The International Journal of Neuropsychopharmacology

Research Article

Differential modulation of intracellular Ca2+ responses in B lymphoblasts by mood stabilizers

Tatiana Perovaa1a2, Melodie Kwana1a2, Peter P. Lia1a2a3 and Jerry J. Warsha1a2a3a4 c1

a1 Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada

a2 Department of Pharmacology, University of Toronto, Toronto, ON, Canada

a3 Department of Psychiatry, University of Toronto, Toronto, ON, Canada

a4 Institute of Medical Science, University of Toronto, Toronto, ON, Canada

Abstract

Irregularities of intracellular calcium (Ca2+) homeostasis have been implicated in the pathophysiology of bipolar disorder (BD). Findings that chronic ex-vivo treatment with lithium modifies lysophosphatidic acid (LPA)-stimulated Ca2+ responses in B lymphoblast cell lines (BLCLs) from BD-I patients and healthy controls, and differentially decreases levels of the type-3 canonical transient receptor potential Ca2+-permeable channel in BLCLs from BD-I patients, support the view that the amelioration of these abnormalities is important in the therapeutic action of lithium. To determine whether other clinically efficacious mood stabilizers share these effects, LPA (100 μm)- and thapsigargin (TG, 200 nm)-stimulated Ca2+ responses were determined in BLCLs from BD-I patients and healthy controls treated acutely (24 h) and chronically (7 d) ex vivo with therapeutically relevant concentrations of lithium (0.75 mm), valproate (0.5 mm), lamotrigine (15 μm) or respective vehicles. Chronic treatment with valproate significantly attenuated LPA-stimulated Ca2+ responses (↓8%: F's=9.1–9.4, d.f.=1, 9, p's<0.05) compared to vehicle in BLCLs from BD-I patients and healthy controls, similar to chronic lithium treatment (↓8%: F=6.2, d.f.=1, 21, p<0.05), but also attenuated TG-evoked Ca2+ responses (↓10% to ↓19%: F's=5.5–15.5, d.f.=1, 12, p's<0.05). However, chronic lamotrigine treatment did not affect LPA- or TG-stimulated Ca2+ responses. These results suggest that chronic lithium and valproate treatments act differently from lamotrigine in respect of modulation of receptor- and/or capacitance-mediated Ca2+ flux. These differential effects on Ca2+ responses may be relevant to the distinctive clinical profiles of these mood stabilizers.

(Received October 14 2008)

(Reviewed January 12 2009)

(Revised February 19 2009)

(Accepted February 20 2009)

(Online publication April 29 2009)

Correspondence:

c1 Address for correspondence: J. J. Warsh, M.D., Ph.D., Head, Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, 250 College Street, Room R20, Toronto, ON, Canada, M5T 1R8. Tel.: 416-979-4279 Fax: 416-979-4730 Email: jerry.warsh@utoronto.ca