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.

FIGURE 1

Structure of hD₃R: (A) hD₃R-G_i complex; (B) binding of the selective agonist PD128907 in the orthosteric binding site (Secondary binding site and ECL2 are also depicted); (C) percent identity of human and rat D₂R and D₃R sequences; (D) comparison of hD₂R (red) and hD₃R (green); (E) comparison of active (green) and inactive (red) conformation of hD₃R*.

FIGURE 2

Correlation between in vitro affinity of various dopaminergic antagonists for human recombinant D₃Rs and D₂Rs [data taken from Sokoloff et al. (80)]; ligand: [¹²⁵I]sulpiride.

FIGURE 3

Correlation between in vitro affinity of antipsychotics for human D₂Rs and D₃Rs (A, data taken from Table 1; various radioligands) and for rat striatal D₂Rs (striatal membrane) and cerebellar D₃Rs (CB L9,10 membrane) (B); rat D₂R and D₃R affinity data derive from the extension of the study of Kiss et al. (81) and Kiss et al. (82). Determination of D₂R and D₃R affinity in membranes from CHO cells expressing human D₃R or cerebellar L9,10 membranes (ligand: [³H]-(+)-PHNO) is described in Kiss et al. (81).

FIGURE 4

Dopamine, pramipexole and selected antipsychotics docked into experimental D₃R structures*.

FIGURE 5

Graphical presentation of percent changes in striatal dopamine turnover indices (DATI) at D₃R (i.e., cerebellar L9, 10) occupancy ED₅₀ doses (A) and at D₂R (i.e., striatal) occupancy ED₅₀ doses (B) in vivo^*,#. *Doses in brackets denote the occupancy ED₅₀ doses (or close to ED₅₀) taken from Table 2. Dopamine turnover index (DATI) was estimated from turnover dose-response curves (consisting of at least 4–5 doses, with five rats in each dose-group) for individual compounds listed in this figure. In cases where the occupancy ED₅₀ values could not be exactly calculated (see Table 2) the turnover indices were determined at doses denoted with asterisks. Dopamine turnover index was defined as DA/(DOPAC+HVA). Determination of tissue dopamine, DOPAC and HVA was carried out exactly as described in Kiss et al. (22) (for abbreviations of drugs’ names, see Table 2). ^#Dopamine turnover data for cariprazine and DD-CAR were published in Kiss et al. (173). Turnover results of other compounds are unpublished and are on file at G. Richter. Plc.