Long-term lithium treatment selectively reduces receptor-coupled inositol phospholipid hydrolysis in rat brain.
Rats were treated with dietary lithium for 30 days, followed by assessment of the activity of the receptor-coupled inositol phospholipid second messenger-producing system in three brain regions. The major effect of long-term lithium treatment was a significant reduction of the response to norepinephrine in all three brain regions that were examined: the cerebral cortex, the hippocampus, and the striatum. After long-term lithium treatment, the response to serotonin was reduced in the hippocampus and striatum, but not the cortex, and the carbachol-induced response was only reduced in the striatum. Lithium treatment did not alter the incorporation of [3H]inositol into phospholipids, the in vitro lithium concentration-dependent accumulation of [3H]inositol monophosphate, or the stimulation by NaF of inositol phospholipid hydrolysis. These results indicate that the decreased responses to agonists after long-term lithium treatment are not likely to be due to depletion of inositol phospholipids or to altered activity of myo-inositol-1-phosphatase, phospholipase C, or the guanine nucleotide-binding protein. It is suggested that long-term lithium treatment may alter receptor number or receptor coupling, perhaps by phosphorylation, thereby selectively lowering the agonist-induced generation of second messengers by the inositol phospholipid system.
Casebolt
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Department of Pharmacology, University of Alabama, Birmingham 35294.
Jope
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D000818:Animals; D001921:Brain / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects; D002712:Chlorides / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects; D006868:Hydrolysis; D007295:Inositol Phosphates / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology*; D018021:Lithium Chloride; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000494:pharmacology; D012969:Sodium Fluoride / Q000494:pharmacology; D013403:Sugar Phosphates / Q000378:metabolism*
D002712:Chlorides; D007295:Inositol Phosphates; D013403:Sugar Phosphates; D012701:Serotonin; D002217:Carbachol; D012969:Sodium Fluoride; D008094:Lithium; D018021:Lithium Chloride; D009638:Norepinephrine