1. ¹Department of Psychiatry, University of Toronto, Toronto, Canada
2. ²Department of Psychiatry, University of Ottawa, Ottawa, Canada
3. ³Department of Psychiatry, McGill University, Montreal, Canada
4. ⁴Center for Research in Neuroscience, McGill University, Montreal, Canada
5. ⁵Department of Psychiatry, Dalhousie University, Halifax, Canada

Correspondence: Martin Alda, Department of Psychiatry, Dalhousie University, 5909 Veterans' Memorial Lane, Halifax, Nova Scotia, Canada B3H 2E2. Tel: +1 902 473 2712; Fax: +1 902 473 1583; E-mail: malda@Dal.ca

Received 17 August 2003; Revised 2 December 2003; Accepted 11 December 2003; Published online 21 January 2004.

Abstract

Lithium, a common drug for the treatment of bipolar disorder (BD), requires chronic administration to prevent recurrences of the illness. The necessity for long-term treatment suggests that changes in genes expression are involved in the mechanism of its action. We studied effects of lithium on gene expression in lymphoblasts from BD patients, all excellent responders to lithium prophylaxis. Gene expression was analyzed using cDNA arrays that included a total of 2400 cDNAs. We found that chronic lithium treatment at a therapeutically relevant concentration decreased the expression of seven genes in lymphoblasts from lithium responders. Five of these candidate lithium-regulated genes, including alpha1B-adrenoceptor (1B-AR), acetylcholine receptor protein alpha chain precursor (ACHR), cAMP-dependent 3',5'-cyclic phosphodiesterase 4D (PDE4D), substance-P receptor (SPR), and ras-related protein RAB7, were verified by Northern blotting analysis in lithium responders. None of these genes were regulated by lithium in healthy control subjects. When we compared the expression of these five genes between bipolar subjects and healthy control subjects at baseline, prior to lithium administration, we found that 1B-AR gene expression was higher in bipolar subjects than in healthy control subjects. Our findings indicate that 1B-AR may play an important role in the mechanism of action of lithium treatment.