Acute Lithium Administration Research Articles

Beneficial effects of low-dose lithium on cognitive ability and pathological alteration of Alzheimer's disease transgenic mice model.

Lithium has been shown to delay the progression of Alzheimer's disease to reduce the prevalence of dementia. However, its narrow therapeutic index and numerous toxic effects at conventional dosage limited its long-term use to older subjects. Here, we tested the effect of low-dose lithium on cognitive impairment and pathology alterations in a mouse model of Alzheimer's disease, the amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mouse. We found that both chronic and acute administration of lithium dose-dependently increased in blood and brain tissues. Long-term administration of low-dose lithium does not affect the body weight of APP/PS1 mice, but can significantly improve spatial memory of APP/PS1 mice. Pathologically, it also reduced β-amyloid plague and p-tau levels. Therefore, our results show that long-term low-dose lithium can ameliorate cognitive dysfunction and pathological alterations of Alzheimer's disease transgenic mice, and provide a theoretical basis for the further application of low-dose lithium in Alzheimer's disease clinical treatment.

Questioning the predictive validity of the amphetamine-induced hyperactivity model for screening mood stabilizing drugs

Animal models are critical for the study of disease mechanisms and the screening of potential novel treatments. In the context of bipolar disorder, amphetamine-induced hyperactivity (AIH) is a frequently used screening model for antimanic effects. Yet, the utility of screening models depends on their predictive (or pharmacological) validity and it is expected that such models will respond to effective treatments. Lithium is the prototypic mood stabilizer but previous data regarding the effects of lithium in the AIH model are not clear and most data comes from studies using acute lithium administration that is not relevant to the therapeutic regimen in patients. To evaluate the pharmacological validity of AIH as a model for mania-like behavior we tested the interaction between chronic oral administration of lithium and amphetamine in ICR (CD-1®) mice and in black Swiss mice. We conducted 4 different experiments where chronic lithium was followed by an acute injection of amphetamine and one experiment where chronic amphetamine was combined with chronic lithium. The results show that amphetamine result in hyperactivity (experiments 1–4) and that lithium has no effects. Moreover, chronic amphetamine (experiment 5) result in sensitization that is not attenuated by lithium. The results clearly show that the predictive validity of the AIH model in ICR or black Swiss mice is problematic and possibly cast doubt on the utilization of the AIH as a screening model for novel mood stabilizers in other strains of mice.

Mania-like elevated mood in rats: Enhanced 50-kHz ultrasonic vocalizations after sleep deprivation

Mania is characterized by elevated drive and mood but animal models of mania have often neglected elevated mood. Ultrasonic vocalizations (USV) of 50-kHz emitted by rats are thought to index the subject's positive affective state. Fifty-kHz USV emission is increased by amphetamine, an effect blocked by lithium administration. Sleep deprivation (SD) is an environmental model of mania and the present study evaluated SD effects on behavioral activity and USV emission, together with the impact of lithium treatment. Adult rats were submitted to 24h or 72h SD, and locomotor activity and USV emission were assessed. To test their sensitivity to a standard antimanic drug, these behavioral parameters were also evaluated after acute administration of lithium carbonate (25, 50 or 100 mg/kg, i.p.). Striatal monoamine content was measured post-mortem. SD (24h and 72h) led to increased locomotor activity, rearing behavior and 50-kHz USV emission, together with a change in the call profile characterized by an increase in the percentage of frequency-modulated 50-kHz USV, which may indicate the mania-like consequences of SD. Importantly, all SD effects were reverted by lithium administration. SD also led to a decrease in dopamine content in the ventral striatum, while increasing dopamine turnover. In conclusion, SD increased 50-kHz USV emission, an effect prevented by acute lithium administration. This suggests 50-kHz USV as a new marker for mania-like elevated mood, which shows construct validity (associated with increased dopaminergic tone), face validity (reflecting increased positive affect) and predictive validity (high sensitivity to lithium treatment).

Lithium attenuates the proconvulsant effect of adolescent social isolation stress via involvement of the nitrergic system.

In this study, we tested whether acute administration of lithium mitigates the deleterious effect of adolescent social isolation stress (SIS) on seizure susceptibility. In comparison with socially conditioned (SC) mice, isolated conditioned (IC) mice exhibited an increase in seizure susceptibility to pentylenetetrazole. Acute administration of lithium (10mg/kg) reversed the proconvulsant effect of SIS in IC mice, but this effect was not observed in SC mice. Coadministration of subthreshold doses of lithium (3mg/kg) with nitric oxide synthase (NOS) inhibitors reversed the effect of SIS on seizure susceptibility and decreased hippocampal nitrite levels in IC animals. In addition, a subthreshold dose of a nitric oxide precursor reduced the protective effect of lithium on seizure susceptibility and increased nitrite levels in the hippocampus of IC mice. These results suggest that lithium exerts a protective influence against the proconvulsant effect of adolescent SIS via a nitrergic system that includes activation of neuronal NOS in the hippocampus.

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.

Protein kinase C inhibition rescues manic-like behaviors and hippocampal cell proliferation deficits in the sleep deprivation model of mania.

Background:Recent studies revealed that bipolar disorder may be associated with deficits of neuroplasticity. Additionally, accumulating evidence has implicated alterations of the intracellular signaling molecule protein kinase C (PKC) in mania.Methods:Using sleep deprivation (SD) as an animal model of mania, this study aimed to examine the possible relationship between PKC and neuroplasticity in mania. Rats were subjected to SD for 72h and tested behaviorally. In parallel, SD-induced changes in hippocampal cell proliferation were evaluated with bromodeoxyuridine (BrdU) labeling. We then examined the effects of the mood stabilizer lithium, the antipsychotic agent aripiprazole, and the PKC inhibitors chelerythrine and tamoxifen on both behavioral and cell proliferation impairments induced by SD. The antidepressant fluoxetine was used as a negative control.Results:We found that SD triggered the manic-like behaviors such as hyperlocomotion and increased sleep latency, and reduced hippocampal cell proliferation. These alterations were counteracted by an acute administration of lithium and aripiprazole but not of fluoxetine, and only a single administration of aripiprazole increased cell proliferation on its own. Importantly, SD rats exhibited increased levels of phosphorylated synaptosomal-associated protein 25 (SNAP-25) in the hippocampus and prefrontal cortex, suggesting PKC overactivity. Moreover, PKC inhibitors attenuated manic-like behaviors and rescued cell proliferation deficits induced by SD.Conclusions:Our findings confirm the relevance of SD as a model of mania, and provide evidence that antimanic agents are also able to prevent SD-induced decrease of hippocampal cell proliferation. Furthermore, they emphasize the therapeutic potential of PKC inhibitors, as revealed by their antimanic-like and pro-proliferative properties.

Acute administration of lithium, but not valproate, modulates cognitive judgment bias in rats.

Rationale and objectivesBoth valproic acid (VPA) and lithium (LI) are well-established treatments for therapy of intense and sustained mood shifts, which are characteristics of affective disorders, such as bipolar disorder (BP). As mood and cognitive judgment bias have been found to be strongly interrelated, the present study investigated, in an animal model, whether acute treatment with VPA or LI could affect cognitive judgment bias.MethodsTo accomplish this goal, two groups of rats received single injections of either VPA or LI after initial behavioral training and were subsequently tested with the ambiguous-cue interpretation (ACI) test. Both drugs were administered in three doses using the fully randomized Latin square design.ResultsVPA (100, 200, and 400 mg/kg) had no significant effect on the interpretation of the ambiguous cue. LI at the lowest dose (10 mg/kg) had no effect; at an intermediate dose (50 mg/kg), it significantly biased animals towards positive interpretation of the ambiguous cue, and at the highest dose (100 mg/kg), it impaired the ability of animals to complete the test.ConclusionTo our knowledge, this is the first study demonstrating lithium’s effects on increased optimistic judgment bias. Future studies may focus on the ability of putative pharmacotherapies to modify the cognitive judgment bias dimension of patients at risk for bipolar disorder or depression.

Early targets of lithium in rat kidney inner medullary collecting duct include p38 and ERK1/2.

Almost half of patients receiving lithium salts have nephrogenic diabetes insipidus. Chronic lithium exposure induces AQP2 downregulation and changes in the cellular composition of the collecting duct. In order to understand these pathophysiological events, we determined the earliest lithium targets in rat inner medullary collecting duct (IMCD) by examining changes in the IMCD phosphoproteome after acute lithium administration. IMCDs were isolated 9 h after lithium exposure, a time when urinary concentrating impairment was evident. We found 1093 unique phosphopeptides corresponding to 492 phosphoproteins identified and quantified by mass spectrometry. Label-free quantification identified 152 upregulated and 56 downregulated phosphopeptides in response to lithium. Bioinformatic analysis highlighted several signaling proteins including MAP kinases and cell-junction proteins. The majority of the upregulated phosphopeptides contained a proline-directed motif, a known target of MAPK. Four hours after lithium exposure, phosphorylation sites in the activation loops of ERK1/2 and p38 were upregulated. Increased expression of phospho-Ser261-AQP2 (proline-directed motif) was concomitant with the increase in urine output. Pretreatment with MAPK inhibitors reversed the increased Ser261-AQP2 phosphorylation. Thus, in IMCD, ERK1/2 and p38 are early targets of lithium and may play a role in the onset of lithium-induced polyuria.

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.

Acute lithium administration selectively lowers tyrosine levels in serum and brain

Lithium exerts anti-dopaminergic behavioral effects. We examined whether some of these might be mediated by changes in brain levels of tyrosine (TYR), the precursor to dopamine. Lithium chloride (LiCl 2) 3.0 mEq/kg IP acutely lowered serum TYR and the ratio of serum TYR to other large neutral amino acids (LNAAs); it also selectively lowered striatum TYR levels as measured in tissue or in vivo. While LiCl 2 3.0 mEq/kg IP also augmented haloperidol (0.19 mg/kg SC)-induced catalepsy, this lithium effect was not attenuated by administration of TYR 100 mg/kg IP. We conclude that lithium acutely and selectively lowers brain TYR by lowering serum levels of tyrosine relative to the LNAAs that compete with it for transport across the blood–brain barrier. However, the lowering of TYR does not appear to significantly contribute to the ability of lithium to potentiate haloperidol-mediated catalepsy.

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.

Antidepressant-like responses to lithium in genetically diverse mouse strains

A mood stabilizing and antidepressant response to lithium is only found in a subgroup of patients with bipolar disorder and depression. Identifying strains of mice that manifest differential behavioral responses to lithium may assist in the identification of genomic and other biologic factors that play a role in lithium responsiveness. Mouse strains were tested in the forced swim test (FST), tail suspension test (TST) and open-field test after acute and chronic systemic and intracerebroventricular (ICV) lithium treatments. Serum and brain lithium levels were measured. Three (129S6/SvEvTac, C3H/HeNHsd and C57BL/6J) of the eight inbred strains tested, and one (CD-1) of the three outbred strains, showed an antidepressant-like response in the FST following acute systemic administration of lithium. The three responsive inbred strains, as well as the DBA/2J strain, displayed antidepressant-like responses to lithium in the FST after chronic administration of lithium. However, in the TST, acute lithium resulted in an antidepressant-like effect only in C3H/HeNHsd mice. Only C57BL/6J and DBA/2J showed an antidepressant-like response to lithium in the TST after chronic administration. ICV lithium administration resulted in a similar response profile in BALB/cJ (non-responsive) and C57BL/6J (responsive) strains. Serum and brain lithium concentrations showed that behavioral results were not because of differential pharmacokinetics of lithium in individual strains, suggesting that genetic factors likely regulate these behavioral responses to lithium. Our results indicate that antidepressant-like responses to lithium in tests of antidepressant efficacy varies among genetically diverse mouse strains. These results will assist in identifying genomic factors associated with lithium responsiveness and the mechanisms of lithium action.

Voltage-dependent calcium channel and NMDA receptor antagonists augment anticonvulsant effects of lithium chloride on pentylenetetrazole-induced clonic seizures in mice

Although lithium is still a mainstay in the treatment of bipolar disorder, its underlying mechanisms of action have not been completely elucidated. Several studies have shown that lithium can also modulate seizure susceptibility in a variety of models. In the present study, using a model of clonic seizures induced with pentylenetetrazole (PTZ) in male Swiss mice, we investigated whether there is any interaction between lithium and either calcium channel blockers (CCBs: nifedipine, verapamil, and diltiazem) or N-methyl-D-aspartate (NMDA) receptor antagonists (ketamine and MK-801) in modulating seizure threshold. Acute lithium administration (5–100 mg/kg, ip) significantly ( P < 0.01) increased seizure threshold. CCBs and NMDA receptor antagonists also exerted dose-dependent anticonvulsant effects on PTZ-induced seizures. Noneffective doses of CCBs (5 mg/kg, ip), when combined with a noneffective dose of lithium (5 mg/kg, ip), exerted significant anticonvulsant effects. Moreover, co-administration of a noneffective dose of either MK-801 (0.05 mg/kg, ip) or ketamine (5 mg/kg, ip) with a noneffective dose of lithium (5 mg/kg, ip) significantly increased seizure threshold. Our findings demonstrate that lithium increases the clonic seizure threshold induced by PTZ in mice and interacts with either CCBs or NMDA receptor antagonists in exerting this effect, suggesting a role for Ca 2+ signaling in the anticonvulsant effects of lithium in the PTZ model of clonic seizures in mice.

Preconditioning with acute and chronic lithium administration reduces ischemia/reperfusion injury mediated by cyclooxygenase not nitric oxide synthase pathway in isolated rat heart

Lithium is widely used for the management of neuropsychiatric symptoms in bipolar disorders. A variety of hypotheses have been invoked to explain the mechanism of action of lithium. To determine if lithium exerts direct cardiac protection, in the present study perfused rat heart model was used. The mechanism of lithium-mediated cardioprotection was explored by combined use of lithium and nitro- l-arginine methyl ester (L-NAME, a non-selective nitric oxide synthase inhibitor) or indomethacin (a non-selective cyclooxygenase pathway inhibitor). Rat isolated hearts were used for Langendorff perfusion. Hearts were either non-preconditioned or preconditioned with acute lithium (3 mM) or chronic lithium (600 mg/l in tap water for 4 weeks, 0.265 ± 0.023 mM in serum) before 30 min global ischemia followed by 90 min reperfusion. Within each of these protocols, hearts were divided into two groups; one group was exposed to L-NAME (0.1 mM) and another group was exposed to indomethacin (10 µM). Infarct size was measured by the triphenyltetrazolium chloride method. Left ventricular function was assessed by left ventricular developed pressure (LVDP), heart rate and coronary flow (CF). In our experiment acute and/or chronic administration of lithium before prolonged ischemia offered significant myoprotective effects in terms of infarct size reduction and improved cardiac function against ischemia/reperfusion injury. The effects of lithium pretreatment were prevented by the administration of indomethacin but not L-NAME. In conclusion, our results demonstrate that preconditioning with acute and/or chronic lithium administration improves recovery of the ventricular function and reduces infarct size via cyclooxygenase (COX) pathway in isolated rat heart.

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).

Inactivation of the Interoceptive Insula Disrupts Drug Craving and Malaise Induced by Lithium

Addiction profoundly alters motivational circuits so that drugs become powerful reinforcers of behavior. The interoceptive system continuously updates homeostatic and emotional information that are important elements in motivational decisions. We tested the idea that interoceptive information is essential in drug craving and in the behavioral signs of malaise. We inactivated the primary interoceptive cortex in amphetamine-experienced rats, which prevented the urge to seek amphetamine in a place preference task. Interoceptive insula inactivation also blunted the signs of malaise induced by acute lithium administration. Drug-seeking and malaise both induced Fos expression, a marker of neuronal activation, in the insula. We conclude that the insular cortex is a key structure in the perception of bodily needs that provides direction to motivated behaviors.

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.

β-Catenin Overexpression in the Mouse Brain Phenocopies Lithium-Sensitive Behaviors

Lithium inhibits glycogen synthase kinase-3 (GSK-3) at therapeutic concentrations; however, it is unclear if this inhibition and its downstream effects on specific signaling pathways are relevant to the treatment of bipolar disorder and depression. One of the targets of GSK-3 is the transcription factor beta-catenin. Normally active GSK-3 phosphorylates beta-catenin, leading to its degradation. Inhibition of GSK-3 therefore increases beta-catenin. We have utilized transgenic mice to investigate the behavioral consequences of CNS beta-catenin overexpression. Transgenic mice overexpressing beta-catenin demonstrated behavioral changes similar to those observed following the administration of lithium, including decreased immobility time in the forced swim test (FST). Further, we show that although acute administration of lithium and overexpression of the beta-catenin transgene inhibits d-amphetamine-induced hyperlocomotion, neither lithium nor the beta-catenin transgene prevents d-amphetamine-induced sensitization, as measured by locomotor activity. Both lithium-treated and beta-catenin mice had an elevated response to d-amphetamine following multiple administrations of the stimulant, though the difference in absolute locomotion was maintained throughout the sensitization time-course. Neither acute lithium nor beta-catenin overexpression had an effect on d-amphetamine-induced stereotyped behavior. The results of this study, in which beta-catenin transgenic mice exhibited behaviors identical to those observed in lithium-treated mice, are consistent with the hypothesis that the behavioral effects of lithium in these models are mediated through its direct inhibition of GSK-3 and the consequent increase in beta-catenin. By associating the behavioral effects of lithium with beta-catenin levels, these data suggest that increasing beta-catenin might be a novel therapeutic strategy for mood disorders.