A neurobiological model for the symmetrical prophylactic action of lithium in bipolar affective disorder

Pharmakopsychiatr Neuropsychopharmakol. 1976 May;9(3):116-26. doi: 10.1055/s-0028-1094486.


By treating rats with lithium chloride or cocaine hydrochloride, or lithium chloride followed by cocaine hydrochloride, we have shown the antagonistic effects of these drugs on two mechanisms that may be involved in regulating serotonin 5-HT) synthesis in the striate cortex. Lithium chloride (5 to 10 meq/kg/day) stimulates the relative velocity of the active uptake of labelled tryptophan and proportionally enhances the conversion of labelled tryptophan to 5-HT in synaptosomally enriched preparations. With continued administration of lithium chloride, the activity of tryptophan hydroxylase from the median raphe and subsequently in lysed synaptosomal preparations from striate cortex is reduced; the substrate uptake remains enhanced, but the conversion of substrate to transmitter returns to control levels. In contrast, an injection of cocaine hydrochloride inhibits the high affinity uptake of tryptophan, reducing the conversion of the amino acid to 5-HT and resulting in an increase in the biosynthetic enzyme activity. However, administration of cocaine hydrochter three daily lithium chloride injections (10 meq/kg) results in no apparent effects on substrate uptake, conversion, or enzyme activity. We theorize that the effect of lithium was to push two regulatory parameters (the uptake of substrate and the enzyme activity) to their respective functional upper and lower limits, leaving the serotonergic neurons "buffered" against the "usual" effects of the stimulant drug, and offer this neurobiological model for consideration in relation to the clinical effects of lithium in the prophylaxis of both mania and depression in some patients.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bipolar Disorder / physiopathology
  • Brain / drug effects
  • Brain / metabolism*
  • Cocaine / pharmacology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Humans
  • Kinetics
  • Lithium / pharmacology*
  • Male
  • Mesencephalon / drug effects
  • Mesencephalon / metabolism
  • Models, Biological
  • Morphine / pharmacology
  • Rats
  • Serotonin / biosynthesis*
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Time Factors
  • Tryptophan / metabolism
  • Tryptophan Hydroxylase / metabolism


  • Serotonin
  • Morphine
  • Tryptophan
  • Lithium
  • Tryptophan Hydroxylase
  • Cocaine