title: Cariprazine delays ouabain-evoked epileptiform spikes and loss of activity in rat hippocampal slices.
abstract: In the only bipolar cycling in vitro model, rat hippocampal slices are treated with the sodium pump inhibitor ouabain, which induces epileptiform activity, followed by refractory activity loss that recovers and cycles back to epileptiform activity. Thus, clinical cycling seen in patients with bipolar disorder is modeled on a cellular level as alternating hyperactivity and hypoactivity interspersed with normal activity. In this study, we tested the ability of cariprazine a new antipsychotic candidate to block ouabain-induced changes in rat hippocampal slices. Cycling of population spikes and epileptiform bursts was evoked using an extracellular stimulation electrode located in the Schaeffer collaterals of 400-µm-thick rat hippocampal slices treated with ouabain (3.3μM) alone or in combination with cariprazine (1, 5, 25, and 50µM). Responses were recorded using an extracellular electrode placed in the cell body layer of the CA1 region. Cariprazine 25 and 50µM delayed ouabain-induced epileptiform burst onset and subsequent activity loss. Lower cariprazine concentrations were ineffective. Cariprazine delays the onset of ouabain-induced epileptiform bursts and the loss of spiking activity similarly to that previously demonstrated with the mood stabilizer lithium. These results suggest that cariprazine may have therapeutic potential for treatment of bipolar disorder.
authors.affiliation: Mood Disorders Research Program, Department of Psychiatry and Behavioral Services, University of Louisville School of Medicine, Louisville, KY, USA. Electronic address: rifaat.elmallakh@louisville.edu.
authors.forename: Rif S
authors.initials: RS
authors.lastname: El-Mallakh
authors.affiliation: Department of Anesthesiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Ralphiel S
authors.initials: RS
authors.lastname: Payne
authors.affiliation: Department of Anesthesiology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Avital
authors.initials: A
authors.lastname: Schurr
authors.affiliation: Mood Disorders Research Program, Department of Psychiatry and Behavioral Services, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Yonglin
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Obstetrics and Gynecology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Zhemin
authors.initials: Z
authors.lastname: Lei
authors.affiliation: Pharmacological and Safety Research, Gedeon Richter Plc., Budapest, Hungary.
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.affiliation: Pharmacological and Safety Research, Gedeon Richter Plc., Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Gyertyán
authors.affiliation: Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Nika
authors.initials: N
authors.lastname: Adham
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000188:drug therapy*; D005071:Evoked Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D010042:Ouabain / Q000009:adverse effects*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D010042:Ouabain; C533287:cariprazine
keywords: Antipsychotic; Bipolar disorder; Dopamine D(3); Dopamine antagonists; Mania; Rapid cycling; Receptors