¹Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, HHS, Bethesda, MD, USA

Correspondence: Dr TD Gould, Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, HHS, Bldg 35, Rm 1C-912, 35 Convent Drive, Bethesda, MD 20892-3711, USA. Tel: +1 301 451 8435; Fax: +1 301 480 0123; E-mail: gouldt@mail.nih.gov

²Current address: Department of Pharmacology, Columbia College of Physicians and Surgeons, 630 West 168th Street, PH 7W 318, New York, NY 10032, USA.

Received 24 April 2006; Revised 6 September 2006; Accepted 2 October 2006; Published online 6 December 2006.

Abstract

Lithium attenuation of stimulant-induced hyperlocomotion is a rodent model that may be useful both to understand the mechanism of the therapeutic action of lithium and to develop novel lithium-mimetic compounds. To lay the foundation for future investigations into the neurobiology and genetics of lithium as a therapeutic agent, we studied the effect of lithium on d-amphetamine-induced hyperlocomotion in 12 (3 outbred) mouse strains. In our initial screening, mice received either (1) no drugs, (2) LiCl only, (3) d-amphetamine only, or (4) d-amphetamine and LiCl. Whereas there was no significant effect of LiCl alone on locomotion in any strain, there was a large degree of strain variation in the effects of LiCl combined with d-amphetamine. LiCl attenuated d-amphetamine-induced hyperlocomotion in C57BL/6J, C57BL/6Tac, Black Swiss, and CBA/J mice, whereas CD-1, FVB/NJ, SWR/J, and NIH Swiss mice, which were responsive to d-amphetamine, showed no significant effect of LiCl. d-Amphetamine-induced hyperlocomotion in the C3H/HeJ strain was increased by pretreatment with lithium. A subset of strains were treated for 4 weeks with lithium carbonate before the d-amphetamine challenge, and in each of these strains, lithium produced effects identical to those seen following acute administration. Strain responsiveness to lithium was not dependent upon the dose of either d-amphetamine or LiCl. Further, the results are not explained by brain lithium levels, which suggests that these behavioral responses to lithium are under the control of inherent genetic or other biological mechanisms specific to the effects of lithium on brain function.