Dopamine receptor D2


The DRD2 gene encodes the D2 subtype of the dopamine receptor, which is coupled to Gi subtype of G protein-coupled receptor. 



This G protein-coupled receptor inhibits adenylyl cyclase activity.



The D2R mediates the cognitive flexibility in humans.



Agonism of D2 receptors inhibits dopamine release; antagonism increases dopaminergic release.



Diisorders in equilibration of D2R states, causes problems in signal transferring between the nervous systems, may lead to diverse serious disorders, such as Schizophrenia, autism and Parkinson’s disease.



Oligomerization of D2R has a main role in biological activities and any disordering in it may lead to mental diseases. 



Most of the older antipsychics are antagonists for the dopamine D2 receptor, but are, in general, very unselective.



Older antipsychotic drugs are selective only for the “D2-like family” receptors and so binding to D2, D3 and D4, and often also to many other receptors such as those for serotonin and histamine, resulting in a range of side-effects and making them poor agents.



Older dopamine agonists used for Parkinson’s disease such as bromocriptine and cabergoline are poorly selective for one dopamine receptor over another.



Several selective D2 ligands are available.



Drugs acting at dopamine D2 receptors (D2R) are commonly used to alleviate symptoms produced by diseases such as Parkinson’s disease, schizophrenia, and depression. 



Dopamine receptors are G protein-coupled receptors and belong to two main families: the D1-like receptor subfamily (D1R), including the D1 and D5 receptors; and the D2-like subfamily, including the D2, D3, and D4 receptors. 



The  primary action of dopamine is to activate neurons through the D1 receptor, and this activation is reduced by concurrent activation of the D2 receptor. 



Some neurons have only D2 or only D1 receptors.



D2/D1 antagonism is common



The D2R is present in many areas of the central nervous system.



It is primarily located in the substantia nigra pars compacta, the ventral tegmental area, the striatum, olfactory tubercule, and the pituitary gland.



D2R can be located both presynaptically, regulating release of dopamine and other neurotransmitters.



D2Rb can be located postsynaptically, where it can inhibit  long-term depression at midbrain excitatory synapses, to inhibition of calcium channels, to control of pacemaker activity and resting potential through activation of GIRK channels.



 Role of Dopamine D2 Receptors in Neurological and Psychiatric Diseases



Dopaminergic dysregulation is implicated in a number of neurological and psychiatric conditions, but no change in dopamine receptor levels has been observed. 



Dysregulation of dopamine signaling could also be due to alterations of the D2R.



Missense mutation in the DRD2 gene causes myoclonus dystonia.



Additional mutations at D2Rs have been associated with a variety of neurological and psychiatric diseases ranging from Parkinson’s disease to substance abuse, schizophrenia, and bipolar disorders.



It is held that every antipsychotic drug must inhibit D2Rs to be clinically effective for schizophrenia.



There is a clear dissociation between the relatively low therapeutic benefit and their high pharmacological selectivity as D2R antagonists.



Schizophrenia is associated with supersensitivity to dopamine.



Some antidepressants act in part by blocking dopamine reuptake and by activating dopamine receptors. 



Upregulation of D2Rs has been observed in patients suffering from depression. 



Enhancing dopamine signaling might represent a promising target to traditional antidepressants, especially when anhedonia and apathy are primary symptoms.



The links between dopamine signaling and depression are tenuous. 



Dopamine is important for motivation and responsiveness to appropriate stimuli, and decreased motivation and loss of responsiveness can be observed in depressed humans. 



Activation of D1 and D2 receptors produces a wide range of functional responses, dependent upon the activity state of the neurons: there is a role for both D2 and D1 in the nucleus accumbens in motivation and goal-directed behaviors.


















Partial agonists





















Atypical antipsychotics 



Domperidone – D2 and D3 antagonist.



Metoclopramide – Antiemetic – crosses Blood-brain Barrier – causes drug induced Parkinsonism.



Hydroxyzine (Vistaril, Atarax)






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