This document provides an overview of the pharmacology of dopamine. It discusses dopamine synthesis, receptors, pathways in the brain, and the role of dopamine in conditions like Parkinson's disease, schizophrenia, and addiction. Dopamine is synthesized from phenylalanine and tyrosine and acts on D1-like and D2-like receptors in the mesolimbic, mesocortical, and nigrostriatal pathways. Imbalances in dopaminergic signaling are implicated in disorders such as Parkinson's, schizophrenia, and ADHD. Drugs that modify dopamine transmission are used to treat these conditions.

1. PHARMACOLOGY OF DOPAMINE
Dr.Sumit Wankhede
JR3,
sumeetwankhede@gmail.com
8308833593
IGGMC,Nagpur

2. OVERVIEW
• Introduction
• Synthesis
• Dopamine receptors
• Dopaminergic pathways
• Drug related to dopamine system
• Recent Researches
• Conclusion
2

3. INTRODUCTION
 Dopamine belongs to the family of
catecholamines
 Hormones, Epinephrine and Norepinephrine
(other catecholamines) are derived from
Dopamine
 Significant role in learning, goal-directed
behavior, regulation of hormones, motor control
3

4. DA SYNTHESIS AND METABOLISM
L phenylalanine (amino acid from diet)
phenyalanine hydroxylase
L- Tyrosine
Tyrosine hydroxylase RLS
L Dopa
Dopa decarboxylase
Dopamine (DA)
Monoamine oxidase (MAO)
Catechol-O-methyl transferase (COMT)
DOPAC + HVA

5. After synthesis, dopamine is packaged into synaptic vesicles via the
vesicular monoamine transporter (VMAT2) and stored there until its
release into the synapse during neurotransmission.

7. DOPAMINE RECEPTORS
• Metabotropic G-protein coupled receptors
• D1 – like family:
– Includes subtypes D1 and D5
– Activation is coupled to Gs ; activates adenylyl
cylcase which leads to increase in concentration of
cAMP
• D2 – like family:
– Includes D2, D3 and D4
– Activation is coupled to Gi ; inhibits adenylyl cyclase
leading to decrease in concentration of Camp
– Also open K channels & closes Ca influx
7

8. DOPAMINE RECEPTORS
8

9. Subtypes Location Function
D1 Putamen, nucleus
accumbens i.e
nigrostrial pathway
Inhibition causes
extrapyrimidal
disorders
D2 Striatum, substantia
nigra , pituitary
Control
behaviour,voluntary,
prolactin release
D3 Midbrain, mucleus
accumbens &
hypothalamus
D4 Frontal cortex,
medulla and
midbrain i.e
mesocortical pathway
D5 Hypothalamus ,
hippocampus

10. DOPAMINERGIC PATHWAYS
• Mesolimbic Pathway
• Mesocortical Pathway
• Nigrostriatal Pathway
• Tuberoinfundibular
Pathway
• Incertohypothalamic
Pathway
• Medullary
Periventricular
• Retinal
10

12. SIGNIFICANCE OF DOPAMINERGIC
PATHWAYS
• Mesolimbic Pathway
– Associated with pleasure, reward and goal directed
behaviour
• Mesocortical Pathway
– Associated with motivational and emotional
responses
• Nigrostriatal Pathway
– Involved in coordination of movement (part of basal
ganglia motor loop/EPS)
• Tuberoinfundibular Pathway
– Regulates secretion of prolactin by pituitary gland
and involved in maternal behavior
12

13. DRUGS MODIFYING DOPAMINERGIC
TRANSMISSION
Mechanism Drug Effect Use
Synthesis L-DOPA ↑ Synth Parkinsons disease
2 methyl-p-
tyrosine
Inhibits tyrosine
hydroxylase
expts
Carbidopa ,
Benserazide
Inhibit dopa
decarboxylase
Parkinsonism
Storage Reserpine,
Tetrabenzine
Disrupt storage Tranquilizer
MAO inhibitors Enhance storage
Release Amphetamine,
Tyramine,
Mazindole
Release
dopamine on
receptors
Anorectic, CNS
stimulant

14. DRUGS MODIFYING DOPAMINERGIC
TRANSMISSION
Mechanism Drug Effect Use
Inactivation of
uptake
Amphetamine,
Cocaine,
CNS stimulant
Anorectic
Benztropine
Benzhexol
Parkinson's
disease
Inactivation of
metabolism
Iproniazid,
Tranylcypromine,
Nonselective
MAO inhibitors
Selegiline MAO inhibitors Parkinson's
disease

15. SCHIZOPHRENIA
 Defective dopamine neurotransmission – relative
excess of central dopaminergic activity
 An increase in DA function in the mesolimbic
system and a decreased function in the
mesocortical DA systems(D1 predominates)
 Behavior similar to the behavioral effects of
psychostimulants
15

16. DOPAMINE HYPOTHESIS
OF SCHIZOPHRENIA

17. DOPAMINE ANTAGONISTS IN SCHIZOPHRENIA
Antipsychotic
Typical
Mechanism of
action
effects toxicity
Phenothiazines
:
-chlorpromazine
-fluphenazine
-thioridazine
Thioxanthenes
Thiothixene
flupenthixol
Blockade of
D2>>5HT2A
Also blocker of
alpha,M,H1.
Akathisia,Dyston
ia, parkinson
symptom ,tardive
dyskinesia,
hyperprolactine
mia
Butyrophenone
s
Haloperidol
Droperidol
domperidone
Blockade of
D2>>5HT2A
Alpha and
minimal M
blockade
Extrapyrimidal
dysfunction

18. Antipsychotic
Atypical
Mechanism of
action
effects toxicity
Aripiprazole
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Blockade of
5HT2A>D2
Some alpha
and M
blockade and
variable H1
blockade
Agranulocytosi
s(Clozapine),W
eight gain, low
seizure
threshold,catra
ct,QT
prolongation

19. PARKINSON’S DISEASE
 Parkinson’s sufferers have low levels
of dopamine
 L-dopa raises DA activity
 People with Parkinson's develop
schizophrenic symptoms if they take
too much L-dopa

20. PARKINSON’S DISEASE
 Substantial loss of Dopamine in the striatum (70
– 80%)
 Loss of dopamine neurons in other systems also
(mesolimbic, mesocortical and hypothalamic
systems)
20

21.  Treatment strategy includes –
 increasing dopamine levels
 nerve grafting with dopamine containing cells
and
 deep brain stimulation

22. subclass effect Pharmacokinetic, toxicity and
interaction
Levodopa
levodopa+Car
bidopa
-Ameliorates all symptoms
of Parkinson's disease
-significant peripheral
dopaminergic effects
Carbidopa inhibits
peripheral metabolism of
levodopa
Oral ~ 6–8 h
Toxicity: GI upset, arrhythmias,
dyskinesias, on-off and wearing-off
phenomena, behavioral disturbances
Interactions: Use with carbidopa
greatly diminishes required dosage,
Use with COMT or MAO-B inhibitors
prolongs duration of effect.
Dopamine
agonists
Pramipexole
(D3Agonist)
Reduces symptoms,
Smooths out fluctuations
in levodopa response
Oral ~ 8 h
Toxicity: Nausea and vomiting,
postural hypotension, dyskinesias
Ropinirole
Bromocriptine
Apomorphine

23. subclass effect Pharmacokinetic,
toxicity and interaction
MAO inhibitors
Selegiline
Rasagiline
Increases dopamine
stores in neurons;
Oral
Toxicity & interactions:
may cause serotonin
syndrome with meperidine
also with SSRIs, tricyclic
antidepressants
COMT inhibitors
Entacapone
Tolcapone
Reduces metabolism of
levodopa and prolongs its
action
Enters CNS
Oral
Toxicity: Increased
levodopa toxicity nausea,
dyskinesias, confusion

25.  Other motor disorders:
 Huntington’s disease
 Tourrette’s syndrome
 D2 Blockers –Chlorpromazine , Haloperidol

26. MOTOR CONTROL OF DOPAMINE

27. ATTENTION DEFICIT HYPERACTIVITY
DISORDER
 Altered dopamine neurotransmission is implicated
in attention deficit hyperactivity disorder (ADHD)
 There are some genetic links between dopamine
receptors, the dopamine transporter and ADHD.
 Some of the most effective therapeutic agents for
ADHD are psychostimulants->
methylphenidate and amphetamine : increase both
dopamine and norepinephrine levels in brain.

28. DOPAMINE AND ADDICTION
 Almost all dependence producing drugs
mesolimbic dopaminergic projection to ventral
striatum --- mechanisms for addiction
 Psychostimulants such as Cocaine and
Amphetamine -- alter dopamine activity in
brain
28

29. ROLE OF DOPAMINE IN VOMITING
PHENOTHIAZINES
• Phenothiazines as prochorperazine ,promethazine are
antipsychotic agents
• Use:
• Chemotherapy-induced vomiting
• Radiotherapy-induced vomiting
• postoperative nausea and vomiting
• Mechanism of the antiemetic action: inhibition of
central dopamine D2 on CTZ, muscarinic and H1
histamine receptors receptors

30. BUTYROPHENONES
• Butyrophenones as droperidole are antipsychotic
agents
• Mechanism of the antiemetic action: inhibition of
central dopamine receptors
• Use:
• Chemotherapy-induced vomiting
• Radiotherapy-induced vomiting
• postoperative nausea and vomiting
• Adverse effects: QT prolongation

31. PROKINETIC DRUGS
(Metoclopramide & domperidone)
The Prokinetic drugs produce the following
effects:
 Hasten esophageal clearance.
 Increase tone of the gastro-esophageal sphincter.
 Accelerate gastric emptying.
 Antiemetic effects by dopamine (D2) blockade.

32.  Antagonise D2 receptors in CTZ.
 Drugs available
Metoclopramide 2.5 mg b.d
Domperidone 10 mg b.d
 Domperidone – oral ; Metoclopramide – oral & i.v
 Metoclopramide crosses BBB but domperidone cannot.

33. ROLE OF DOPAMINE O PROLACTIN
SECRETION
 Inhibits secretion of prolactin by acting on D2
receptors.
 Treatment of hyperprolactinemia
 Ergot derivatives : bromocriptine, cabergoline,
pergolide.
 Non ergot : Quinagolide

34.  Cabergoline – 0.25(max 1) mg orally twice a week
 Quinagolide – 0.2 -0.6 mg orally per day
longer t1/2 , better toleratted than ergot derivative
 Bromocriptine 2.5 mg OD/BD upto 15 days.

35. ROLE OF DOPAMINE IN RENAL SYSTEM
 At low dose (0.5 to 3 micg /kg /min ):-
 Selectively activates dopamine specific
receptors in the renal and splanchnic circulation.
 Increase blood flow in these region.
 Increase GFR.
 Increase in urinary Na excretion

36. HEART AND VASCULATURE
 At low concentrations, circulating DA primarily
stimulates vascular D1 receptors, causing
vasodilation and reducing cardiac afterload.
 DA is able to activate adrenergic receptors to
further increase cardiac contractility.
 The net result is a decrease in blood pressure and
an increase in cardiac contractility.

37. RECENT RESEARCHES
 Anti-insulin
 Analgesic
 Role in apoptosis
 Memory
 Immune

38. CONCLUSION
 The scene is now set for the development of drugs
selective for particular receptor subtypes which
can be used to elucidate receptor subtype
function and treat disorders of dopamine function

39. REFERENCES
 Goodman and Gilman’s The Pharmacological Basis
of Therapeutics 12th edi; chap 15,16,22: 932-964
 Bertram Katzung ; Basic and clinical
pharmacology ; Drug of abuse ;553-568 ;12th
edition 2012.
 HL Sharma and KK;Antipsychotics ;2nd
edition;chap 33; 532-542.

40.  Rang H.P. and Dale M.M;Antipsychotics;7th
edition; 39,45,49; 557
 Blanca Rubí and Pierre Maechler; Minireview:
New Roles for Peripheral Dopamine on Metabolic
Control and Tumor Growth; Endocrinology,
December 2010, 151(12):5570–5581
 http://en.wikipedia.org/wiki/Dopamine
 Kaplan & Sadock's Comprehensive Textbook of
Psychiatry

41. THANK YOU