Premium
The inositol depletion hypothesis is not sufficient to explain the behavioral effect of lithium in murine brain
Author(s) -
Johanson Roy A.,
O’Brien W. Timothy,
Buccafusca Roberto,
Klein Peter S.,
Berry Gerard T.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a486
Subject(s) - lithium (medication) , endocrinology , medicine , inositol , hippocampal formation , chemistry , behavioural despair test , hippocampus , biology , antidepressant , receptor
A decrease in phosphoinositide synthesis secondary to a decrease in myo‐inositol (Ins) levels is central to the inositol depletion hypothesis and has been used to explain the behavioral effects of lithium. In mice, lithium reduces brain Ins content and causes a marked decrease in the time of immobility in the forced swim test (FST). A murine Ins transporter (SMIT1 or SLC5A3) knock‐out model developed in our laboratory in which adult SMIT1 (+/−) carrier mice manifest reduced SMIT1 mRNA levels in brain tissue has provided a unique opportunity to test whether the effect of lithium in the FST is mediated by reduced Ins levels. Carrier (+/−) and wild type (+/+) mice with and without lithium treatment were subjected to the FST and then sacrificed for determinations of brain Ins content by GC/MS. The untreated (+/+) and the carriers were immobile for mean times of 92 ± 15 sec (n = 12) and 93 ± 15 sec (n = 12), respectively, while the lithium treated (+/+) mice were immobile for 25 ± 8 sec (n = 12, p = 0.001). The mean hippocampal Ins levels were 7.3 ± 0.2 (n = 6), 5.4 ± 0.6 (n = 6), and 4.9 ± 0.4 (n = 6) mmoles/ kg wet wt. for the (+/+), (+/+) with lithium treatment, and (+/−) mice, respectively. Compared to (+/+) mice, the mean Ins level was decreased by 25% in (+/+) plus lithium (p < 0.05) and by 33% in (+/−) mice (p < 0.05). The absence of a behavioral effect in carriers with Ins deficiency indicates that Ins deficiency is not sufficient to explain the effect of lithium on brain function.