Kandell, Schwartz and Jessell, 2001)
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Dopaminergic regulation by SN

• SN pc excites the direct pathway overall
  excitation of cortex
• SN pc inhibits the indirect pathway overall
  excitation of the cortex

(Figure from Kandell, Schwartz and Jessell, 2001)
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Procholinergic effect of dopamine blockade

• acetylcholine and dopamine have a reciprocal
  relationship in the nigrostriatal pathway
• dopamine inhibits acetylcholine release
• dopamine blockade has procholinergic effect

(Figure from Kandell, Schwartz and Jessell, 2001)
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Functional aspects

• Disorders of basal ganglia manifest as
• disturbances of muscle tone
• increased generally (eg in PD)
• dystonia (selective muscle groups only)
• tone may be decreased
• involuntary movements
• tremors
• movements chorea (brisk), athetosis (slow),
  ballismus (violent)

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3A. Acute dystonia

• affects face, neck and trunk
• especially likely after parenteral admin
• within hrs to days, especially young males
• Sx
• laryngeal spasm (potentially fatal)
• oculogyric crisis (involuntary contractions of
  eye mm resulting in conjugate gaze usually in
  upward direction) and opisthotonus (tetanic spasm
  in mm of back
• Tx benztropine 1-2mg IMI, every 10-15 min if
  necessary (max 6mg/24hr)

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3B. Parkinsonism

• signs and symptoms tremor, rigidity, difficulty
  moving
• bradykinesia (inability to initiate movement,
  and, when the movement starts, inability to stop
  it)
• resting tremor (high frequency, pill rolling)
• muscular rigidity (increased tone, lead pipe
  rigidity, cogwheeling)
• positive signs extra movements (tremor, tone)
• negative signs loss of function, expressionless,
  drooling
• can we explain signs and symptoms via simplified
  circuit? NO!..but lets try
• SN pc excites the direct pathway overall
  excitation of cortex
• SN pc inhibits the indirect pathway overall
  excitation of the cortex
• if we block dopamine lose excitation of SN on
  direct pathway (less excitation), lose inhibition
  on indirect pathway (inhibition)
• benztropine 0.5-2mg daily

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3C. Akasthisia

• severe sense of agitation and restlessness of the
  limbs
• may present as a feeling of inner restlessness
• develops within hrs to days
• Tx
• propanolol 20-40mg orally TDS-QID or
• diazepam 2-5mg orally, TDS

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3D. Tardive dyskinesia

• complex syndrome of involuntary hyperkinetic
  movements
• mostly affect mouth, lips, tongue, jaw
• no effective treatments available
• slowly withdraw causative agent
• consider alternative AP

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3E. NMS

• 2 of pt on AP, can occur any time, but usually
  in first 30 days, mortality 5-20
• Sx evolve over 1-2 days, recover over 2-3 weeks
• triad altered mental state, autonomic
  instability (temp, BP), neuromuscular
  hyperactivity (change in tone)
• ? systemic dopamine blockade

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3E. NMS

• DDs NMS, SS, lithium toxicity, drug
  intoxication, drug withdrawal
• complications metabolic acidosis,
  myoglobulinaemia, renal failure, PE, chronic
  cerebellar syndrome, DIC, death
• Ix obs, check med chart!, IV access and measure
  CK, UEC, coags, lithium level, other drug levels,
  UDS
• Tx cease AP, resuscitate (cooling, BP,
  rehydrate), fluids, medical review, DA agonist,
  mm relaxant, heparin

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4. Hyperprolactinaemia

• DA cell bodies in the hypothalamic arcuate
  nucelus (A12) project to the pituitary gland
• inhibit prolactin and growth hormone
• inhibition of DA at tuberoinfundibular pathway by
  neuroleptic leads to increased prolactin
• weight gain, galactorrhoea, gynecomastia, sexual
  dysfunction, amenorrhoea/menstrual irregularity,
  infertility, ?osteoporosis

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Other side effects of neuroleptics

• depends on class and dose of medication
• 5. anticholinergic
• strong anticholinergic activity correlates with
  decreased EPSE (limits the procholinergic effect
  of dopamine blockade!)
• muscarinic blockade dry mouth, blurred vision
  (loss of accommodation), constipation, urinary
  hesitancy/ retention, cognitive blunting
• 6. anti alpha adrenergic
• postural hypotension, hypothermia, impotence,
  failure to ejaculate
• 7. antihistaminergic
• weight gain and drowsiness

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Atypicals v typicals 5HT activity

• Atypicals are serotonin AND dopamine antagonists
• Parallel pathways from the brainstem DA and 5HT
• 5HT inhibits DA release from axon terminals in
  the various DA pathways, but the degree of
  control differs from one pathway to another
• The ability of one neuroleptic to block 5HT also
  depends on the class and dose of the medication

Figures from Stahl
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Serotoninergic blockade facilitates dopamine
release

• by blocking the 5HT receptor, DA is released
• this DA can compete with the neuroleptic in the
  synapse, and reverse the blockade of DA receptors
• results in a net increase of DA activity in the
  mesocortical pathway (improve negative and
  neurocogntive symptoms), as the 5HT2A receptors
  predominate over D2 receptors there (ie the
  neuroleptic occupies the 5HT2A site)
• decreased side effects (increased DA in the
  nigrostriatal and tuberoinfundibular pathways)
  here D2 receptors predominate over 5HT2A

Figures from Stahl
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Why dont atypical neuroleptics increase positive
symptoms?

• this mechanism fails to reverse D2 antagonism in
  the mesolimbic system (otherwise positive
  symptoms would increase)
• the strength of the serotonin pathway in the
  mesolimbic system is thought not to be as robust
  as in the other pathways
• other evidence pointing towards selective D2/3
  activity (eg aripiprazole, amisulpride)

D2
5HT
D3
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Figures from

• 1. The Human Brain, Nolte (1991), 3rd edition,
  London.
• 2. Principles of neural science, Kandell,
  Schwartz and Jessell (1991), 3rd edition, Sydney.
• 3. Neuroanatomy, an atlas of structures, sections
  and systems, Haines, DE (1991) 3rd edition,
  Sydney.
• 4. Lecture and tutorial notes, Dr John Mitrofanis
  (2000), The University of Sydney.
• 5. Lecture notes G Shymko (2006), Fremantle
  Hospital, WA.
• 6. Essential Psychopharmacology, Stahl (2002),
  2nd edition, Cambridge.