Days Of Lithium Administration Research Articles

Effect of lithium on phosphoinositide metabolism in human brain: a proton decoupled 31P magnetic resonance spectroscopy study

Background: The objective of our study was to evaluate whether lithium increases brain phosphomonoester (PME) levels in human subjects.Methods: Proton decoupled 31P magnetic resonance spectra were obtained from eight healthy volunteers before and after the administration of lithium carbonate, 450 mg b.i.d., for 7 and 14 days.Results: Pairwise comparisons of the mole percent PME revealed a significant increase from baseline at day 7 and day 14 of lithium administration.Conclusions: An increase in PME concentration with 7 and 14 days of lithium administration in the human brain in vivo was observed. Because the inositol-1-monophosphate contributes to the PME peak, this result suggests that some of the initial actions of lithium may occur through a reduction of myo-inositol, which in turn may initiate a cascade of secondary changes at different levels of signal transduction process and gene expression in brain, effects that are ultimately responsible for the therapeutic benefits of lithium.

Chronic Lithium Treatment Decreases Neuronal Activity in the Nucleus Accumbens and Cingulate Cortex of the Rat

Although the efficacy of lithium as a mood stabilizer is well documented, the mechanism of its therapeutic effect associated with prolonged treatment remains unknown. Identifying discrete brain regions and neural pathways that are functionally altered following long-term lithium treatment is central to elucidating a psychotherapeutic mechanism. We have used a sensitive and quantitative histochemical assay for the determination of cytochrome oxidase (CO) activity, a mitochondrial marker of neuronal activity, to determine the effect of repeated lithium treatment on regional neuronal activity in the rat brain. Oral lithium treatment (21 days) selectively decreased cytochrome oxidase activity in the cingulate cortex and regions of the nucleus accumbens. These decreases were not seen after 5 days of lithium administration, although serum lithium concentrations were similar after both 5 and 21 days of treatment. The analysis of interregional correlations further suggests a role for amygdala pathways in the effects of lithium following 21 days of treatment. The implications of these data for understanding the mechanisms of action of lithium are discussed.

Adaptive changes in the rat dopaminergic transmission following repeated lithium administration.

In the present study the alterations in the contents of dopamine (DA) and metabolites, as well as in the levels of mRNA coding for DA receptor D2, were determined in the rat striatum (STR) and nucleus accumbens septi (NAS), in correlation with the duration of lithium administration. Single or subchronic (3 days) administration of lithium produced less consistent effects as far as the levels of DA and metabolites are concerned; however, following 7 or 14 days of lithium administration, the DA release from terminals was significantly attenuated and the effect was more pronounced in NAS. After the same time of treatment, the increase in the levels of mRNA coding for the D2 receptor was increased; this might be interpreted as an adaptive change to the decreased dopaminergic transmission following the prolonged administration of lithium.

The effect of prolonged administration of lithium on the level of dopamine D2 receptor mRNA in the rat striatum and nucleus accumbens.

In the present study the alterations in the levels of mRNA coding for dopamine receptor D2, were determined in the rat striatum (STR) and the nucleus accumbens septi (NAS), in dependence on duration of lithium administration. The levels of mRNA coding for D2 receptor (determined using an in situ hybridization technique) were determined after 1, 7 and 14 days of lithium administration (LiCl, 6 mEq/kg, p.o.), at 3 and 24 h after the last dose of the drug. This treatment resulted in the increase in the levels of mRNA coding for dopamine receptor D2 in all brain regions examined and the effect depended on the time after lithium administration. However, the effect was most pronounced in the shell region of NAS, 24 h after the 14-day treatment.

The effect of lithium on cholinergically mediated GH responses in healthy volunteers

AbstractThe phosphoinositide (PI) cycle second messenger system mediates the effect of muscarinic receptor binding. Inositol, which is an essential substrate for phosphoinositide synthesis penetrates the blood‐brain barrier poorly, and is vulnerable to depletion. Lithium uncompetitively inhibits inositol‐1‐monophosphatase, a key enzyme in the recycling of inositol for the PI messanger system. There is evidence for cholinergic overactivity in depression from clinical and experimental observations. Among these, pyridostigmine (PYD) stimulated growth hormone (GH) release is found to be elevated relative to healthy controls. PYD/GH responses were examined in six healthy male volunteers before and after 10 days of lithium administration. GH responses did not differ significantly after lithium from those observed at baseline. These results suggest that lithium does not significantly inhibit cholinergically mediated GH secretion in healthy volunteers and provide further support for the selective action of lithium on upregulated cholinergic tracts, consistent with uncompetitive inhibition of the phosphoinositide cycle.

Increase in Na+/K+ pump numbers in vivo in healthy volunteers taking oral lithium carbonate and further upregulation in response to lithium in vitro.

1. We have measured [3H]-ouabain binding to lymphocyte membranes in eight healthy volunteers before and after they had taken lithium carbonate for 14 days in doses which maintained the serum lithium concentration in the range 0.5-1.0 mmol 1-1. 2. There was a statistically significant increase in the [3H]-ouabain binding capacity of the lymphocyte membranes (reflecting the number of Na+, K+-ATPase molecules) after 14 days of lithium administration in vivo. This suggests that a failure to increase pump numbers after similar exposure to lithium in vivo in patients with manic-depressive psychosis is a primary abnormality associated with the disease. 3. In vivo lithium administration did not alter the normal adaptive (upregulatory) response of lymphocyte Na+, K+-ATPase to standard pharmacological challenges, involving in vitro incubation for 3 days with lithium chloride (8 mmol 1-1) or sodium ethacrynate (1 mumol 1-1). 4. We have previously found that there is an impaired response of the Na+, K+-ATPase to these in vitro stimuli in patients with manic-depressive psychosis, and our present data suggest that this abnormality is attributable to the disease itself and not to in vivo lithium therapy. 5. The data also suggest that the increase in vivo Na+/K+ pump activity which we have previously described in healthy volunteers after 21 days of lithium administration is at least partly due to an increase in Na+/K+ pump numbers.

Lithium administration modulates platelet G i in humans

Platelet G proteins were assessed in 7 normal volunteers before and after 14 days of lithium administration at therapeutic plasma levels. Cholera and pertussis toxin catalyzed ADP-ribosylation of platelet membrane proteins were measured by SDS-PAGE. Immunoblotting with specific antibodies was used to measure platelet membrane α i content. There was a statistically significant 37% increase in pertussis toxin mediated ADP-ribosylation of a 40,000 Mr protein in platelet membranes after lithium administration, but cholera toxin mediated ADP-ribosylation of a 45,000 Mr protein and α i immunoblotting were unchanged by lithium. Increased pertussis toxin stimulated ADP-ribosylation in the absence of changes in α i content could be explained by a shift in platelet G i in favor of its undissociated, inactive form. This would be consistent with increased platelet adenylyl cyclase activity found in these same subjects after lithium.

Effect of lithium on the dynamics of electroencephalographic vigilance in healthy subjects

Eleven healthy male volunteers had EEG recordings before lithium, after 10 days of lithium administration and 2 weeks after discontinuation of lithium. As postulated from previous investigations the typical lithium effect on the dynamics of electroencephalographic vigilance proved to consist of: (1) a decrease of non-alpha segments, i.e., an increase of alpha continuity or an enhancement of alpha activity; (2) an increase of the anterior/posterior ratio of absolute alpha power (AQ); (3) a decrease of the dynamic variability of this alpha anteriorization (CV-AQ). In addition the decrease of dynamic variability of alpha anteriorization was found to be associated with an increase in the amplitude of P1/N1 components of auditory evoked potentials.

Effect of lithium on synaptosomal brain enzymes

During 7 days of lithium administration to rats, the levels of adenylate cyclase bound to brain synaptosomes decreased, while those of acetylcholinesterase increased. Both enzyme levels returned to their initial values after 1 month of treatment. Monoamine oxidase, which is bound to a mitochondrial membrane, was not affected by lithium treatment. Arrhenius plots of the brain synaptosomal enzymes (Na + K)ATPase and acetylcholinesterase from rats treated with LiCl for 7 or 30 days showed a lower transition temperature. Also, when these synaptosomal enzymes were exposed to such exogenous agents as detergents or alcohol, the reaction of the enzymes obtained from lithium treated rats was different than that of control rats. These effects disappeared after ceasing lithium administration for one week. These data indicate changes in the structure of brain membranes after lithium administration.

Effects of lithium, and lithium and alcohol administration on (NA + K)-ATPase

An increase in alcohol toxicity by lithium and vanadate was evidenced by the marked decrease found in time response to challenge by 3.1% ethanol of goldfish adapted to lithium (1 mM) or vanadate (1 μM). The maximal effect (approx. 50 per cent) occurred after 2 days exposure to lithium or vanadate, and it diminished with longer exposure; also, it is reversible after 2 days immersion in tap-water. Lithium intake by fish and rats reduces the brain (Na + K)-ATPase activity in 2 and 6 days respectively, to one-half that of the brains from control animals, but the enzyme level slowly increased to approx. 90 per cent of the original levels during longer periods of treatment. These data can be correlated with the inhibition of rat brain protein synthesis found after several days of lithium administration. Membrane ATPase levels (liver, heart, kidney and blood) were increased, but no alteration was observed in other liver and brain enzymes tested. Rats treated with lithium for a week showed a lower level of (Na + K)-ATPase in brain, as well as in liver, heart and kidney, when tested after either acute or chronic ethanol intoxication. The results presented in this paper, together with previous reports, indicate that brain (Na + K)ATPase is affected by lithium and alcohol and that these compounds can interact synergistically on the enzyme.

Lithium-induced acute renal failure in the rat

The toxic effects of lithium on kidney function were examined in rats given 8 mmol per kg body weight (ip) of lithium chloride as a 150 m m solution once a day. After 2 to 4 days of lithium administration the animals had lost 10 to 20 g body weight. Other signs of intoxication were impaired gastric emptying, muscle twitchings, hyperexcitability, and increased serum urea concentration. The rats were anesthetized with sodium amytal and hydrated with isotonic NaCl before and during the clearance determinations. Inulin clearance ( C in) was lowered by 40%, and T mPAH and renal plasma flow were lowered in proportion to C in. Plasma renin concentration was increased by a sixfold factor. The results suggest that lithium led to acute renal failure. Both circulatory disturbances and a direct toxic effect of lithium in the tubules are considered possible causes of the acute renal failure.

Lithium treatment of depression

Lithium carbonate in high doses was administered to 22 patients hospitalized for endogenous depression. A statistically significant difference in response was observed between bipolar and unipolar patients. All six with a prior history of mania responded to the drug, whereas only 7 of 16, or 44%, of those without such a history showed a favorable response. Among the 13 patients that responded to lithium, a dose of 1800 mg daily was well tolerated despite the development of mild neuromuscular side effects in many. A clinical response that first appeared between the 6th and 13th days of lithium administration generally plateaued by the end of 3 weeks. Following placebo substitution, symptoms reemerged in nine patients. This investigation has again shown that bipolar depressions are more responsive to lithium than are unipolar ones. It suggests that further efforts be made to identify those unipolar depressions having a high probability of responding to lithium.

Effect of lithium on plasma renin activity

The effect of lithium on renin secretion and on plasma renin activity (PRA) was studied in the rat. Administration of 3 mmoles/kg of LiCl caused a significant lowering of PRA within one day of beginning treatment and continued throughout the 14 days of lithium administration. Progressive increase of the dose of LiCl from 2 mmoles/kg to 16 mmoles/kg produced lowering of PRA at small doses and elevation of PRA at higher doses of lithium. The increase of PRA by high doses of lithium was abolished by the simultaneous injection of NaCl. Perfusion of the isolated rat kidney with a solution containing LiCl(> 5 mM) caused increased release of renin into the renal vein. Kidneys from rats pretreated with LiCl showed lower rates of renin secretion into the renal vein when perfused with lithium-free solutions. The possible mechanisms of the dual effect of lithium on renin levels are discussed.