Abstract
RationaleAberrant glutamatergic, dopaminergic, and GABAergic neurotransmission has been implicated in schizophrenia. Cariprazine reverses the behavioral effects observed in the rat phencyclidine (PCP)-induced model of schizophrenia; however, little is known about its in vivo neurochemistry.ObjectivesThe study aims to compare the effects of cariprazine and aripiprazole on PCP-induced changes in the extracellular levels of glutamate, dopamine, serotonin, noradrenaline, and GABA in the rat medial prefrontal cortex (mPFC), and on locomotor activation.MethodsMicrodialysis was performed in awake rats with probes placed into the mPFC. Rats (n = 7/group) received vehicle (saline), cariprazine (0.05, 0.2, or 0.8 mg/kg), or aripiprazole (3 or 20 mg/kg) via gavage. After 60 min, 5 mg/kg PCP was administered intraperitoneally (i.p.). Samples were taken before drug administration, during pretreatment, and after PCP injection. Locomotor activity recording and microdialysis sampling occurred simultaneously.ResultsPCP treatment increased extracellular levels of all the neurotransmitters tested except GABA, for which there were no significant changes. Cariprazine and aripiprazole dose-dependently inhibited the PCP-induced increases of tested neurotransmitters. Overall effects were significant for higher cariprazine doses and both aripiprazole doses for glutamate and noradrenaline, for higher cariprazine doses and 20 mg/kg aripiprazole for dopamine, and for 0.8 mg/kg cariprazine and 20 mg/kg aripiprazole for serotonin and locomotor activity.ConclusionBoth cariprazine and aripiprazole dose-dependently attenuated PCP-induced hyperlocomotion and acute increases in glutamate, dopamine, noradrenaline, and serotonin levels in the mPFC; cariprazine was approximately 5-fold more potent than aripiprazole.
Highlights
Schizophrenia is a debilitating, lifelong psychiatric disorder affecting approximately 1% of the population
Cariprazine was developed based on the hypothesis that high affinity at D3 and D2 receptors may result in potent antipsychotic efficacy through D2 receptor blockade and confer additional D3 receptormediated benefits in the treatment of affective and cognitive deficits associated with schizophrenia and bipolar disorder (Gyertyán et al 2008; Kiss et al 2008)
Cariprazine differs from currently used atypical antipsychotics (Ellenbroek and Cesura 2014) by having higher in vitro affinity and selectivity for D3 versus D2 receptors (Kiss et al 2010) and high levels of in vivo occupancy of both D3 and D2 receptors at antipsychotic-like effective doses in rats (Gyertyán et al 2011) and clinically active dose ranges in patients with schizophrenia (Girgis et al 2016)
Summary
Schizophrenia is a debilitating, lifelong psychiatric disorder affecting approximately 1% of the population. Cariprazine differs from currently used atypical antipsychotics (Ellenbroek and Cesura 2014) by having higher in vitro affinity and selectivity (almost an order of magnitude) for D3 versus D2 receptors (Kiss et al 2010) and high levels of in vivo occupancy of both D3 and D2 receptors at antipsychotic-like effective doses in rats (Gyertyán et al 2011) and clinically active dose ranges in patients with schizophrenia (Girgis et al 2016). These data indicate that cariprazine can modulate in vivo D3 receptor activity to a greater extent than other antipsychotics
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