The role of dopamine D₃receptors in the mechanism of action of cariprazine

Abstract

Cariprazine is a new atypical antipsychotic drug (APD) with a unique pharmacodynamic profile, different from both typical and atypical APDs. Specifically, cariprazine acts as a partial agonist at the dopamine (DA) D2 and D3 receptors and serotonin 5-HT1A receptors, and as an antagonist at the 5-HT2B receptors. Moreover, it shows moderate affinities for adrenergic, histaminergic, and cholinergic receptors that are involved in mediating the side effects characteristic of typical APDs. In this review, we discuss the contribution of DA D3 receptors (D3Rs) in the etiology and pathophysiology of schizophrenia and the potential benefits that may be associated with a more selective targeting of D3R by APDs, as compared to other dopaminergic and non-dopaminergic receptor subtypes. Cariprazine, by acting on D3Rs, ameliorates anhedonia and cognitive deficits in animal models based on environmental or pharmacological manipulation. The reviewed results support the potential benefits of cariprazine in treating negative symptoms and cognitive deficits of schizophrenia, and therefore representing a promising approach in addressing the unmet clinical needs for the improved treatment of this serious neuropsychiatric disorder.

Decline in Psychotic Symptoms in Addition to Cardiac and Metabolic Safety with Cariprazine After Poor Response to Previous Antipsychotic Treatments – A Series of Two Cases

“…4,6,9,11 In addition, the novel molecule and its receptor profile offer a range of advantages for clinical use. In particular, the undesirable consequences, such as metabolic and cardiovascular effects, [5][6][7]14 described for other newer preparations are rare. 3,9,11,15 The efficacy extends to the entire schizophrenia symptom spectrum.…”

“…Cariprazine has the highest D3 receptor affinity of any of the newer antipsychotics. [4][5][6][7] The particular metabolic-related aspects of the cases reported here occurred under previous medications. Cognitive disorders and negative symptoms also improved in the course of the process.…”

“…Cariprazine, approved in 2017 in the EU, is a new antipsychotic agent within the therapeutic armamentarium in clinical psychiatry. 3,[5][6][7] Cariprazine is a dopamine D3/D2 receptor agonist and a serotonin 5-HT1A receptor partial agonist, among other receptors. Cariprazine has the highest D3 receptor affinity of all newgeneration antipsychotic drugs.…”

Impaired working memory, cognitive flexibility and reward processing in mice genetically lacking Gpr88: Evidence for a key role for Gpr88 in multiple cortico‐striatal‐thalamic circuits

“…However, interference with dopaminergic signalling in other regions like the basal ganglia and frontal cortex may lead to unwanted motor and cognitive‐side effects 18 . Further, despite the integration of serotonergic, dopamine D3 and other properties, control of negative symptoms and the cognitive impairment of schizophrenia is poor 19‐23 . The enriched location of GPR88 in the striatum offers a potentially attractive alternative target for modulating cortico‐striatal‐thalamic circuitry dysfunctional in schizophrenia and accordingly achieving a broad‐based control of symptoms.…”

Cariprazine in the Management of Negative Symptoms of Schizophrenia: State of the art and Future Perspectives

“…Dopamine (DA) is a key brain neurotransmitter that contributes to control of different functions, such as cognition, motivation and rewards, as well as locomotion [1][2][3]. Alterations in dopaminergic function represent a hallmark in numerous mental diseases, including schizophrenia.…”