Dopamine is an important neurotransmitter in the brain. This presentation explains its role in physiology and pathology of the central nervous system.

1. DOPAMINE
DR MRUNAL DHOLE
3,4-DIHYDROXYPHENYLETHYLAMINE

2. LAYOUT
• History
• Synthesis & Metabolism
• Dopamine receptors
• Physiological Actions of Dopamine
• Dopamine Pathways in Brain
• Dopamine receptor agonists
• Dopamine receptor antagonists

3. SCIENTIST CONTRIBUTION TO DOPAMINE
George Barger & James Ewens Synthesized DA for the first time in 1910
Henry Dale Found DA a weak sympathomimetic,
adrenaline-like compound; also named it
dopamine
Peter Holtz & Hermann Blaschko Discovered DA to be an intermediate
metabolite in synthesis of Adr & NA; also
detected DA in peripheral tissues
Kathleen Montagu Showed presence of DA in brain
Arvid Carlsson Proved DA to be a neurotransmitter
Oleh Hornykiewicz Depletion of DA in Parkinsonian brain
HISTORY

4. JAMES EWENS

5. SYNTHESIS & METABOLISM
PHENYLALANINE
TYROSINE
DIHYDROXY PHENYLALANINE
DOPAMINE
NORADRENALINE
ADRENALINE
Phenylalanine hydroxylase
Tyrosine hydroxylase
Dopa decarboxylase
Dopamine β-hydroxylase
N-methyl transferase

7. DOPAMINE RECEPTORS
• Dopamine receptors → adrenoreceptors; structurally G-protein coupled
receptors
• Broadly classified as
1. D1-like receptors – D1, D5 → link to Gs → activates adenylyl cyclase
2. D2-like receptors – D2, D3, D4 → link to Gi / Go → inhibits adenylyl cyclase,
activates K+ channels & inhibits Ca2+ channels
RECEPTOR TYPE LOCATION
D1-like Brain – limbic system, corpus striatum,
hypothalamus, thalamus
Others - mesenteric & renal blood vessels
D2-like Brain – limbic system, corpus striatum,
hypothalamus, thalamus, pituitary
Others - cardiac muscle, sympathetic fibres
innervating heart

8. PRESYNAPTIC D2 AUTORECEPTORS
• D2 receptors located presynaptically function as autoreceptors
• When dopamine is not bound to these receptors, they allow its
release from the neuron
• When dopamine builds up in the synapse, it binds to these receptors
and inhibit its release
• Thus they provide negative feedback input and act as gatekeepers for
dopamine

9. PHYSIOLOGICAL ACTIONS OF DOPAMINE
1. HEART & VASCULATURE
• Low concentration - stimulates D1 receptors → vasodilation → ↓ BP
• High concentration - stimulates β receptors → ↑ in cardiac
contractility
• Very high concentration - stimulates α receptors → vasoconstriction
→ ↑ BP
2. KIDNEY
• Stimulates D1 receptors on proximal tubular cells → ↑ natriuresis
• ↑ renal blood flow & glomerular filtration
• Activates D1 receptors → ↑ renin secretion
• D3 receptors → ↓ renin secretion

10. 3. PITUITARY GLAND
• Stimulates pituitary lactrotroph D2 receptors → inhibit prolactin
secretion
• ↑ growth hormone secretion
4. CATECHOLAMINE RELEASE
• D1 receptor activation → promotes release of Adr & NA
• D2 receptor activation → inhibits release of Adr & NA

11. DOPAMINE PATHWAYS IN BRAIN1. MESOLIMBIC PATHWAY
2. MESOCORTICAL
PATHWAY
3. NIGROSTRIATAL
PATHWAY
4. TUBEROINFUNDIBULAR
PATHWAY
Tuberoinfundibular
Pathway
Nigrostriatal
Pathway
Mesocortical
Pathway
Mesolimbic
Pathway

12. DOPAMINE PATHWAYS IN BRAIN
1. MESOLIMBIC DOPAMINE PATHWAY
• Projects from ventral tegmental area of brainstem to nucleus
accumbens in ventral striatum
• Hyperactivity of this pathway → positive symptoms of psychosis in
schizophrenia
• Also involved in motivation, pleasure and reward
• Drugs of abuse → ↑ DA in nucleus accumbens

13. 2. MESOCORTICAL DOPAMINE PATHWAY
• Arises from ventral tegmental area but projects to prefrontal cortex
• Deficit of dopamine in fibres projecting to
i. dorsolateral prefrontal cortex → negative and cognitive symptoms
of schizophrenia
ii. ventromedial prefrontal cortex → negative and affective
symptoms of schizophrenia

14. 3. NIGROSTRIATAL DOPAMINE PATHWAY (75% of the total
dopamine)
• Part of extrapyramidal nervous system → controls motor
movements
• Deficiency of dopamine in this pathway →Parkinson’s disease and
Restless Leg Syndrome
• Hyperactivity → chorea, dyskinesias and tics

15. 4. TUBEROINFUNDIBULAR DOPAMINE PATHWAY
• Projects from hypothalamus to anterior pituitary gland
• Release of dopamine from neurons in this pathway → inhibits
prolactin release
• Postpartum state → activity of these neurons ↓ → prolactin levels ↑
→ lactation

16. DOPAMINE RECEPTOR AGONISTS &
ANTAGONISTS
AGONISTS ANTAGONISTS
Dopamine, Dopexamine Typical antipsychotics
Fenoldopam Vesicular monoamine transporter
inhibitors
Ergot Alkaloids Prokinetic drugs
Non-Ergot Alkaloids
Aripiprazole
Dopamine reuptake inhibitors

17. DOPAMINE RECEPTOR AGONISTS
Indicated in the treatment of
• Hypovolaemic shock
• Congestive heart failure
• Hypertensive crisis
• Hyperprolactinaemia
• Parkinson’s disease (PD)
• Restless leg syndrome
• Attention Deficit-Hyperactivity Disorder (ADHD)

18. DOPAMINE
The pharmacological & hemodynamic effects of dopamine are
concentration dependent
DOSE (by
infusion)
(µg/kg/min)
RECEPTOR PHARMACOLOGICAL EFFECT INDICATION
Low (2-5) D1 (renal &
mesenteric)
Renal & mesenteric vasodilation → perfusion
of renal & visceral tissues maintained
Hypovolemic shock
Intermediate
(5-10)
β1 (cardiac) ↑ myocardial contractility → ↑ HR & ↑ CO Short term
management of
CHF
High
(10-20)
α (vascular) Vasoconstriction → ↑ BP; ↓ renal blood flow,
↓ urine output

19. FENOLDOPAM
• Short acting D1 receptor agonist
• Mechanism of action → peripheral & renal vasodilation, natriuresis
• Short term management of hypertensive crisis with impaired renal
function
• ↑ intraocular pressure

20. HYPERPROLACTINAEMIA
ERGOT & NON-ERGOT ALKALOIDS → Activate pituitary D2 receptors → inhibit
prolactin release
ERGOT ALKALOIDS
BROMOCRIPTINE & CABERGOLINE
• Cessation of Bromocriptine → Recurrence of hyperprolactinaemia
• Notable adverse effects → nausea, headache & postural hypotension
NON-ERGOT ALKALOIDS
QUINAGOLIDE

21. PARKINSON’S DISEASE (PD)
• Loss of > 80% of dopaminergic neurons of substantia nigra pars
compacta → symptoms
• Dopamine does not cross the blood-brain barrier → cannot be used
to treat Parkinson’s disease
PHARMACOTHERAPY OF PARKINSON’S DISEASE
Levodopa
Non-Ergot Alkaloids
Apomorphine
COMT inhibitors
MAO B inhibitors

22. LEVODOPA
• Levodopa → immediate metabolic precursor of DA
• When given alone, only 1-3% of levodopa reaches the brain unaltered
as most of it is decarboxylated peripherally to DA
• To prevent this, levodopa is given in combination with a peripheral
dopa decarboxylase inhibitor → CARBIDOPA/BENSERAZIDE
ADVANTAGES OF LEVODOPA-CARBIDOPA COMBINATION
• Plasma t1/2 prolonged; dose reduced to 1/4th
• DA conc. in periphery ↓ → Nausea/vomiting & cardiac complications
negligent
• Sustained DA levels in brain → ↓ “wearing off” phenomenon

23. NON-ERGOT ALKALOIDS
PRAMIPEXOLE (D3 receptor); ROPINIROLE, ROTIGOTINE
• First line treatment in mild PD/young patients
• Addition to low dose levodopa-carbidopa combination
ADVANTAGES OVER LEVODOPA
1. Do not require enzymatic conversion to an active metabolite →
No dependance on functional capacities of nigrostriatal neurons
2. Do not have to compete for active transport
3. Their duration of action is substantially longer (8-24 hours) than
that of levodopa
4. Advanced PD → counter end-of-dose akinesia/on-off
phenomena due to levodopa

24. APOMORPHINE
• Indication – Temporary relief of off-periods of akinesia in patients
on optimized dopaminergic therapy (rescue medication)
NON-ERGOT ALKALOIDS - ADVERSE EFFECTS
• Similar to those seen with levodopa → nausea, hallucinosis &
confusion, postural hypotension
• Impulse control disorders → gambling disorders, compulsive
shopping or hypersexuality enhanced by activation of D2 or D3
dopamine receptors
• Somnolence (rare) → discontinuation of the drug

25. CATECHOL-O-METHYL TRANSFERASE (COMT) INHIBITORS
• Carbidopa → inhibits dopa decarboxylase → Levodopa metabolized to
3-O-methyldopa (3-OMD) by COMT
• COMT inhibitors - TOLCAPONE & ENTACAPONE → block peripheral
conversion to 3-OMD → ↑ both plasma t1/2 of levodopa & fraction of
each dose that reaches CNS
• Stalevo (FDC) → Levodopa + Carbidopa + Entacapone
MONOAMINE OXIDASE B (MAO-B) INHIBITORS
• MAO-B inhibitors - SELEGILINE & RASAGILINE → inhibit MAO-B
present in the striatum irreversibly → prevent breakdown of
dopamine

26. ATTENTION DEFICIT/HYPERACTIVITY
DISORDER (ADHD)
• Less than optimal stimulation of postsynaptic D1 receptors by
dopamine in the prefrontal cortex
• Pharmacotherapy - DOPAMINE REUPTAKE INHIBITORS
d-METHYLPHENIDATE
• Piperidine derivative, structurally related to amphetamine
• Blocks the reuptake pumps NET & DAT allosterically → prevents DA
reuptake → ↑ synaptic availability of DA
• Extended release tablets & transdermal formulations used → slow
onset & long duration of action → limits its abuse potential

27. DEXAMPHETAMINE
• d-isomer form of amphetamine → more potent on DAT binding
• It acts as a pseudosubstrate for both NET & DAT → bind at the same
site for DA → taken up into the presynaptic DA terminal → inhibit
dopamine uptake
LISDEXAMFETAMINE
• Prodrug of dexamphetamine, linked to the amino acid lysine
• Cleaved to dexamphetamine in the stomach → slower onset of action
→ reduced abuse potential

28. DOPAMINE RECEPTOR ANTAGONISTS
Indicated in the treatment of
• Schizophrenia
• Huntington’s chorea
• Tourette’s syndrome
• Emesis

29. SCHIZOPHRENIA
• ↑ DA in mesolimbic pathway → positive symptoms of psychosis in
schizophrenia
• Pharmacotherapy – TYPICAL ANTIPSYCHOTICS
• Selectively block D2 receptors; also have weak antagonistic effects on 5-HT2A
receptors
• Blockade of about 80% of the D2 receptors in the striatum → therapeutic
effect
CHEMICAL CLASS DRUGS
Phenothiazines
Aliphatic Chlorpromazine, Triflupromazine
Piperidine Thioridazine, Mesoridazine
Piperazine Fluphenazine, Trifluoperazine
Thioxanthenes Thiothixene, Flupenthixol
Butyrophenones Haloperidol

30. SCHIZOPHRENIA – DOPAMINE HYPOTHESIS
• PET → ↑ DA receptor density in treated/untreated schizophrenics
• Postmortem studies of brains of schizophrenics → presence of ↑ DA
receptor densities
• Levodopa (DA precursor) or amphetamine (DA releaser) or
apomorphine (DA receptor agonist) → aggravate schizophrenia or
precipitate symptoms of schizophrenia in a normal person
• Early phase → D2 receptor blockade by typical antipsychotics → ↑
synthesis & release of DA → HVA & DOPAC in blood, urine & CSF
• DA builds up in synapse → feedback inhibition of DA release
(prolonged therapy)

31. ADVERSE EFFECTS
1. Extrapyramidal side effects
2. Hyperprolactinaemia due to D2 receptor blockade in the
tuberoinfundibular pathway
Due to block of nigrostriatal D2 receptors Due to to supersensitivity of D2
receptors in the striatum
Occur within first few weeks of treatment Develops months/years after
treatment; in 20-40%
Reversible Irreversible
Acute dystonias, akathesia, Rabbit syndrome,
Parkinson’s syndrome, Neuroleptic malignant
syndrome
Tardive dyskinesia

32. ARIPIPRAZOLE
• Partial agonist at D2
Mechanism of action:
• Reduces D2 receptor hyperactivation in mesolimbic pathway →
alleviates positive symptoms of schizophrenia
• Provides D2 receptor stimulation in mesocortical pathway → alleviates
negative symptoms
• Compared to typical antipsychotics, it causes less prolactin secretion
as well as less severe EPS

33. HUNTIGTON’S CHOREA
• Degeneration of GABAergic neurons in basal ganglia → loss of
GABA mediated inhibition → hyperactivity of dopaminergic
neurons
• TETRABENAZINE → reversible inhibitor of VMAT2 → depletes
dopamine stores
TOURETTE’S SYNDROME
• Characterized by chronic multiple tics
• Tics → supersensitivity of D2 receptors in basal ganglia &
prefrontal cortex
• Typical antipsychotics → PIMOZIDE (first line drug) and
HALOPERIDOL reduce the frequency and intensity of tics by 60%
• Adverse effects of pimozide same as haloperidol

34. EMESIS
Dopamine receptor antagonists used to treat emesis are categorized
into
• Block D2 receptors in chemoreceptor trigger zone → Relief of nausea
& vomiting
TYPICAL ANTIPSYCHOTICS PROKINETIC DRUGS
Chlorpromazine, Levomepromazine Metoclopromide
Perphenazine Domperidone
Prochlorperazine, Trifluoperazine
Haloperidol, Doperidol

35. ROLE OF DOPAMINE
1. DEPRESSION - Anhedonia, ↓ ability to conc. & motivation → ↓ DA
activity
• Pramipexole - High doses; treatment-resistant depressive episodes in
unipolar and bipolar depression
2. ALZHEIMER’S DISEASE
• Early stages: Aβ peptides → ↓ glutamate release → ↓ DA in Nucleus
Acc. & PFC → Apathy
• Later stages: hyperphosphorylation of tau proteins →
neurodegenerative changes in substantia nigra → EPS in 35-40%
cases

36. THANK YOU.

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