Potential Mechanisms for Why Not All Antipsychotics Are Able to Occupy Dopamine D3 Receptors in the Brain in vivo

Abstract

Dysfunctions of the dopaminergic system are believed to play a major role in the core symptoms of schizophrenia such as positive, negative, and cognitive symptoms. The first line of treatment of schizophrenia are antipsychotics, a class of medications that targets several neurotransmitter receptors in the brain, including dopaminergic, serotonergic, adrenergic and/or muscarinic receptors, depending on the given agent. Although the currently used antipsychotics display in vitro activity at several receptors, majority of them share the common property of having high/moderate in vitro affinity for dopamine D₂ receptors (D₂Rs) and D₃ receptors (D₃Rs). In terms of mode of action, these antipsychotics are either antagonist or partial agonist at the above-mentioned receptors. Although D₂Rs and D₃Rs possess high degree of homology in their molecular structure, have common signaling pathways and similar in vitro pharmacology, they have different in vivo pharmacology and therefore behavioral roles. The aim of this review, with summarizing preclinical and clinical evidence is to demonstrate that while currently used antipsychotics display substantial in vitro affinity for both D₃Rs and D₂Rs, only very few can significantly occupy D₃Rs in vivo. The relative importance of the level of endogenous extracellular dopamine in the brain and the degree of in vitro D₃Rs receptor affinity and selectivity as determinant factors for in vivo D₃Rs occupancy by antipsychotics, are also discussed.

Keywords: D2 receptor; D3 receptor; antipsychotics; brain occupancy; dopamine; schizophrenia.