Homozygote inositol transporter knockout mice show a lithium-like phenotype.
OBJECTIVE
Lithium inhibits inositol monophosphatase and also reduces inositol transporter function. To determine if one or more of these mechanisms might underlie the behavioral effects of lithium, we studied inositol transporter knockout mice. We previously reported that heterozygous knockout mice with reduction of 15-37% in brain inositol had no abnormalities of pilocarpine sensitivity or antidepressant-like behavior in the Porsolt forced swim test. We now report on studies of homozygous inositol transporter knockout mice.


METHODS
Homozygote knockout mice were rescued by 2% inositol supplementation to the drinking water of the dam mice through pregnancy and lactation. Genotyping was carried out by polymerase chain reaction followed by agarose electrophoresis. Brain free myo-inositol levels were determined gas-chromatographically. Motor activity and coordination were assessed by the rotarod test. Behavior of the mice was studied in lithium-pilocarpine seizure models for lithium action and in the Porsolt forced swim test model for depression.


RESULTS
In homozygote knockout mice, free inositol levels were reduced by 55% in the frontal cortex and by 60% in the hippocampus. There were no differences in weight or motor coordination by the rotarod test. They behaved similarly to lithium-treated animals in the model of pilocarpine seizures and in the Porsolt forced swimming test model of depression.


CONCLUSIONS
Reduction of brain inositol more than 15-37% may be required to elicit lithium-like neurobehavioral effects.
Bersudsky
Yuly
Y
Stanley Research Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel.
Shaldubina
Alona
A
Agam
Galila
G
Berry
Gerard T
GT
Belmaker
Robert H
RH
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D007294:Inositol / Q000378:metabolism; D018020:Lithium Compounds / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010641:Phenotype; D010862:Pilocarpine / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051269:Sodium-Glucose Transporter 1 / Q000172:deficiency*; D013550:Swimming
D018020:Lithium Compounds; C495675:Slc5a1 protein, mouse; D051269:Sodium-Glucose Transporter 1; D010862:Pilocarpine; D007294:Inositol