Effect Of Acute Lithium Administration Research Articles

Effect of acute lithium administration on penile erection: involvement of nitric oxide system

Lithium has been the treatment of choice for bipolar disorder (BD) for many years. Although erectile dysfunction is a known adverse effect of this drug, the mechanism of action by which lithium affects erectile function is still unknown. The aim was to investigate the possible involvement of nitric oxide (NO) in modulatory effect of lithium on penile erection (PE). We further evaluated the possible role of Sildenafil in treatment of lithium-induced erectile dysfunction. Erectile function was determined using rat model of apomorphine-induced erections. For evaluating the effect of lithium on penile erection, rats received intraperitoneal injection of graded doses of lithium chloride 30 mins before subcutaneous injection of apomorphine. To determine the possible role of NO pathway, sub-effective dose of N (G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, was administered 15 min before administration of sub-effective dose of lithium chloride. In other separate experimental groups, sub- effective dose of the nitric oxide precursor, L-arginine, or Sildenafil was injected into the animals 15 min before administration of a potent dose of lithium. 30 min after administration of lithium chloride, animals were assessed in apomorphine test. Serum lithium levels were measured 30 min after administration of effective dose of lithium. Lithium at 50 and 100 mg/kg significantly decreased number of PE (p<0.001), whereas at lower doses (5, 10 and 30 mg/kg) had no effect on apomorphine induced PE. The serum Li+ level of rats receiving 50 mg/kg lithium was 1±0.15 mmol/L which is in therapeutic range of lithium. The inhibitory effect of Lithium was blocked by administration of sub-effective dose of nitric oxide precursor L-arginine (100 mg/kg) (p<0.001) and sildenafil (3.5 mg/kg) (p<0.001) whereas pretreatment with a low and sub-effective dose of L-NAME (10mg/kg) potentiated sub-effective dose of lithium, (p<0.001). These results suggest acute treatments with lithium cause erectile dysfunction in an in-vivo rat model. Furthermore it seems that the NO pathway might play role in erectile dysfunction associated with lithium treatment. Findings also suggest that Sildenafil may be effective in treatment of lithium-associated erectile dysfunction.

Protective effects of acute lithium preconditioning against renal ischemia/reperfusion injury in rat: Role of nitric oxide and cyclooxygenase systems

Delayed graft function secondary to ischemia/reperfusion injury has been shown to be associated with increased rate of allograft failure following kidney transplantation. Previously, we have shown that chronic lithium pretreatment protects kidney against ischemia/reperfusion injury. In the present study we aimed to examine the effects of acute lithium administration on the renal ischemia/reperfusion injury in rat. Ischemia/reperfusion injury was induced by clamping left renal pedicle for 60min, two weeks after right nephrectomy. The mechanism of lithium-mediated renoprotection was explored by combined use of lithium and nitro-l-arginine methyl ester (L-NAME) (non-selective nitric oxide synthase inhibitor) and/or indomethacin (non-selective cyclooxygenase pathway inhibitor). Lithium-treated animals were given 40mg/kg lithium chloride intraperitoneally, 30min before ischemia. To investigate the role of nitric oxide and cyclooxygenase pathways in renoprotective effect of lithium, L-NAME and/or indomethacin were administered before lithium injection. Serum creatinine, blood urea nitrogen, and renal histology were assessed after 24h of reperfusion. Lithium preconditioning significantly reduced creatinine and blood urea nitrogen (P<0.001) and improved renal histology. Administration of L-NAME completely reversed renoprotective effect of lithium. In contrast indomethacin significantly potentiated the lithium renoprotection. Moreover, co-administration of L-NAME and indomethacin completely abolished the protective effects of lithium. The results show that a single dose of lithium significantly improves renal function following ischemia/reperfusion injury. In conclusion, the ability of lithium to enhance renal tissue tolerance against ischemia/reperfusion injury suggests a potential clinical application in the setting of kidney transplantation. However, more detailed investigations are required before any definite conclusion.

Effect of lithium treatments on the tyrosine-aminopeptidase activities in the rat brain and the pituitary gland.

Lithium (CAS 7439-93-2) is being utilized widely for the treatment of manic-depressive illness. However, the neurochemical mechanism of the ion action still remains relatively obscure. In the present work, the effect of acute lithium administration on soluble and membrane-bound enkephalin-degrading tyrosine-aminopeptidase activities in discrete brain areas and the pituitary gland is described. Tyrosine-aminopeptidase activities have been measured fluorometrically using Tyr-beta-naphthylamide as substrate and puromycin as selective inhibitor of one of the two membrane activities. Soluble and membrane-bound puromycin-insensitive Tyr-aminopeptidase activities are greater in the pituitary gland after treatment with 5 and 10 meq/kg of lithium. It is suggested that these enzyme activities could play a part in the lithium action mechanism.

Lithium decreased endothelium‐mediated, but not nonadrenergic noncholinergic, relaxation of guinea pig corpus cavernosum in vitro: a role for nitrergic system

Lithium causes erectile dysfunction in patients but its mechanism is yet unknown. The aim of our study was to verify the effect of acute lithium administration on the nonadrenergic noncholinergic (NANC)- and endothelium-mediated relaxation of guinea pig isolated corpus cavernosum. Although lithium (0.5, 1, and 5mm) had no effect on the neurogenic relaxations, it significantly (P<0.001) attenuated the relaxant responses to acetylcholine in a concentration-dependent manner. Combination of low concentration of lithium (0.5mm) with either 0.1 or 1μm l-NAME significantly (P<0.001) reduced the endothelium-mediated relaxation. Although the Nitric oxide (NO) precursor l-arginine at 1mm did not alter the relaxant responses to acetylcholine in control strips, it improved the inhibition by lithium (1mm) of relaxant responses to acetylcholine. Sodium nitroprusside (SNP; 10nm-1mm) produced similar concentration-dependent relaxations in both groups. Our experiments indicated that lithium can result in impairment of the NO-mediated endothelium-dependent but not NANC relaxation of guinea pig corpus cavernosum.

Nitric oxide modulates the antidepressant-like effect of acute lithium administration in the mouse forced swimming test

Background Lithium has largely met its initial promise as the first drug to be discovered in the modern era of psychopharmacology, yet no definitive mechanism for its effect has been established. In the present study we evaluated the involvement of L-arginine/nitric oxide (NO)/cGMP pathway in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test (FST).

Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test

In the present study we evaluated the involvement of l-arginine/nitric oxide (NO)/cGMP pathway in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test (FST). Lithium, at 30 and 100 mg/kg, significantly reduced the immobility times of mice in the FST, whereas at lower doses (0.5, 5 and 10 mg/kg) had no effect on the immobility time. The NO synthase (NOS) inhibitor N G-nitro- l-arginine methyl ester ( l-NAME), at 10 and 30 mg/kg, and the selective neuronal NOS inhibitor N ω-propyl- l-arginine ( l-NPA), at 5 and 15 mg/kg, had no significant effects on the FST, whereas they significantly decreased the immobility time at 100 and 30 mg/kg, respectively. Combination of non-effective dose of lithium (10 mg/kg) with low doses of l-NAME (30 mg/kg) or l-NPA (15 mg/kg) significantly reduced the immobility times in the FST. Moreover, the guanylyl cyclase inhibitor ODQ at 50 mg/kg significantly decreased the immobility time of mice, whereas it had not significant effects on the FST at 2, 10 and 20 mg/kg. Combination of lithium (10 mg/kg) with 20 mg/kg ODQ significantly decreased the immobility times in the FST. Non-effective doses of l-arginine (750 mg/kg) or sildenafil (5 mg/kg) significantly reversed the antidepressant-like effect of 30 mg/kg lithium in the FST. Neither of the drugs had effect on the locomotor activity. These data indicate the involvement of l-arginine/NO/cGMP pathway in the antidepressant-like effect of lithium in the mouse FST and also might suggest the concurrent administration of NOS inhibitors and lithium as an appropriate strategy for treatment of depression.

Nitric oxide involvement in the effect of acute lithium administration on the nonadrenergic noncholinergic-mediated relaxation of rat gastric fundus

Introduction. Lithium has largely met its initial promise as the first drug to be discovered in the modern era of psychopharmacology. However, the mechanism for its action remains an enigma. The aim of the present study was to verify the effect of acute lithium administration on the nonadrenergic noncholinergic (NANC)-mediated relaxation of rat isolated gastric fundus and to evaluate the role of nitric oxide pathway in this manner. Materials and methods. The isolated rat gastric fundus strips were precontracted with 0.5 μM serotonin and electrical field stimulation (EFS) was applied at 5 Hz frequency to obtain NANC-mediated relaxation in the presence or absence of lithium (0.1, 0.5, 1 and 5 mM). Also, effects of combining lithium (0.1 mM) with the NO synthase (NOS) inhibitor l-NAME (0.03 μM) or the guanylyl cyclase inhibitor ODQ (1 μM) on relaxant responses to EFS was investigated. Moreover, effects of combining lithium (1 mM) with 0.1 mM l-arginine (a precursor of NO) on neurogenic relaxation were assessed. Also, the effect of lithium (1 mM) on relaxation to sodium nitroprusside (SNP; 1 nM–0.1 mM) and glyceryltrinitrate (GTN; 0.1–10 μM) was investigated. Results. The NANC-mediated relaxation was significantly ( P < 0.001) reduced by lithium in a dose- and time-dependent manner. Combination of lithium (0.1 mM) with l-NAME (0.03 μM), which separately had partial inhibitory effect on relaxations, significantly ( P < 0.001) reduced the NANC-mediated relaxation of gastric fundus. ODQ (1 μM) significantly inhibited the neurogenic relaxations in the presence or absence of lithium (0.1 and 1 mM). Although l-arginine at 0.1 mM had no effect on relaxation to EFS, it prevented the inhibition by lithium (1 mM) of relaxant responses to EFS. Also, SNP and GTN produced concentration-dependent relaxation in precontracted rat gastric fundus which was not altered by lithium incubation (1 mM). Discussion. Our experiments indicated that lithium likely by interfering with l-arginine/NO pathway in nitrergic nerve can result in impairment of NANC-mediated relaxation of rat gastric fundus.

Effect of lithium on endothelium-dependent and neurogenic relaxation of rat corpus cavernosum: Role of nitric oxide pathway

Introduction Some studies have reported erectile dysfunction in patients receiving lithium through a mechanism that has not yet been defined. The aim of the present study was to verify the effect of acute lithium administration on the nonadrenergic noncholinergic (NANC)- and endothelium-mediated relaxation of rat isolated corpus cavernosum. Materials and methods The isolated rat corporeal strips were precontracted with phenylephrine hydrochloride (7.5 μM) and electrical field stimulation (EFS) was applied at different frequencies (2, 5, 10, and 15 Hz) to obtain NANC-mediated relaxation or relaxed by adding cumulative doses of acetylcholine (10 nM–1 mM) to obtain endothelium-dependent relaxation in the presence or absence of lithium (0.3, 0.5, 1, and 5 mM). Also, effects of combining lithium (0.3 mM) with 30 nM and 0.1 nM l-NAME (an NO synthase inhibitor) on NANC- and acetylcholine-mediated relaxation was investigated, respectively. Moreover, effects of combining lithium (1 mM) with 0.1 mM and 10 μM l-arginine (a precursor of NO) on NANC- and endothelium-mediated relaxation was assessed, respectively. Also, the effect of lithium (1 mM) on relaxation to sodium nitroprusside (SNP; 1 nM–1 mM), an NO donor, was investigated. Results The NANC-mediated relaxation was significantly ( P < 0.001) reduced by 1 and 5 mM, but not by 0.3 and 0.5 mM lithium. Lithium significantly ( P < 0.001) attenuated the maximum response to acetylcholine in a concentration-dependent manner. Combination of lithium (0.3 mM) with 30 and 0.1 nM l-NAME, which separately had a minimum effect on NANC- and endothelium-mediated relaxation, significantly ( P < 0.001) reduced the NANC- and endothelium-mediated relaxation, respectively. Although l-arginine at 10 μM and 0.1 mM did not alter the relaxant responses to acetylcholine and EFS, it improved the inhibition by lithium (1 mM) of relaxant responses to acetylcholine and EFS, respectively. Also, SNP produced similar concentration-dependent relaxations from both groups. Discussion Our experiments indicated that lithium likely by interfering with NO pathway in both endothelium and nitrergic nerve can result in impairment of both the endothelium- and NANC-mediated relaxation of rat corpus cavernosum.

Metabolism of inositol 1,4,5-trisphosphate in mouse brain due to decapitation ischemic insult: effects of acute lithium administration and temporal relationship to diacylglycerols, free fatty acids and energy metabolites

Previous studies have shown that global cerebral ischemia induced by decapitation leads to the stimulated hydrolysis of poly-phosphoinositides. In this study, the decapitation model was used to further examine the temporal events related to metabolism of Ins(1,4,5)P 3 and the release of diacylglycerols (DGs) and free fatty acids (FFAs) in the mouse brain. Since lithium administration is known to inhibit inositol monophosphatase activity in brain, the effects of acute lithium injection on Ins(1,4,5)P 3 metabolism were also examined. Cerebral ischemia induced by decapitation of C57 B1/6J mice resulted in transient increases of Ins(1,4,5)P 3, Ins(1,4)P 2 and Ins(4)P which peaked at 35, 65 and 125 s, respectively. The level of Ins(1)P, however, was not altered. Mice administered lithium by intraperitoneal injection (8 meq/kg for 4 h) gave rise to a 40- and 4-fold increase in levels of Ins(1)P, Ins(4)P, respectively, a 20% increase in levels of Ins(1,4)P 2 but no apparent changes in the levels of Ins(1,4,5) P 3. Decapitation also induced an increase in the levels of DGs and FFAs. Unlike the transient appearance of Ins(1,4,5)P 3, however, DG levels increased steadily for 2 min and then reached a plateau whereas the FFAs showed a lag time of 35 s prior to a biphasic increase. During the initial 2 min after decapitation, there was a preferential increase in the DG species containing 18:0 and 20:4. Lithium administration did not alter the decapitation-induced release of DG and FFA. As expected, decapitation gave rise to a rapid decrese iin the levels of phosphocreatine and ATP and the decline in ATP was marked by a transient appearance of ADP and a concomitant increase in AMP. With the exception of a slight change in the level of phosphocreatine at the 5 s time point, the temporal changes in energy metabolites were not different in mice that were administered lithium.

Serotonin does not mediate the adrenal catecholamine-releasing effect of acute lithium administration in rats

The activity of central serotonin (5-hydroxytryptamine, 5-HT) systems has been reported to be affected by repeated, and to a lesser extent by acute, lithium chloride (LiCl) treatment. Because (1) acute LiCl administration increases sympathoadrenal function, and in turn plasma glucose levels, and (2) stimulation of either the 5-HT 1A, the 5-HT 1C or the 5-HT 2 receptor subtype has adrenal catecholamine-releasing and hyperglycemic effects, we have investigated the influence of prior blockade of either of these receptor subtypes on plasma catecholamine and glucose responses to acute LiCl administration in conscious, catheterized rats. Acute administration of LiCl (1–8 mEq/kg IV) triggered dose-dependent increases in plasma epinephrine (Epi), norepinephrine (NE), and glucose levels throughout the 60-min analysis. In contrast, administration of NaCl (8 mEq/kg IV) did not alter plasma Epi or NE levels, nor did it affect plasma glucose levels. Prior blockade of 5-HT 1A receptor and β-adrenoceptors by means of (−)-propranolol (5 mg/kg IV), 10 min beforehand) did not affect plasma Epi and NE responses to LiCl (4 mEq/kg), but it did prevent the hyperglycemic effect of LiCl. Plasma Epi, NE and glucose responses to LiCl remained intact in rats pretreated with the 5-HT 1C/5-HT 2 receptor antagonist LY 53857 (1 mg/kg IV), 10 min beforehand). These results strongly suggest that LiCl-induced adrenal catecholamine release (and hyperglycemia) is not mediated by increased 5-HT release.

Lithium as an Adjunct in the Treatment of Major Depression

This paper reports a double-blind cross-over study (1) to investigate the efficacy of lithium carbonate to produce rapid relief of major depression in patients who were previously unresponsive to at least 4 weeks of antidepressant therapy; (2) to study the effect of acute lithium administration on antidepressant blood levels. In contrast to other studies, lithium was found to be no more effective than placebo. The effect of lithium adjunct on antidepressant levels was not significant.

The effect of acute lithium administration on brain monoamine synthesis and the precursor amino acids tyrosine and tryptophan in brain and plasma in rats.

The effect of a single i.p. injection of lithium chloride on brain monoamine synthesis and tyrosine and tryptophan levels in brain and plasma in rats was studied. Acute lithium administration was found to decrease brain tyrosine levels, which most likely was due to decreased plasma tyrosine levels. Brain tryptophan levels were mainly unaffected whereas plasma tryptophan leves were slightly decreased at 8 hours after lithium administration. Brain catecholamine synthesis was decreased at 4 hours and increased at 48 hours after the injection of lithium. Brain 5-hydroxytryptamine (5-HT) synthesis was decreased at all time intervals after the injection of lithium. It is concluded that the effects of acute lithium administration on brain monoamine synthesis are not mainly due to its effect on brain tyrosine and tryptophan levels in rats. Furthermore acute lithium administration appears to affect 5-HT synthesis to a greater extent than it affects catecholamine synthesis.

Effects of acute lithium administration on conditioned avoidance behavior and monoamine synthesis in rats.

The effect of a single injection of various doses of lithium chloride was tested on conditioned avoidance behavior and on the accumulation of DOPA and 5-HTP after inhibition of aromatic amino acid decarboxylase. Lithium specifically suppressed conditioned avoidance behavior and reduced formation of DOPA, but not 5-HTP. The behavioral effect of lithium could be completely antagonized with additional L-DOPA treatment. The results indicate that lithium has a neuroleptlike effect on avoidance behavior, and it is suggested that some of the behavioral effects of lithium may be mediated via interference with central catecholaminergic mechanisms.