Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

Abstract

Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.

PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells

“…S10d, e ). In contrast, PharmacoSTORM imaging successfully detected the low copy number of D 3 Rs in the adjacent ventral striatum, but not in the dorsal striatum, where D 3 receptors are known to be either present or absent, respectively 46 (Supplementary Fig. S10b, c, f, g ).…”

“…These findings suggest that D 3 Rs in this region mediate important behavioral effects of this recently approved medicine. Despite earlier low-resolution in situ hybridization and autoradiography experiments that suggested the presence of D 3 Rs 46 , 66 , 67 , surprisingly, the functional involvement of the Islands of Calleja in the action of antipsychotics and antidepressants has not yet been experimentally demonstrated. Certainly, D 3 Rs are also likely to be present in other brain regions 68 – 72 , albeit at much lower concentration.…”

“…The impaired functionality of emotional salience is also a hallmark of negative symptoms in patients with schizophrenia spectrum disorders. Therefore, the identification of high-density binding sites in the Islands of Calleja for cariprazine that displays uniquely high efficacy in the treatment of negative symptoms is clinically highly relevant 35 , 36 , 46 . In addition, the widespread role of D 3 Rs in other psychiatric disorders 71 , 73 , 76 and the emerging therapeutic significance of cariprazine in the treatment of other psychiatric conditions 35 – 37 , 46 , further emphasizes that the strategic nanoscale localization of in vivo cariprazine binding discovered by PharmacoSTORM imaging, is expected to draw major attention to the clinical importance of Islands of Calleja granule cells.…”

Sex, Pramipexole and Tiagabine Affect Behavioral and Hormonal Response to Traumatic Stress in a Mouse Model of PTSD

“…Pramipexole may improve trauma memory extinction ( Gerlicher et al, 2018 ). Furthermore, as the D 3 -preferring agonist, pramipexole aims at the promising target for the treatment of neuropsychiatric disorders, which share some common symptoms with PTSD ( Leggio et al, 2019 ; Leggio et al, 2021 ; for the review, see; Kiss et al, 2021 ). The concept of D 3 receptors' role in PTSD has already been proposed, being further discussed in Torrisi et al (2019) .…”

Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases

“…The notion of multitarget target drugs is intimately linked with the D3Rs as the newer antipsychotic drugs, including cariprazine [ 3 ] display a high affinity for D3Rs. Bela Kiss et al developed a fundamental approach to the knowledge accumulated on D3Rs [ 4 ]. They reviewed the distribution of D3Rs in the central nervous system (CNS) and periphery and its signaling and molecular properties.…”