A novel action of lithium: stimulation of glutamate release and inositol 1,4,5 trisphosphate accumulation via activation of the N-methyl D-aspartate receptor in monkey and mouse cerebral cortex slices

Adv Enzyme Regul. 1996;36:229-44. doi: 10.1016/0065-2571(95)00021-6.


Beginning at therapeutic concentrations (1-1.5mM), the anti-manic-depressive drug, lithium, stimulated the release of the major excitatory central neurotransmitter, glutamate, in monkey cerebral cortex slices in a time- and concentration-dependent manner, and this was associated with increased inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] accumulation. (+/-)-3-(2-Carboxypiperazin-4-yl)-propyl-1-phosphoric acid (CPP), dizocilpine (MK-801), ketamine, and Mg(2+)-antagonists to the N-methyl D-aspartate (NMDA) receptor/channel complex selectivity inhibited lithium-stimulated Ins(1,4,5)P3 accumulation. Antagonists to cholinergic-muscarinic, alpha 1-adrenergic, 5-HT2-serotoninergic and H1-histaminergic receptors had no effect. Antagonists to non-NMDA glutamate receptors had no effect on lithium-stimulated Ins(1,4,5)P3 accumulation. Possible reasons for this are discussed. Similar results were obtained in mouse cerebral cortex slices. Carbetapentane, which inhibits glutamate release, inhibited lithium-induced Ins(1,4,5)P3 accumulation in this model. It is concluded that the primary effect of lithium in the cerebral cortex slice model is stimulation of glutamate release, which, via activation of the NMDA receptor, leads to Ca2+ entry. Ca2+ entry, in turn, activates phospholipase C. These effects may have relevance to the therapeutic action of lithium in the treatment of manic-depression, as well as its toxic effects, especially at lithium blood levels above 1.5mM. A general conclusion which can be drawn from these studies and earlier studies in our laboratory is that lithium potentiates the action of phospholipase C, whether this enzyme is activated by lithium-induced presynaptic release of neurotransmitter, such as glutamate, or by the addition of an exogenous neurotransmitter, such as acetylcholine. However, this does not appear to be due to a direct activation of phospholipase C.

Publication types

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

MeSH terms

  • Animals
  • Calcium Channels / metabolism
  • Cerebral Cortex / metabolism*
  • Cyclopentanes / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Glutamic Acid / metabolism*
  • Haplorhini
  • Inositol 1,4,5-Trisphosphate / metabolism*
  • Inositol 1,4,5-Trisphosphate Receptors
  • Lithium / pharmacology*
  • Mice
  • Piperazines / pharmacology
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Valproic Acid / pharmacology


  • Calcium Channels
  • Cyclopentanes
  • Excitatory Amino Acid Antagonists
  • Inositol 1,4,5-Trisphosphate Receptors
  • Piperazines
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, N-Methyl-D-Aspartate
  • carbetapentane
  • Glutamic Acid
  • Valproic Acid
  • Inositol 1,4,5-Trisphosphate
  • 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid
  • Lithium