Strain Differences in Lithium Attenuation of d-Amphetamine-Induced Hyperlocomotion: A Mouse Model for the Genetics of Clinical Response to Lithium

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) damphetamine 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 damphetamine 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.

Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

“…However, brain lithium levels ( Figure 1b) were significantly different among groups: F(2, 23) = 62.53, p < 0.0001. This is consistent with the finding from numerous groups that establishment of steady-state brain lithium levels in the rodent brain lags behind serum lithium levels (Ghoshdastidar et al, 1989;Gould et al, 2007b;Morrison et al, 1971). Bersudsky and colleagues recently reported that the effect of lithium in the FST after long-term treatment requires serum levels above 0.8 mM (Bersudsky et al, 2007).…”

“…Whole brain lithium levels (mmol/kg wet weight) were determined following polytron homogenization of the entire brain (Kinematica AG Model PCU 11, Littau, Switzerland) in 3 volumes of 0.5 N trichloroacetic acid (Hamburger-Bar et al, 1986) (Gould et al, 2007b). Following centrifugation, lithium assays were performed on the supernatant with a digital flame photometer (Cole-Palmer Model 2655-00, Chicago, Illinois).…”

“…Bersudsky and colleagues recently reported that the effect of lithium in the FST after long-term treatment requires serum levels above 0.8 mM (Bersudsky et al, 2007). Following long-term administration of lithium to rodents, whole brain lithium concentrations and serum lithium concentrations are generally equal (Ghoshdastidar et al, 1989;Gould et al, 2007b), suggesting that brain lithium levels above 0.8 mM would be required to elicit antidepressantlike effects in the FST. Brain levels for 1 day and 1.5 days were 0.64 ± 0.02 and 0.94 ± 0.02 respectively.…”

Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis

“…One such model is methamphetamine-induced hyperlocomotion/mania, which is known to be responsive to lithium in many mouse strains (37). Interestingly, although no molecular mechanisms have been offered, methamphetamine has also been suspected of modulating GSK3β signaling in the nucleus accumbens (38), impinging on dendritic spine formation (39) and effecting Ca 2+ channel expression (40).…”

Convergent functional genomics of psychiatric disorders

“…That work was subsequently extended to look at the gene expression changes in blood from the animals on the different treatments, as a way of identifying brain-blood biomarkers [Le-Niculescu et al, 2009b]. Niculescu et al, 2008Niculescu et al, , 2011b Nile grass rat [Ashkenazy-Frolinger et al, 2010] Methamphetamine [Niculescu et al, 2000;Macedo et al, 2013] Learned helplessness [Mingmalairak et al, 2010] CLOCK [Roybal et al, 2007;Mukherjee et al, 2010;Arey et al, 2013] Flinders Sensitive Line (FSL) rats [Malkesman and Weller, 2009] Methamphetamine/valproate [Ogden et al, 2004] Isolation housing [Le-Niculescu et al, 2008;Niwa et al, 2013] CTNNB1 [Gould et al, 2008] Wistar Kyoto (WKY) rats [Will et al, 2003;Malkesman and Weller, 2009] Amphetamine-chlordiazepoxide [Kelly et al, 2009] Forced swim test [Le-Niculescu et al, 2008] POLG [Kasahara et al, 2006;Kubota et al, 2010] Madison (MSN) [Saul et al, 2012] Lithium [Gould et al, 2007;Johnson et al, 2009;Kovacsics and Gould, 2010] Tail suspension test [Le-Niculescu et al, 2008] HINT1 [Barbier and Wang, 2009] Other mood stabilizers: Lamotrigene [Li et al, 2010], Topiramate [Bourin et al, 2009] Restraint stress [Johnson et al, 2009;Koo et al, 2010] GRIN2A [Taniguchi et al, 2009] Ouabain [Herman et al, 2007] Shock-induced aggression …”