DOPAMINE RECEPTORSPHARMACOLOGY 1

By:- Manisha

M.Pharm. (Pharmacology) Deptt. of Pharmaceutical sciences

M.D. University Rohtak, 124001

Contents Dopamine Biosynthesis of dopamine Functions of dopamine Dopaminergic pathways Dopamine receptors Dopamine agonists Dopamine antagonists Dopamine related diseases

Dopamine

Dopamine is a monoamine neurotransmitter that upon binding to a dopamine receptor releases a variety of downstream signals.

Biosynthesis of dopamine

Dopamine is synthesized in a restricted set of cell type called dopaminergic neurons.

The metabolic pathway is: -

L-Tyrosine

L-DOPA

Dopamine

Functions of dopamine

Some of its notable functions are in: Movement Memory Pleasurable reward Behavior and cognition Inhibition of prolactin production Nausea and vomiting

Dopaminergic pathway

• Nigrostriatal pathway- substantia nigra to the caudate putamen (dorsal striatum) , primarily associated with motor acivity

• Mesolimbic pathways- VTA to the limbic areas of the brain (accumbens, ventral striatum and amygdala), associated with cognition and behavior

• Mesocortical pathway-VTA to the cortex (medial, prefrontal, cingulate and entorhinal cortex), associated with reward and schizophrenia

• Tuberoinfundibular pathway- arcuate and periventricular nuclei of the hypothalamus to the intermediate lobe of the pituitary and the median eminence, inhibitory control of prolactin

Dopaminergic pathways

Dopamine receptor

Dopamine receptors are a class of G protein-coupled receptors

Dopamine Receptor SubtypesD1- like family :• Includes subtypes D1 and D5• Activation is coupled to Gs ; activates adenylyl

cyclase which leads to increase in concentration of cAMP

• These receptor genes do not contain introns in their coding genes

D2- like family :• Includes D2, D3 and D4• Activation is coupled to Gi; inhibits adenylyl cyclase

leading in decreased concentration of cAMP• Genes that encodes these receptors contain introns

Locations and MOA of dopamine receptors

Receptors

D1 Like D2 likeD1 D5 D2 D3 D4

Locations

caudate/ putamen, nucleus accumbens, olfactory tubercle, hypothalamus, thalamus, frontal cortex

hippocampus, thalamus, lateral mamillary nucleus, striatum, cerebral cortex (all low)

caudate/ putamen, nucleus accumbens, olfactory tubercle, cerebral cortex (low)

nucleus accumbens, olfactory tubercle, islands of Calleja, cerebral cortex (low)

frontal cortex, midbrain, amygdala, hippocampus, hypothalamus, medulla (all low), retina

Response

adenylyl cyclase activated

adenylyl cyclase activated

adenylyl cyclase inhibited

adenylyl cyclase inhibited

adenylyl cyclase inhibited

Dopamine agonists

Act directly on dopamine receptors and mimic the endogenous neurotransmitter.

Bromocriptine Pergolide Lisuride Cabergoline Ropinirole Pramipexole

Dopamine antagonists

ProchlorperazinePerphenazineTrimethobenzamideMetoclopramideDroperidol

Dopamine related diseasesParkinson’s disease

Caused by the loss of dopaminargic neurons in the substantia nigra.

• Signs and symptoms- Rigidity, tremors, bradykinesia

Schizophrenia Hyperactive dopaminergic signal transduction• Signs and symptoms-  Hallucinations, delusions, disorganized

thinking and speech

Drug addiction Dopamine is the primary neurotransmitter involved

in the reward pathway in the brain. Recreational drugs (cocaine and substituted amphetamines) inhibit the dopamine transporter (DAT), the protein

responsible for removing dopamine from the neural synapse. synapse floods with dopamine

increases dopaminergic signaling (particularly in nucleus accumbens)

mediates the "rewarding" stimulus of drug intake.

Attention-deficit hyperactivity disorder

Due to decreased level of dopamine• Signs and symptoms Impaired cognitive control, attentional

control, inhibitory control, forgetting things or missing details

References

Marsden A. Charles, “Dopamine: the rewarding years”, British Journal Pharmacology, published online 2008 Jan 9, doi- 10.1038/sj.bjp.0706473

Missale Cristina, Nash S. Russel, “ Dopamine Receptor:From structure to function”, Physiological Reviews, Published 1 Jan 1998, vol. 78, no. 1, 189-225

Brisch Ralf, Saniotis Arthur,”The Role of Dopamine in Schizophrenia fron a Neurobiological and Evolutionary Perspective: old fashioned but still in vogye”, Published online 2014 May 19, doi. 10.3389/fpsyt 2014.00047