Current perspectives on the selective regulation of dopamine D2 and D3 receptors

Abstract

Among the characterized dopamine receptor subtypes, D₂ receptor (D₂R) and D₃ receptor (D₃R) are the main targets of neuroleptics that are currently in use. In particular, D₃R is closely related to the etiology of schizophrenia and drug addiction. The spatial expression patterns of D₂R and D₃R are distinct in certain areas of the brain. D₂R are heavily expressed in the regions responsible for motor functions, whereas D₃R are more selectively expressed in the limbic regions, which are associated with cognitive and emotional functions. Therefore, disturbances in the motor and endocrine functions, which are the most serious problems caused by the current neuroleptics, are likely to result from the non-selective blockade of D₂R. Selective regulation of D₃R is needed to separate the desired therapeutic activities from unwanted side effects that result from promiscuous blockade of other receptors. D₂R and D₃R possess high sequence homology and employ similar signaling pathways, and it is difficult to selectively regulate them. In this review, we discuss the signaling mechanisms, intracellular trafficking, and desensitization properties of D₂R and D₃R. In addition, the proteins interacting with D₂R or D₃R are discussed in relation to their roles in the regulation of receptor functions, followed by the current status of the development of selective D₃R ligands.

The Effect of Cariprazine on Hostility Associated With Schizophrenia

“…Among available atypical antipsychotics, cariprazine is unique in that it has shown almost 10-fold greater affinity for D 3 than D 2 receptors in vitro 28 and high and balanced in vivo occupancy of both D 2 and D 3 receptors. 29,30 The dopamine D 3 receptor is thought to be an important factor in modulating mood and cognition, [31][32][33][34][35] and preclinical evidence suggests that cariprazine may be beneficial in treating negative symptoms, mood dysphoria, and cognitive impairment associated with schizophrenia. 33,[36][37][38][39][40][41] Additionally, short-term clinical trials have suggested that cariprazine is generally well tolerated, with no clinically relevant adverse effects on metabolic parameters, prolactin, or electrocardiogram QT interval.…”

Efficacy and Safety of Low- and High-Dose Cariprazine in Acute and Mixed Mania Associated With Bipolar I Disorder

“…3 The D 3 receptor is also thought to be involved in the modulation of mood and may present a novel target for the treatment of the broad mood symptoms associated with bipolar disorder. [4][5][6] The high and balanced occupancy of cariprazine at both D 2 and D 3 receptors, which is unique to cariprazine, 7 may provide distinct benefits in treating acute and mixed mania.…”

Pharmacological Treatment of Schizophrenia:

“…Compared with aripiprazole, cariprazine showed lower affinity for D 2 and higher affinity for D 3 receptors [30]. The dopamine D 3 receptor is thought to play roles in the regulation of cognitive and emotional functions [31]. Cariprazine acts as antagonist with moderate affinity at 5-HT 2A and H 1 receptors, but it has no affinity for muscarinic receptors [30].…”