D2 Receptors in Psychopharmacology

Authors:  Kiran Panesar, BPharm, MRPharmS, RPh, CPh and Flavio Guzman, MD

Last updated: February 9, 2018

Dopamine receptors can be divided into two classes (D1-like and D2-like) on the basis of their biochemical and physiological effects. In this article we discuss D2-like receptors, their pharmacodynamics and how they relate to pathological disease processes such as schizophrenia and Parkinson’s disease.

With a better understanding of the pathways behind the normal functioning of the receptors, researchers endeavor to develop novel drugs that can be used to appropriately manage associated pathological conditions.

Structural Features and Pharmacodynamics

Dopamine receptors are divided into two major subfamilies: D1-like and D2-like.

Dopamine receptors are divided into two major subfamilies: D1-like and D2-like.

Dopamine is a catecholamine neurotransmitter that mediates physiological functions in both the central and peripheral nervous system by interacting with dopamine cell surface receptors. Dopamine receptors are metabotropic G-protein coupled receptors (GPCRS) that are classified into D1-like and D2-like receptors based upon their biochemical, pharmacological and physiological effects.

D2 receptors are G-protein coupled receptors

D2 receptors are G-protein coupled receptors

GPRCS are made up of seven membrane spanning segments whereby the amino (N) terminal is extracellular and the carboxyl (C) terminal is intracellular. One of the intracellular loops is larger than the rest and it is this loop that interacts with the G-protein. G-proteins are made up of three protein subunits, α,β and γ whereby the βγ subunit serves to anchor the protein into the membrane. G proteins are functionally classified into several classes such as Gαs and Gαi.

D2 receptors-structure 2

D2 receptors: intracellular signalling (illustration is simplified for didactic purposes)

The D2-like receptor subfamily includes D2, D3 and D4 receptors, which are specifically coupled to Gαi and Gα0 proteins. Upon ligand binding, Gα proteins promote the replacement of GDP by GTP and the α-subunit dissociates from the βγ complex. At this point both the α-subunit and the βγ-complex are free to transduce a signal and activate a number of effector systems. The Gαi and Gαo subfamilies downregulate the production of cyclic AMP via the inhibition of adenyl cyclase (AC), leading to a reduced activation of protein kinase A (PKA).

PKA plays an extensive role in neuroplasticity which it achieves through several other pathways. Moreover, the Gβγ subunit complex activates phospholipase C (PLC) leading to the production of inositol triphosphate (IP3) that phosphorylates other targets further along the signaling cascade.

Location of D2 Receptors in the Human Brain

The different sub-types of D2 receptor possess broad and varied anatomical distribution patterns in the brain and periphery. D2 are highly expressed in the caudate, putamen (basal ganglia), nucleus accumbens, ventral tegmental area and the substantia nigra and in lower concentrations in the septal region, amygdala, hippocampus, thalamus, cerebellum and cerebral cortex. Specifically in the cerebellum the highest concentrations are in lobules IX and X.

D3 receptors have a more limited pattern of distribution and favor limbic expression such as the nucleus accumbens. Lower levels are detectable in the substantia nigra, ventral tegmental area, septal region, thalamus, cerebellum and cerebral cortex.

D4 has the lowest level of expression in the brain. It is found in moderate levels in the hippocampus, substantia nigra, nucleus accumbens, ventral tegmenta area, amygdala and frontal cerebral cortex.


Dopamine receptors are target of action for drugs used to treat schizophrenia and Parkinson’s disease in addition to other disorders such as substance abuse, depression, Tourette’s syndrome and attention deficit hyperactivity disorder (ADHD).


Schizophrenia is a disabling psychiatric disorder characterized by a myriad of positive, negative and cognitive symptoms that can be attributable to an imbalance between dopaminergic pathways that signal D2 and D1 receptors.

According to the classical theory, the positive symptoms of schizophrenia are attributable to hyperactivity of dopamine at D2 receptors in the mesolimbic pathway. This occurs in different stages including changes in dopamine synthesis, dopamine release, as well as the dopamine D2 receptors. Advances in neurochemical imaging studies have demonstrated that the presynaptic striatial dopamine availability is increased. Following this it has been observed that in schizophrenia the release of dopamine from the striatial synapse is also increased, leading to an increase in the baseline occupancy of D2 receptors by dopamine.

At the receptor level, an increase in striatial D2 and D3 receptor density in schizophrenic patients has been described. Alongside this, a higher sensitivity of existing postsynaptic dopamine D2 receptors and an increase in the proportion of dopamine D2 receptors that are in a high affinity state has been recorded.

Hypothetically, the negative and cognitive symptoms associated with schizophrenia are attributable to hypo stimulation of D1 receptors.

Parkinson’s disease

Parkinson’s disease (PD) is an extrapyramidal motor disorder characterized by dopaminergic neuronal degeneration in the substantia nigra. Most of the dopaminergic projections are found in the striatum, degeneration of the cells tends to follow a pattern with the highest degree of dopaminergic depletion being seen in the dorso-lateral putamen. There is very little change in the dopaminergic neurons in the mesolimbic and mesocortical systems.

It has been shown that D2 dopamine receptor density is altered in the basal ganglia in patients with PD. This is a complex change that is thought to be dependent upon the stage of the disease.

When neurons die, the D2 receptors located on the nigrostriatial terminals are lost. However, further along the disease, the concentration of the D2 receptors in the striatal region increases, possibly due to an up regulation of postsynaptic D2 receptors. In addition, the coupling of D2 receptors to Gαi may be enhanced and the remaining D2 receptors are super sensitized.

The loss of D2 receptors means a reduction in inhibitory control over corticostriatal transmission and enhanced glutamatergic activity.

List of D2 agonists and antagonists

This list serves as an example of drugs in clinical use that have the ability to bind to D2 receptors.


  • Bromocriptine
  • Cabergoline
  • Pramipexole
  • Ropirinole
  • Apomorphine

Partial agonist


Learn more about CNS receptors


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