Effects of cariprazine on extracellular levels of glutamate, GABA, dopamine, noradrenaline and serotonin in the medial prefrontal cortex in the rat phencyclidine model of schizophrenia studied by microdialysis and simultaneous recordings of locomotor activity

• Published in: PSYCHOPHARMACOLOGY Vol. 235; no. 5; pp. 1593 - 1607
• Main Authors: Kehr, Jan, Yoshitake, Takashi, Ichinose, Fumio, Yoshitake, Shimako, Kiss, Béla, Gyertyán, István, Adham, Nika
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2018; Springer Nature B.V
• Subjects: Animals; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; Antipsychotics; Aripiprazole; Biomedical and Life Sciences; Biomedicine; Disease Models, Animal; Dopamine; Dopamine - metabolism; Dopamine receptors; Dose-Response Relationship, Drug; Extracellular Fluid - drug effects; Extracellular Fluid - metabolism; Extracellular levels; gamma-Aminobutyric Acid - metabolism; Glutamatergic transmission; Glutamic Acid - metabolism; Locomotion - drug effects; Locomotion - physiology; Locomotor activity; Male; Medicin och hälsovetenskap; Mental disorders; Microdialysis; Microdialysis - methods; Neurosciences; Neurotransmission; Neurotransmitters; Noradrenaline; Norepinephrine; Norepinephrine - metabolism; Original Investigation; Pharmacology/Toxicology; Phencyclidine; Phencyclidine - toxicity; Piperazines - pharmacology; Piperazines - therapeutic use; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Pretreatment; Psychiatry; Rats; Rats, Sprague-Dawley; Rodents; Schizophrenia; Schizophrenia - chemically induced; Schizophrenia - drug therapy; Schizophrenia - metabolism; Serotonin; Serotonin - metabolism; γ-Aminobutyric acid; Schizophrenia; Rat phencyclidine model; Microdialysis; Aripiprazole; Cariprazine
• DOI: 10.1007/s00213-018-4874-z
• ISSN: 0033-3158; 1432-2072

Rationale Aberrant 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. Objectives The 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. Methods Microdialysis 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. Results PCP 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. Conclusion Both 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.