A model for the neurobiological mechanisms of action involved in lithium prophylaxis of bipolar affective disorder.
The effects of chronic administration of lithium chloride on the serotonin synthesizing apparatus in rat brain suggest a theoretical model that could explain how chronic treatment with lithium is prophylactic against both poles of affect in manic-depressive disorder. After three to five days of lithium chloride administration the Vmax of high affinity uptake of (14C) tryptophan into striate synaptosomes increased to 140% of control values, and tryptophan-to-serotonin conversion activity increased to about the same degree. These events were followed by an apparently compensatory decrease in the Vmax of midbrain activity cell body and striate nerve ending tryptophan hydroxylase activity. After 21 days of drug administration (14C)-tryptophan uptake remained above control levels, and soluble midbrain and solubilized striate synaptosomal enzyme activity remained below control levels, but synaptosomal conversion activity had returned to control levels. In vitro, drug concentrations from 10 to 53 mM did not affect the enzyme activity, but did enhance the uptake and conversion measures. Also, increasing tryptophan levels either by pre-incubation with L-tryptophan in vitro or by the administration of L-tryptophan (20 to 60 mg/kg) in vivo enhanced the uptake and conversion measures. The data suggest the possibility that lithium pushed two complementary adaptive mechanisms to their capacities, and the net result is restricted but balanced function of serotonergic transmission in the brain.
D000342:Affective Symptoms / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000648:ultrastructure; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D008636:Mesencephalon / Q000201:enzymology; D008954:Models, Biological; D051381:Rats; D012701:Serotonin / Q000096:biosynthesis; D013268:Stimulation, Chemical; D013347:Subcellular Fractions / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D012701:Serotonin; D014443:Tyrosine; D014364:Tryptophan; D008094:Lithium; D014365:Tryptophan Hydroxylase