The document provides an overview of dopamine, including its synthesis, receptors, pathways, and the disorders associated with dopamine dysregulation such as Parkinson's disease and schizophrenia. Key pathways mentioned are the mesolimbic, mesocortical, and nigrostriatal pathways, with stated roles in motivation, reward, and movement regulation. It also highlights the involvement of dopamine in ADHD and how imbalances can lead to cognitive difficulties and behavioral issues.

1. DOPAMINE
DR HARI RAM SEDAI
1ST
YEAR RESIDENT
PSYCHIATRY/NMCTH

2. Content
Introduction
Dopamine synthesis
Dopamine receptors
Dopamine pathways
Disorder of Dopamine Pathways

3. History
First Synthesized in
1910 by
George Barger and
James Ewens
Recognized as a
Neurotransmitter in
1958 by
Arvid Carlsson and
Nils Ake Hillarp

4. Introduction
• Chemically derived from an amino acid
• Belongs to a small family of related compounds known as
catecholamine
• Contains a catechol group (benzene ring with two adjacent
hydroxyl groups) and an amine group

5. Majority of dopaminergic innervation in the
brain is provided by long projection neurons
arising from:
• Midbrain (mesencephalon)
• Substantia nigra
• Ventral tegmental area

6. Dopaminergic sites
 Brain
• Midbrain
• Substantia nigra
• Ventral tegmental area
• Periaqueductal gray
• Hypothalamus
 Outside Brain
• Olfactory bulb
• Retina
• Kidney (Adrenal medulla)

7. Dopamine Synthesis
• Synthesized from Tyrosine
• Precursor: L-dopa
• Rate limiting enzyme: Tyrosine
hydroxylase
• Final step: Decarboxylation from
L-dopa
• Co-factor involved: Pyridoxal
phosphate

8. • Tyrosine is derived from dietary protein & Phenylaline metabolism
• Enters brain by Large neutral amino acid (LNAA) metabolism
• In cytosol: Tyrosine converted to L-dopa by tyrosine hydroxylase
• Next step: Decrboxylation of L-dopa by aromatic amino acid
decarboxylase (AADC)
• AADC decarboxylates L-dopa so avidly that the level of this amino
acid in the brain is very low under normal conditions

9. Transportation
• VMAT2: Storage and release
• DAT: Reuptake
• Presynaptic D2 Auto receptor:
Regulates release of DA

10. Vesicular Transport
• Vesicles in presynaptic terminal is specialized for the uptake and
storage of catecholamines by enzyme Monoamine oxidase (MAO)
found in mitochondria
• Vesicular monoamine transporter (VMAT)- accumulation and
concentration of catecholamine transmitters inside the vesicles
2 Forms:
• VMAT-1- expressed in extraneuronal tisuue - chromaffin cells
• VMAT-2- neuronal cells of cns, pns, enteric nervous system

11. Degradation
 Centrally: MOA A & MOA B (Mitochondria
of presynaptic neuron)
• MOA-A- located in dopaminergic and non
adrenergic neurons
• MOA-B: Located in serotonergic neurons
& glia
 Peripherally: COMT (extracellular)
 End product: Homovanillic acid

12. Monoamine Oxidase (MAO)
• Located on outer membrane of mitochondria
• MAO-A & MAO-B (Major form)
• Dopamine and norepinephrine are effective substrates for both
forms
• Serotonin is a preferential substrate for MAO-A
• MAO-B inhibitor that is used in the treatment of Parkinson disease,
usually in combination with L-dopa to prolong or enhance the
effect of dopamine formed from L-dopa

13. Catechol-O-Methyl Transferase (COMT)
• Membrane bound form has higher affinity for catecholamines
• COMT plays a more significant role in dopamine metabolism in the
prefrontal cortex
• COMT inhibitors- Tolcapone and Entacapone, are used as adjuncts
to L-dopa in the treatment of Parkinson disease to slow L-dopa
metabolism and thereby prolong its effects

14. Dopamine Receptors
 D1 like
• D1 & D5
• Nigrostriatal, mesolimbic, and mesocortical system
 D2 like
• D2, D3, D4
• Striatum and nucleus accumbens

15.  D1 like Dopamine receptors
• Activate the Gs family of G proteins
• Increase adenylate cyclase activity
• Found postsynaptically on dopamine-receptive cells
 D2-like Dopamine receptors
• Couple to the Gi family
• Inhibit adenylate cyclase activity
• Expressed both postsynaptically on dopamine-receptive cells &
presynaptically on dopaminergic neurons

17. AADC: Aromatic amino acid
decarboxylase
AC: Adenylate cyclase
COMT: Catechol-O-
methyltransferase
DOPAC: Dihydroxyphenylacetic acid
HVA: Homovanillic acid
MAO: Monoamine oxidase
VMAT: Vesicular monoamine
transporter.
Schematic model of a dopaminergic synapse with sites of drug action

18. Dopaminergic Pathways
Nigrostriatal Pathway
Mesolimbic Pathway
Mesocortical Pathway
Tuberoinfundibular Pathway

20. Mesolimbic Pathway
• Carries dopamine from the Midbrain Ventral Tegmental Area to the
Nucleus Accumbens via amygdala and hippocampus
• Motivations, pleasure, reward
• Positive symptoms (hallucinations, delusions) of schizophrenia
• Positive symptoms (Impulsive, agitation, aggressive & hostile) of
psychosis

21. Mesocortical Pathway
• Projects from Ventral Tegmental Area to Prefrontal Cortex
• Regulates motivation, concentration and initiation of goal-
directed and complex executive cognitive tasks
• Believed to be involved in the negative, cognitive and affective
symptoms of schizophrenia

22. Nigrostriatal Pathway
• Projects from Substantia Nigra (Pars compacta) to Striatum (Caudate
& putamen)
• It is part of the extrapyramidal nervous system and plays a key role in
regulating movements
• When dopamine is deficient, it can cause parkinsonism with tremor,
rigidity, and akinesia/bradykinesia
• When DA is in excess, it can cause hyperkinetic movements like tics
and dyskinesias.

23. Tubulofundibular Pathway
• Projects from Arcuate Nucleus and
the Periventricular area of
Hypothalamus to Infundibulum and
Anterior pituitary
• It regulates prolactin secretion into
circulation by inhibiting prolactin
secretion Anterior Pituitary
Infundibulum
Hypothalamus

24. Reward Pathway
• The dopaminergic pathway mostly involved in reward is Mesolimbic
System
• Formed by projections of midbrain dopamine neurons of the ventral
tegmental area (VTA) to the striatum, prefrontal cortex, amygdala,
hippocampus
• When rewarding stimuli are experienced, the dopaminergic
mesolimbic system is activated which causes the release of
dopamine to the targeted nuclei

25. • The ventral striatum, including the nucleus accumbens (NAcc), is
a major substrate involved in reward pathway
• The dorsal striatum is critically involved in action selection and
initiation components of decision making
• Mediates feedback properties such as valiance and magnitude in
addition to controlling habitual behaviour

26. Parkinson disease
• Degeneration of dopaminergic neurons in the substantia nigra
• Dysfunction in dorsal striatal dopamine transmission
• Hypokinesia, rigidity, and tremor originate from a loss of striatal
dopaminergic innervation

27. Schizophrenia
• Excessive dopamine activity in striatal and limbic regions
• Psychosis symptoms of schizophrenia were associated with
increased dorsal/associative striatum dopamine release
• Negative symptoms and cognitive impairments were associated
with reductions in cortical and ventral/limbic striatal dopamine
release

28. ADHD
• Dysfunction of dopaminergic neurotransmission in limbic and cortical
regions
• Less than optimal stimulation of Postsynaptic D1 receptors by Dopamine
in Prefrontal cortex
• Deficiency in dopamine levels, which affects their ability to experience
reward and motivation
• This deficiency can lead to difficulties in focusing, completing tasks, and
regulating behaviour

29. References
• Kaplan & Sadock’s Comprehensive Textbook Of Psychiatry, 11th
edition
• Stahl's Essential Psychopharmacology: Neuroscientific Basis and
Practical Applications 4th Edition
• Textbook of Medical Physiology, Guyton and Hall, 12th edition