LITHIUM EFFECTS ON CHOLINERGIC ACTIVITY

Project: Research project

Description

Although lithium is the primary treatment for bipolar affective disorders,
its mechanism of action is unknown. However, results from this and other
laboratories have identified two potentially important effects of
therapeutically relevant concentrations of lithium after chronic
administration to rats, impairment of second messenger formation
(especially phosphoinositide hydrolysis) in brain, and enhanced responses
to cholinergic agonists. Therefore, this proposal is designed to test
several specific hypotheses as to the mechanism of action of lithium on
these systems as well as studying basic modulatory mechanisms of second
messenger production and acetylcholine metabolism. To test the hypothesis that chronic lithium treatment impairs
phosphoinositide hydrolysis both in vivo and in vitro methods will be used.
We have recently applied a new method which measures the endogenous
unlabelled concentrations of inositol phosphates in rat brain regions after
sacrifice by microwave irradiation and found after chronic lithium an 80%
depletion of inositol trisphosphate and a reduced response to stimuli.
Dose-response, time course, and interactions with specific agonists and
antagonists will be carried out. In vitro measures of phosphoinositide
hydrolysis will be carried out to more completely identify mechanisms of
modulation of phosphoinositide hydrolysis. To test the hypothesis that chronic lithium treatment and other drugs, as
antidepressants and glucocorticoids, alter the function of G-proteins, we
will (i) apply Northern blot analysis using cDNA's for 5 G-proteins to
measure mRNA concentrations, (ii) use monoclonal antibodies and immunoblot
analysis to measure G-proteins, and (iii) measure ADP-ribosylation
catalyzed by cholera toxin, pertussis toxin, and the endogenous ADP-
ribosylation factor. To test the hypothesis that lithium potentiates cholinergic function, we
will (i) use EEG recordings in rats treated with cholinomimetics and either
lithium, which potentiates their actions causing seizures, or pertussis
toxin, which also potentiates cholinomimetic function, and (ii) measure
acetylcholine metabolism in vitro to identify modulatory effects of second
messengers and the effect of lithium. To test the hypothesis that lithium impairs cyclic AMP production, but less
so than phosphoinositide hydrolysis, the G-proteins associated with the
cyclic AMP system are included in the studies given above and cyclic AMP
concentrations will be measured after the same treatments used to measure
inositol phosphate production.
StatusFinished
Effective start/end date2/1/845/31/17

Funding

  • National Institutes of Health: $367,200.00
  • National Institutes of Health: $220,902.00
  • National Institutes of Health: $382,500.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $108,750.00
  • National Institutes of Health: $382,500.00
  • National Institutes of Health: $17,881.00
  • National Institutes of Health: $377,762.00
  • National Institutes of Health: $215,250.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $380,380.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $309,188.00
  • National Institutes of Health: $40,486.00
  • National Institutes of Health: $373,613.00
  • National Institutes of Health: $215,250.00
  • National Institutes of Health: $179,375.00
  • National Institutes of Health
  • National Institutes of Health: $300,222.00
  • National Institutes of Health: $366,250.00
  • National Institutes of Health
  • National Institutes of Health: $300,222.00
  • National Institutes of Health: $221,977.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Lithium
Cholinergic Agents
Glycogen Synthase Kinase 3
Mood Disorders
Phosphatidylinositols
GTP-Binding Proteins
Phosphorylation
Brain
Hydrolysis
Pharmaceutical Preparations
Bipolar Disorder
Valproic Acid
Inositol
Catenins
Therapeutics
Carbamazepine
Neurogenesis
Lipoylation
Protein Kinase C

ASJC

  • Medicine(all)