The document discusses dopaminergic pathways and receptors in the central nervous system. It describes four main dopaminergic pathways, their functions, and the dopamine receptor subtypes involved in various functions like locomotion, learning, and endocrine control. It then discusses non-CNS functions of dopamine in systems like the cardiovascular and renal systems. The roles of dopamine agonists and antagonists in clinical conditions like Parkinson's disease and schizophrenia are outlined. Finally, it summarizes how abnormalities in dopaminergic neurotransmission can contribute to diseases and conditions like attention deficit hyperactivity disorder, addiction, hypertension, pain, nausea, and Parkinsonism.

1. Dopaminergic Receptors
By-
Pallavi S. Rane
NIPER- Ahmedabad

5. Dopaminergic pathways in CNS
P, Pituitary gland; Ac, nucleus accumbens; SN, substantia nigra; VTA, ventral
tegmental area; Am, amygdaloid nucleus; C, cerebellum; Hyp, hypothalamus;
MFB, medial forebrain bundle; Str, corpus striatum

6. Four main dopaminergic pathways in the brain
1. The nigrostriatal pathway, consists of cell bodies largely in the substantia
nigra whose axons terminate in the corpus striatum. These fibres run in the
medial forebrain bundle along with other monoamine containing fibres.
Function: motor control
2. The mesolimbic pathway, whose cell bodies occur in the midbrain ventral
tegmental area (VTA), whose fibres project via the medial forebrain bundle to
parts of the limbic system, especially the nucleus accumbens and the
amygdaloid nucleus.
Function: behavioural effects
3. The mesocortical pathway, whose cell bodies also lie in the VTA and which
project via the medial forebrain bundle to the frontal cortex.
Function: behavioural effects
4. The tuberohypophyseal (or tuberoinfundibular) system is a group of short
neurons running from the ventral hypothalamus to the median eminence and
pituitary gland, the secretions of which they regulate.
Function: endocrine control

8. Functions of Dopamine receptors
Functions Type of receptors involved
Locomotion D1, D2, D3
Learning and memory D1, D2
Cognition D3, D4, D5
Attention, impulse control, decision
making,
motor learning, sleep, reproductive
behaviors and the regulation of food
intake
D1, D2, D3, D4, D5
hormonal regulation, such as
the regulation of prolactin secretion;
renin secretion;
aldosterone secretion
D2
D1
D2
regulation of renal function; blood
pressure
regulation; vasodilation; and
gastrointestinal motility
D1, D2, D4

9. Non-CNS functions of Dopamine
1) Cardio-pulmonary system
In humans, the pulmonary artery expresses D1, D2, D4 receptors, which
may account for vasodilatory effects of dopamine in the blood.
D4 receptors have been identified in the human heart. Dopamine
increases myocardial contractility and cardiac output, without changing heart
rate, by signaling through dopamine receptors.
2)Renal system
Dopamine receptors are present along the nephron in the kidney,
with proximal tubule epithelial cells showing the highest density. Dopamine
signaling affects diuresis and natriuresis.

10. Dopamine Agonist Major Clinacal implications
Apomorphine PD, erectile dysfunction
Bromocriptine PD, pituitary tumors, hyperprolactinemia,
type
2 diabetes
Cabergoline Pituitary tumors, hyperprolactinemia
Fenoldopam Hypertension
Pramipexole PD, restless legs syndrome, bipolar disorder,
depression
Pergolide PD
Ropinirole PD, restless legs syndrome
Rotigotine PD, bipolar disorder and depression

11. Dopamine Antagonist Major Clinical implications
Amisulpride, Aripiprazole, Olanzapine,
Ziprasidone, Quetiapine
Schizophrenia, bipolar disorder, depression
Chlorpromazine, Clopenthixol,
Clozapine, Promazine, Droperidol,
Haloperidol
Schizophrenia
Domperidone, Metoclopramide Nausea
Risperidone Schizophrenia, bipolar disorder
Prochlorperazine Schizophrenia, nausea
Sulpiride Schizophrenia, depression

12. Dopamine receptors in disease
1) Attention-deficit hyperactivity disorder (ADHD)
(ADHD) appears to be related to two neurotransmitters - Dopamine and
Norepinephrine.
In ADHD children, both systems of stimulation and repression are not working
correctly. Studies suggest that ADHD Children/Adults may have only ten to twenty-
five percent of these two neurotransmitters found in the normal brain.
In attention and distractibility appear to be related to low levels of Norepinephrine.
The impulse and behavior problems is found due to low levels of Dopamine in the
brain
Drugs used to treat ADHD, including methylphenidate and amphetamine, have
significant effects on neuronal dopamine signaling.

13. 2) Schizophrenia
Abnormally high dopaminergic transmission has been linked to psychosis.
Increased dopaminergic functional activity, specifically in the mesolimbic
pathway, is found in schizophrenic individuals. However, decreased activity in
the mesocortical pathway, may also be involved.
Drugs such as amphetamines, methamphetamine and cocaine, which can
increase dopamine levels by more than tenfold, can temporarily cause psychosis.
Many non-dopaminergic drugs can induce acute and chronic psychosis.
Eg: NMDA antagonists Ketamine is used in research to produce symptoms
commonly associated with schizophrenia.
Antipsychotic medications act largely as dopamine antagonists, inhibiting
dopamine at the receptor level.
 The typical antipsychotics most commonly act on D2 receptors,
 The atypical drugs also act on D1, D3 and D4 receptors, though they have a
lower affinity for dopamine receptors in general.

14. 3) Addictive drugs
Dopamine is the primary neurotransmitter involved in the reward pathway in the
brain. Thus, drugs that increase dopamine signaling may produce euphoric effects.
Many recreational drugs, such as cocaine and substituted amphetamines, inhibit
the dopamine transporter (DAT), the protein responsible for removing dopamine
from the neural synapse.
When DAT activity is blocked, the synapse floods with dopamine and increases
dopaminergic signaling.
 When this occurs, particularly in the nucleus accumbens, increased D1 and
decreased D2 receptor signaling mediates the "rewarding" stimulus of drug intake.
4) Genetic hypertension
Dopamine receptor mutations can cause genetic hypertension in humans.
Cells use the DRD4 gene to make dopamine receptor.
People having an extra long form of this gene have shown high blood pressure
as this gene is also found to play role in regulating release of salt by the kidneys.

15. 5) Pain
Decreased levels of dopamine have been associated with painful symptoms that
frequently occur in Parkinson's disease.
 Abnormalities in dopaminergic neurotransmission have also been demonstrated
in painful clinical conditions, including burning mouth syndrome, fibromyalgia, and
restless legs syndrome.
In general, the analgesic capacity of dopamine occurs as a result of dopamine
D2 receptor activation.
In addition, D1 receptor activation in the insular cortex appears to attenuate
subsequent pain-related behavior.

16. 6) Nausea
Nausea and vomiting are largely determined by activity in a brainstem area
known as the chemoreceptor trigger zone as this area contains a large
population of type D2 dopamine receptors.
 Consequently, drugs that activate D2 receptors have a high potential to cause
nausea. This group includes some medications that are administered
for Parkinson's disease, as well as other dopamine agonists such
as apomorphine.
 In many cases, D2-receptor antagonists such as metoclopramide and
domperidone are useful as anti-nausea drugs.

17. 7) Parkinsonism
It is a slowly progressive neurodegenerative disease characterized by rigidity,
tremor, hypokinesia with secondary manifestations like defective posture and gait.
The motor symptoms of Parkinson’s disease result due to loss of dopaminergic
neurons in the substantia nigra and degeneration of nerve terminals.
This leads to an imbalance in dopaminergic and cholinergic system which causes
all the symptoms.

18. Drugs to treat Parkinsonism

19. References
David R. Sibley, 2011, The Physiology, Signaling, and Pharmacology of
Dopamine Receptors; The American Society for Pharmacology and Experimental
Therapeutics, pp. 63:182–217.
Rang and dale’s Pharmacology; 2012; seventh edition; Elsevier Inc; pp. 463-
466; 485-487.
Cristina missale; 1998; Dopamine Receptors: From Structure to Function;
Physiological reviews; Vol. 78.
Pandey et al.; 2013; A synergistic approach towards understanding the
functional significance of dopamine receptor interactions; Journal of Molecular
Signaling, pp. 8-13.

20. Thank You