The novel antipsychotic cariprazine stabilizes gamma oscillations in rat hippocampal slices

Abstract

Background and Purpose Gamma oscillations are fast rhythmic fluctuations of neuronal network activity ranging from 30 to 90 Hz that establish a precise temporal background for cognitive processes such as perception, sensory processing, learning, and memory. Alterations of gamma oscillations have been observed in schizophrenia and are suggested to play crucial roles in the generation of positive, negative, and cognitive symptoms of the disease. Experimental Approach In this study, we investigated the effects of the novel antipsychotic cariprazine, a D3‐preferring dopamine D3/D2 receptor partial agonist, on cholinergically induced gamma oscillations in rat hippocampal slices from treatment‐naïve and MK‐801‐treated rats, a model of acute first‐episode schizophrenia. Key Results The D3 receptor‐preferring agonist pramipexole effectively decreased the power of gamma oscillations, while the D3 receptor antagonist SB‐277011 had no effect. In treatment‐naïve animals, cariprazine did not modulate strong gamma oscillations but slightly improved the periodicity of non‐saturated gamma activity. Cariprazine showed a clear partial agonistic profile at D3 receptors at the network level by potentiating the inhibitory effects when the D3 receptor tone was low and antagonizing the effects when the tone was high. In hippocampal slices of MK‐801‐treated rats, cariprazine allowed stabilization of the aberrant increase in gamma oscillation power and potentiated resynchronization of the oscillations. Conclusion and Implications Data from this study indicate that cariprazine stabilizes pathological hippocampal gamma oscillations, presumably by its partial agonistic profile. The results demonstrate in vitro gamma oscillations as predictive biomarkers to study the effects of antipsychotics preclinically at the network level.

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…The D3 controlled PFCx projections to hippocampus are interesting in this sense (Provenzano et al, 2020). The recent paper from Meier et al shows the effect of a preferential D3 partial agonist Cariprazine on gamma oscillations in hippocampal slides further supporting the general assumption that gamma waves could predict psychosis and in vitro NMDA hypofunction, and that D3 functional reduction can stabilize the alterations of the signal caused by NMDA hypofunction (Meier et al, 2020). Treatment response to antipsychotics may be predicted looking at the effect on hippocampal-cortical connections and again these changes could be in part D3 related (Guma et al, 2019;Blessing et al, 2020).…”

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

“…In accordance with the theories of generation, the abnormalities in oscillatory activity in schizophrenia are believed to connect to alterations in GABAergic function [ 273 , 274 ]. The D3R-preferring partial agonist cariprazine could improve the periodicity of moderate and unsaturated gamma activity while it stabilized the power of gamma oscillations altered by MK-801 treatment in rat hippocampal slices suggesting a benefit arising from the partial agonistic character on D3R by cariprazine [ 278 ].…”

Cariprazine alleviates core behavioral deficits in the prenatal valproic acid exposure model of autism spectrum disorder

“…Specifically, an excitatory and inhibitory imbalance in the brain is a key hypothesis of ASD neurophysiology, which is associated with abnormal gamma-band oscillations and suggested to be linked with perceptual and cognitive functions that are compromised in autism (David et al 2016 ; Peiker et al 2015 ; Rojas and Wilson 2014 ). Findings of an ex vivo study by Meier et al ( 2019 ) demonstrate a stabilizing role of cariprazine on gamma oscillations, presumably due to its partial agonist properties on dopamine D 3 receptors. While changes in brain oscillation are not exclusively specific to ASD, more direct evidence can be gained from dedicated preclinical disease models of ASD such as behavioral investigation after prenatal exposure to valproic acid (VPA) in rodents.…”