Dopaminergic Receptors

By-Pallavi S. Rane

NIPER- Ahmedabad

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

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

Functions of Dopamine receptorsFunctions Type of receptors involvedLocomotion 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 asthe regulation of prolactin secretion;

renin secretion; aldosterone secretion

D2D1D2

regulation of renal function; blood pressure

regulation; vasodilation; and gastrointestinal motility

D1, D2, D4

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.

Dopamine Agonist Major Clinacal implicationsApomorphine 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

Dopamine Antagonist Major Clinical implicationsAmisulpride, Aripiprazole, Olanzapine,

Ziprasidone, QuetiapineSchizophrenia, bipolar disorder, depression

Chlorpromazine, Clopenthixol, Clozapine, Promazine, Droperidol,

Haloperidol

Schizophrenia

Domperidone, Metoclopramide Nausea

Risperidone Schizophrenia, bipolar disorder

Prochlorperazine Schizophrenia, nausea

Sulpiride Schizophrenia, depression

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.

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. 

3) Addictive drugsDopamine 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 hypertensionDopamine 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. 

5) PainDecreased 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.

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.

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 dopaminergicneurons in the substantia nigra and degeneration of nerve terminals.

This leads to an imbalance in dopaminergic and cholinergic system which causes all the symptoms.

Drugs to treat Parkinsonism

References

David R. Sibley, 2011, The Physiology, Signaling, and Pharmacology ofDopamine 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.

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