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.

Antipsychotic-induced bone loss: the role of dopamine, serotonin and adrenergic receptor signalling

“…First generation antipsychotics are associated with a number of undesirable side effects including hyperprolactinemia, sedation, weight gain, autonomic and cardiovascular effects, akathisia, parkinsonism, dystonia and tardive dyskinesia ( Mailman and Murthy, 2010 ), thus, spurring on the development of second generation antipsychotics. Second generation antipsychotics are D 2 and serotonin (5HT) antagonists with affinity ratio greater than 1.12 for D 2 /5HT 2A which have been more effective in reducing negative and cognitive symptoms compared to FGAs, but associated with greater weight gain and metabolic syndromes such as hypertriglyceridemia, elevated glucose, insulin and low-density lipoprotein cholesterol levels ( Lieberman, 2004 ; Mailman and Murthy, 2010 ; Pillinger et al, 2020 ; Kiss et al, 2022 ). A third generation of antipsychotics such as aripiprazole, cariprazine and brexpiprazole were introduced most recently and have been successful in treating positive, negative and cognitive symptoms ( Vasiliu, 2022 ).…”

Cariprazine-Associated Obsessive-Compulsive Symptoms in a Patient With Bipolar Disorder

“…Cariprazine has 5.8 times higher in vitro human receptor affinity to D 3 Rs than D 2 Rs, 6 can block or stimulate the receptors in both dose-dependent and dopaminergic tone-dependent manner, 19 and showed the highest in vivo D 3 R affinity 6 among all molecules approved for the treatment of psychiatric disorders and higher affinity for D 3 Rs than dopamine at clinically relevant doses. 6 Our patient experienced OCSs at a very low dose of cariprazine and took 15 weeks after cariprazine discontinuation to recover from OCSs, suggesting the role of cariprazine's long half-life (1-3 weeks) active metabolite, didesmethyl-cariprazine, in the OCSs. Our case report and other evidence suggests that D 3 R is implicated in the pathophysiology of antipsychotic-associated OCSs.…”

“…Reported second-generation antipsychotics include clozapine, 1 olanzapine, 2 risperidone, 3 quetiapine, 4 aripiprazole, 5 and ziprasidone 2 . Cariprazine, an approved medication for the management of schizophrenia and bipolar I disorder with a partial agonism at dopamine D 2 /D 3 receptors (D 2 /D 3 Rs) and serotonin 5-HT 1A Rs as well as antagonism at 5HT 2A Rs and 5-HT 2B Rs, 6 has never been reported to be associated with OCSs. Here we report the first case of cariprazine-associated OCSs in a patient with bipolar disorder.…”

“…Clozapine, which has very high D 3 R selectivity over D 2 R and high 5HT 2A R antagonism, is the most common antipsychotics reported to be associated with OCSs 2 . On the other hand, aripiprazole, which has reports of an antiobsessive effect, 9–11,17,18 has very low occupancy of in vivo D 3 Rs 6 . Noteworthy, amisulpride is the only medication reported to improve antipsychotic-associated OCSs without any report of the opposite effect despite its high affinity to D 2 /D 3 Rs.…”

Olanzapine Use in Schizophrenia and the Modulation of Its Response by Genetic Variations

“…Dopamine D2 receptors are G-protein coupled receptors mostly expressed in the striatum, brain, and limbic system. The occupancy of 65 percent of brain dopamine receptors is required for therapeutic effectiveness, whereas occupancy of more than 72 percent causes prolactin rise, and 77 percent or more causes EPS (Kiss, Krámos, and Laszlovszky 2022). Second-generation antipsychotics have a moderate to high affinity for D2, D3, and D4 receptors, whereas first-generation antipsychotics have a significant dopamine affinity (Li, L Snyder, and E Vanover 2016).…”