Neural and developmental actions of lithium: A unifying hypothesis

  title={Neural and developmental actions of lithium: A unifying hypothesis},
  author={Michael John Berridge and C. Peter Downes and Michael R. Hanley},

Lithium and synaptic plasticity.

Findings demonstrate that lithium directly inhibits, in a non-competitive fashion, the activity of glycogen synthase kinase (GSK)-3beta, a serine/threonine kinase highly expressed in the central nervous system, which raises the possibility for developing new therapeutic approaches for the treatment of bipolar disorders.

Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilisers

The results suggest that regulation of signalling pathways may play a major part in the long-term actions of mood stabilisers and may exert underappreciated neuroprotective effects.

Phosphoinositide metabolism, lithium and manic depressive illness

It is likely that the enzyme IMPase, other that being the key point in initiating lithium's therapeutic effects, may also play a critical role in the physiology underlying manic depressive illness.

Signal transduction pathways. Molecular targets for lithium's actions.

The identification of key components of signal transduction pathways (in particular, guanine nucleotide-binding proteins [G proteins], adenylyl cyclases, and protein kinase C isozymes) as targets for lithium's actions are reviewed to integrate these effects with the large body of data emphasizing alterations in various neurotransmitter systems.

Neural network dysfunction in bipolar depression: clues from the efficacy of lamotrigine.

In healthy volunteers, lamotrigine had a facilitatory effect on the BOLD response to TMS (transcranial magnetic stimulation) of the prefrontal cortex, and in vitro, lamOTrigine enhanced the power of gamma frequency network oscillations induced by kainic acid in the rat hippocampus, an effect that was not observed with valproic acid.

Neurobiology of lithium: an update.

The accumulated preclinical and clinical evidence for the action of lithium in the brain is critically examined and areas that may be most productive for future investigation are suggested, i.e., membrane transport systems, neurotransmitter receptor regulation, second messenger generating systems, protein kinase C (PKC) regulation, and gene expression.

Signalling pathways in the brain: cellular transduction of mood stabilisation in the treatment of manic-depressive illness.

Chronic lithium administration produces a reduction in the expression of PKC alpha and epsilon, as well as a major PKC substrate, MARCKS, which has been implicated in long-term neuroplastic events in the developing and adult brain.

Lithium: the pharmacodynamic actions of the amazing ion

Support is provided for a role for the inhibition of glycogen synthase kinase 3 and inositol monophosphatase in the pharmacodynamic actions of lithium, and how inhibition of these enzymes by lithium can lead to downstream effects of clinical relevance, both for mood disorders and neurodegenerative diseases.

Lithium and valproic acid: parallels and contrasts in diverse signaling contexts.

Long‐term action of lithium: A role for transcriptional and posttranscriptional factors regulated by protein kinase C

Evidence is presented to show that chronic lithium exerts significant transcriptional and posttranscriptional effects, and that these actions of lithium may be mediated via protein kinase C (PKC)‐induced alterations in nuclear transcription regulatory factors responsible for modulating the expression of proteins involved in long‐term neural plasticity and cellular response.



Lithium dampens neurotransmitter response in smooth muscle: relevance to action in affective illness.

Dampening of neurotransmitter responses by lithium treatment may explain the unique ability of lithium to relieve and prevent both mania and depression.

Neural function: metabolism and actions of inositol metabolites in mammalian brain.

  • M. HanleyT. Jackson A. Pini
  • Biology
    Philosophical transactions of the Royal Society of London. Series B, Biological sciences
  • 1988
The results suggest that the inositol lipid signalling pathways may generate both intracellular and extracellular signals in brain.

Occurrence and extracellular actions of inositol pentakis- and hexakisphosphate in mammalian brain

Evidence that InsP5 and InsP6 are synthesized in intact brain after labelling with [3H]inositol in vivo is reported and it is shown that local infusion of InsP4,5,6 into a discrete brain stem nucleus implicated in cardiovascular regulation, results in dose-dependent changes in heart rate and blood pressure.

Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands.

The ability of Li+ to greatly amplify the agonist-dependent accumulation of myo-inositol 1-phosphate offers a novel technique for identifying those receptors that function by hydrolysing phosphatidyl inositol, which may help reset the sensitivity of those multifunctional receptors that generate second messengers such as Ca2+, cyclic GMP and the prostaglandins.

Acute and chronic lithium treatments influence agonist and depolarization-stimulated inositol phospholipid hydrolysis in rat cerebral cortex.

In conclusion, acute and chronic Li treatments producing less than [1 mM] in cerebral tissue, severely disrupts phosphoinositide metabolism, and such effects may well be secondary to inhibition of inositol-monophosphatase, and therefore do not appear to result from depletedosphoinositides.

Lithium blocks a phosphoinositide-mediated cholinergic response in hippocampal slices.

A dampening of phosphoinositide-mediated neurotransmission may explain the normalizing effects of lithium in treating both mania and depression.

Subacute and Chronic In Vivo Lithium Treatment Inhibits Agonist‐ and Sodium Fluoride‐Stimulated Inositol Phosphate Production in Rat Cortex

The results indicate that subacute or chronic in vivo lithium treatment reduces agonist‐stimulated inositol phospholipid metabolism in cerebral cortex; this persistent inhibition appears to be at the level of G‐protein–phospholipase C coupling.

Structure and functional expression of cloned rat serotonin 5HT‐2 receptor.

A complementary DNA (cDNA) encoding a serotonin receptor with 51% sequence identity to the 5HT‐1C subtype was isolated from a rat brain cDNA library by homology screening. Transient expression of the

Systemic cholinergic agents induce seizures and brain damage in lithium-treated rats.

Administration of pilocarpine or physostigmine to rats treated with lithium chloride produced sustained limbic seizures, widespread brain damage, and increased concentrations of