Dose Of Lithium Chloride Research Articles

Differential effects of mood stabilizers on brain reward and on the reward-facilitating effect of d-amphetamine

Event Abstract Back to Event Differential effects of mood stabilizers on brain reward and on the reward-facilitating effect of d-amphetamine Maria Mavrikaki1*, George G. Nomikos2 and George Panagis1 1 University of Crete, Greece 2 Takeda Global Research and Development Center, United States Psychostimulants, including amphetamine, induce manic symptoms in humans and exacerbate mania in individuals with bipolar disorder, effects that are counteracted by mood stabilizers. Psychostimulants reportedly facilitate intracranial self-stimulation (ICSS) behavior in rats, which might be related to the increases in elation and hedonistic drive of bipolar patients. We utilized the ICSS paradigm to examine the effects of acute treatment of different mood stabilizers on brain reward function and on the reward facilitating effect of d-amphetamine. First, rats were injected (ip) acutely with different doses of lithium chloride (LiCl), valproate (VPA), combined LiCl & VPA, lamotrigine (LTG) or aripiprazole (ARP). Secondly, we examined the effects of acute pretreatment with these mood stabilizers on the reward facilitating effect of d-amphetamine (0.5, 1mg/kg, ip). LiCl (100, 200mg/kg), VPA (400mg/kg), combined LiCl & VPA (50 & 200mg/kg ) and ARP (0.75, 1.5, 2.5mg/kg), but not LTG, increased ICSS thresholds. Then, LiCl (100mg/kg) or combined LiCl & VPA, in contrast to VPA or LTG alone, attenuated the reward facilitating effect of d-amphetamine. Interestingly, ARP demonstrated a biphasic profile in this model: a low dose of ARP (0.075mg/kg) increased the reward-facilitating effect of d-amphetamine (an effect that indicates a synergic action with d-amphetamine), while a higher ARP dose (1.5mg/kg) attenuated d-amphetamine's reward-facilitating effects. These results might explain the different effects of these mood stabilizers observed in patients with bipolar disorder, e.g. the fact that lithium is more effective than VPA in reducing manic relapses, whereas VPA is more effective during the depressive phases of the disorder. Conclusively, the ICSS model combined with d-amphetamine can be used to simulate in rats the elation and increased hedonistic drive observed in bipolar patients and ultimately contribute to identifying novel drug treatments for bipolar disorder. Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Mavrikaki M, Nomikos GG and Panagis G (2009). Differential effects of mood stabilizers on brain reward and on the reward-facilitating effect of d-amphetamine. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.227 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Jun 2009; Published Online: 11 Jun 2009. * Correspondence: Maria Mavrikaki, University of Crete, Crete, Greece, panagis@uoc.gr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Maria Mavrikaki George G Nomikos George Panagis Google Maria Mavrikaki George G Nomikos George Panagis Google Scholar Maria Mavrikaki George G Nomikos George Panagis PubMed Maria Mavrikaki George G Nomikos George Panagis Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Lithium's effect in forced-swim test is blood level dependent but not dependent on weight loss

The effects of lithium in models of depression are often inconsistent. We aimed to replicate a regimen that induces robust antidepressant effects in the forced-swim test. Mice were treated with three different doses of lithium chloride (LiCl) 0.25, 0.4 or 0.5% in food and the forced-swim test or open field test was performed on day 15. We yoked control mice to food deprivation to test whether lithium-induced food deprivation could cause the lithium effects in the forced-swim test. Treatment with LiCl doses leading to blood levels of 1.3 and 1.4 mmol/l led to highly significant reduction in immobility time in the forced-swim test, but the dose leading to a blood level of 0.8 mmol/l was not different from controls in immobility time. Mice yoked to lithium-induced food deprivation showed no difference in the forced-swim test compared with controls. In conclusion these results suggest that lithium effects in mice in the forced-swim test are dose dependent but not owing to lithium-induced weight loss.

Effect of previous taste experiences on taste neophobia in young-adult and aged rats

Neophobia is an innate response that can be defined as the reluctance to consume novel-tasting substances. The differential effect of previous aversive and nonaversive taste memory on a subsequent neophobic response was studied in young-adult (Experiment 1) and aged rats (Experiment 2). Surprising, a previous nonaversive taste experience eliminated the subsequent neophobic response to a solution of 1% sodium chloride (NaCl) in young-adult and aged rats. This result is interpreted as a generalization of the previous safe taste memory and the emotional responses that might be induced when a new taste is presented. However, a differential effect associated with aging was found for a previous aversive taste memory induced with a low dose of lithium chloride (0.15 M; 1% b.w.). While in young-adult rats this aversive taste memory did not change the neophobic response to an NaCl solution, in aged rats this memory potentiated the subsequent neophobic response to NaCl. This result is interpreted as an increase in the generalization of aversive taste memory and the emotional responses associated with aging.

Intraoral cheek fistulae: a refined technique

Taste reactivity testing (TRT), which entails infusing a solution into the oral cavity of subjects, is used across a wide range of studies. For laboratories inexperienced in the conventional technique of implanting cheek fistulae, the surgery can be problematic for both the subjects and the experimenter. We have proposed a refined method for fistulae implantation that is less invasive, thereby reducing the pain and distress of the animals. Using this refined technique, we were able to replicate the findings of previous TRT studies, namely that a high dose of lithium chloride produces an increase in aversive and a decrease in ingestive orofacial and somatic responses. Using indices of health, we demonstrate that unlike animals with the conventional method of fistulae implantation, subjects that receive the refined technique regain their pre-surgery body weights rapidly and show no physical signs of discomfort. Additional advantages of the refined technique are discussed.

Basolateral amygdala glutamatergic activation enhances taste aversion through NMDA receptor activation in the insular cortex

In conditioned taste aversion (CTA), a subject learns to associate a novel taste with visceral malaise. Brainstem, limbic and neocortical structures have been implicated in CTA memory formation. Nevertheless, the role of interactions between forebrain structures during these processes is still unknown. The present experiment was aimed at investigating the possible interaction between the basolateral nucleus of the amygdala (BLA) and the insular cortex (IC) during CTA memory formation. Injection of a low dose of lithium chloride (30 mg/kg, i.p.) 30 min after novel taste consumption (saccharin 0.1%) induces a weak CTA. Unilateral BLA injection of glutamate (2 microg in 0.5 microL) just before low lithium induces a stronger CTA. Unilateral injection of an N-methyl-d-aspartate (NMDA) receptor antagonist (AP5, 5 microg in 0.5 microL) in IC has no effect. However, AP5 treatment in IC at the same time or 1 h after the ipsilateral BLA injection reverses the glutamate-induced CTA enhancement. Injection of AP5 in IC 3 h after BLA injection does not interfere with the glutamate effect. Moreover, the CTA-enhancing effect of glutamate was also blocked by contralateral IC injection of AP5 at the same time. These results provide strong evidence that NMDA receptor activation in the IC is essential to enable CTA enhancement induced by glutamate infusion in the BLA during a limited time period that extends to 1 but not to 3 hours. These findings indicate that BLA-IC interactions regulate the strength of CTA. The bilateral nature of these amygdalo-cortical interactions is discussed.

Herbivore experience with plant defense compounds influences acquisition of new flavor aversions

Multiple experiments were conducted with a mammalian herbivore to determine how experience with plant secondary metabolites (terpenes and tannins) influenced acquisition of new aversions to diets containing these same plant metabolites. Goats ( Capra aegagrus hircus) were employed as behavioral models for this study. Twenty-four subjects were assigned to three treatment groups that received 20 days of experience with test diets: (A) terpene diet only; (B) tannin diet only; and (C) terpene and tannin diets offered singly on alternate days. In experiment 1, all subjects were offered both diets in a two-choice test to determine if experience affected diet preference. Both treatments A and B demonstrated significant preferences for the terpene diet, while treatment C subjects did not exhibit a diet preference. Both diets were offered to all subjects and immediately followed with a 150 mg/kg dose of lithium chloride (LiCl) in experiment 2. A two-choice preference test was conducted to determine if lithium-induced toxicosis would be associated with the least familiar diet. As in experiment 1, treatments A and B preferred terpene diet while treatment C did not demonstrate a preference. Lithium chloride exposure was specifically paired with one of the test diets in experiment 3. A two-choice preference test demonstrated that treatments A, B, and C acquired aversions to tannin diet when it was paired with LiCl administration. However, terpene-paired LiCl administration did not produce an aversion to the terpene diet in treatments A and B. Treatment C preferred tannin diet when the terpene diet was paired with LiCl. A novel flavor was added to the choice of diets in experiment 4. All subjects were offered citric acid (CA), terpene, and tannin-containing diets and immediately dosed with LiCl. Subjects that acquired aversions to the tannin diet in experiment 3 continued to avoid tannin diet in experiment 4 and preferred terpene diet while eating significant quantities of the novel CA diet. Only treatment C subjects with previous terpene-paired LiCl exposures demonstrated aversions to the CA diet. These results have implications for the conduct of flavor aversion studies and the application of flavor aversion learning (FAL).

Effects of lithium on primary cultured cerebrocortical neurons of rat

To explore the neuroprotection and the impact on brain development of lithium, the effects of lithium salt on the growth and survival of primary cultured cerebrocortical neurons were studied. The technique of primary cultured cerebrocortical neurons of newborn rats with serum-free medium was established, and the growth and survival of neurons treated with different doses of lithium chloride (0.625, 1.250, 2.500, 5.000, 10.000 mmol/L) were observed. The length of neuronal synapse, cell viability by MTT reduction assay were also measured. The neurons were brighter, germinated rapidly, the neuronal synapse lengthened markedly, and the neurons viability was also better after treated with lithium chloride. Among the five doses, 5.000 mmol/L had the best effect [(53.80 +/- 5.84) micro m, P < 0.01]. Lithium chloride can promote the growth and survival of neurons.

A method for peripheral chromatolysis in neurons of trigeminal and dorsal root ganglia, produced in rats by lithium

In classical chromatolysis, Nissl bodies are initially lost centrally with subsequent progression to the periphery of the neuron. Peripheral chromatolysis has the opposite pattern; it is less common and more difficult to produce. We describe a new method for producing peripheral chromatolysis in neurons of trigeminal ganglia and dorsal root ganglia that requires only injection of large doses of lithium chloride (LiCl) for two, three or four consecutive daily doses. This method may be useful for elucidating the intraneuronal mechanisms that control the location and structure of the Nissl bodies.

Acute effects of corticosterone on LiCl-induced rapid gustatory conditioning in rats: a microstructural analysis of licking patterns

Acute administration of corticosterone (Cort) has been shown to potentiate a variety of learning processes. Here, the effects of Cort on rapid gustatory conditioning were examined using a lick monitoring system. Over a 3-day period, animals were given intraperitoneal (ip) injections of either a low dose of lithium chloride (LiCl; 0.75 mEq, ip) toxin or saline control (NaCl; 0.9%, ip) and then received an injection of Cort (5 mg/kg, ip) or cyclodextrin vehicle. In order to investigate the effect of acute increases in systemic Cort on gustatory conditioning, patterns of licking behavior were recorded while animals were exposed to a novel sucrose (0.3 M) tastant. Increased post-injection serum Cort levels were verified by radioimmunoassay analysis of trunk blood samples. Analysis of the licking patterns revealed evidence of rapid gustatory conditioning. Significantly reduced sucrose intake volumes and fewer total licks during the test sessions on Conditioning days were found in all groups that had received LiCl injections. Evidence of a Cort-potentiated conditioning effect was also found. Animals that had received Cort in addition to LiCl exhibited significantly shorter meal durations than did animals that had been administered LiCl alone and Cort significantly influenced the effects of LiCl on cluster number. These findings indicate that Cort facilitates conditioning, possibly by modulation of LiCl-induced visceral afferent and/or central feedback mechanisms.

Lithium-induced outcome devaluation in instrumental conditioning: Dose–effect analysis

Three experiments with rats assessed the effectiveness of various doses of lithium chloride (LiCl) in producing an aversion to the reinforcer on subsequent instrumental performance in extinction. In Experiments 1A and 1B, subjects were injected with LiCl at a dose of 3.0 and 1.5 meq/kg, respectively. These doses were administered in the form of either an isotonic solution (0.15 M) or a hypertonic solution (0.6 M). While there was an effect of the reinforcer devaluation on the instrumental performance that did not depend on the molarity of the solution with the high LiCl dose, there was no effect of devaluation with the low LiCl dose. Experiment 2 compared the 3.0- and 1.5-meq/kg dose levels directly. A depression of instrumental performance after outcome devaluation was observed in the animals injected with the high LiCl dose independently of the molarity of the solution, an effect that was absent in the low-dose condition. These results were interpreted as evidence that an instrumental reinforcer devaluation effect induced by pairing the reinforcer with illness depends upon the absolute quantity of LiCl injected and not on the concentration of solution.

Lithium chloride dilution as a new method of cardiac output determination in the dog: effect of lithium chloride dosage on serum lithium concentration

We have previously demonstrated excellent agreement in the dog between thermodilution (TD) and lithium chloride dilution (LCD) as measures of CO, with an intraclass correlation of 0.989. LCD results in an accumulation of lithium (Li) in the body, which results in background interference for subsequent determinations. The manufacturer of the LCD sensor has calculated a theoretical upper serum Li value of 0.2 mmol L−1, above which interference may become significant. The purpose of this study was: (1) to determine the relationship between the dose of lithium chloride (LiCl) administered and the background serum Li level; and (2) to examine the relationship between background serum Li levels and the degree of agreement for CO measured by LCD and TD.

Acute effects of corticosterone on LiCl-induced rapid gustatory conditioning in rats: a taste reactivity analysis.

Previous research has shown that acute corticosterone treatment can have rapid effects on learning and memory. Using the taste reactivity test (TRT), the present study examined the effect of acute administration of corticosterone on sucrose palatability and the development of LiCl-induced rapid gustatory conditioning. On each of two conditioning days rats were injected with either a low dose of lithium chloride (LiCl; 0.75 mEq, i.p.) or saline (NaCl; 0.9%, i.p.) and 10 min later, received a second injection of either corticosterone (5 mg/kg, i.p.) or cyclodextrin vehicle. Rats were then placed in the TRT chamber, where 1 min intraoral infusions of sucrose (0.3 M) were delivered every 10 min. Taste reactivity responses were videotaped and later analyzed for frequency of occurrence. Rats treated with both LiCl and corticosterone showed enhanced aversive responding and reduced ingestive responding relative to control rats treated with LiCl and vehicle. The implication that corticosterone may have a rapid enhancing effect on gustatory conditioning is discussed.

The Role of CNS Glucagon-Like Peptide-1 (7-36) Amide Receptors in Mediating the Visceral Illness Effects of Lithium Chloride

Peripheral administration of large doses of lithium chloride (LiCl) to rats causes a spectrum of effects that are consistent with visceral illness. LiCl reduces food intake, decreases salt ingestion after sodium depletion, induces pica, and produces robust conditioned taste aversions. Because some of the effects of peripheral LiCl are mimicked by centrally administered glucagon-like peptide-1 (7-36) amide (GLP-1), we hypothesized that this peptide is involved in the neural pathways by which LiCl causes visceral illness. To test this hypothesis, we pretreated rats with a selective and potent GLP-1 receptor antagonist given directly into the third ventricle via an indwelling cannula before administration of peripheral LiCl. The GLP-1 receptor antagonist completely blocked the effect of LiCl to reduce food intake, induce pica, and produce a conditioned taste aversion. The same dose of GLP-1 receptor antagonist did not reverse the LiCl-induced reduction in NaCl intake. The data indicate a role for GLP-1 receptors in the CNS pathway that mediates some of the effects of visceral illness.

A low dose of lithium chloride selectively induces fos protein in the central nucleus of the amygdala of rat brain

1. 1. Lithium is a very effective treatment for mood disorders. To elucidate the neural substrates of the mood stabilizing actions of lithium, in the present study the authors investigated the effects of a low dose of lithium on regional expression of Fos protein. 2. 2. The administrations of a high dose of lithium chloride (100 mg/kg) induced Fos in widespread areas of the rat brain. In contrast, administration of a low dose of lithium chloride, equivalent to a therapeutic dose in humans, induced Fos only in the central nucleus of the amygdala. 3. 3. These results demonstrate that the central nucleus of the amygdala plays important role in the neural framework that is responsible for the mood-stabilizing effect of lithium.

Lithium Chloride Induces the Expression of Tyrosine Hydroxylase in hNT Neurons

In the present study, several doses of lithium chloride were tested for their ability to induce the expression of tyrosine hydroxylase (TH) in neurons derived from a human teratocarcinoma cell line (hNT) after 5 and 10 days in vitro (DIV). Following immunocytochemical staining for tyrosine hydroxylase, the percentage of TH-positive neurons was determined and morphometric analysis, including mean soma profile area and neuritic length, was performed. hNT neurons responded to lithium treatment in a dose-dependent manner. In 5 DIV, the most effective dose of lithium chloride (1.0 mM) increased the number of TH-positive neurons approximately sixfold. In addition, both TH-positive hNT neuron mean soma profile area and neurite length were significantly larger than controls by 60 and 70%, respectively. Moreover, even after withdrawal of lithium chloride on day 5, the number of TH-positive neurons in 10 DIV cultures remained significantly increased. These data suggest that hNT cells are indeed responsive to lithium exposure and may serve as a continual source of TH-expressing neurons in new therapeutic approaches to degenerative brain disease.

α-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function

Background: Many neuropsychiatric disorders are associated with high levels of noradrenergic turnover, and most antipsychotic medications have α-1 adrenoceptor blocking properties, yet little is known about α-1 influences on higher cortical function. Methods: The α-1 adrenergic agonist, phenylephrine, was infused into the prefrontal cortex (PFC) of rats (0.1 μg/0.5 μL) performing a spatial working memory task, delayed alternation. The phenylephrine response was challenged with coinfusion of the α-1 adrenergic antagonist, uripidil (0.01 μg), or with a dose of lithium chloride (4 mEq/kg, IP, 18 hours) known to suppress phosphotidylinositol (PI) turnover, the second messenger pathway coupled to α-1 adrenoceptors. Results: Phenylephrine infusions in PFC markedly impaired delayed alternation performance. The phenylephrine response was reversed by coinfusion of uripidil, or by pretreatment with lithium, consistent with actions at α-1 adrenoceptors coupled to a PI pathway. Conclusions: These findings demonstrate that α-1 adrenoceptor stimulation in the PFC impairs cognitive function. Excessive stimulation of α-1 adrenoceptors may contribute to PFC deficits (e.g., distractibility, impulsivity) in disorders such as mania, dementia, and anxiety associated with high noradrenergic turnover.

Lithium treatment causes gliosis and modifies the morphology of hippocampal astrocytes in rats.

The biological basis of the clinical efficacy of lithium in the treatment of mental illness has been extensively studied in neurones, but little is known about the effects of the drug on glia. Recently we showed that treatment of rats with clinically relevant doses of lithium chloride results in a 35% increase in the immunocontent of the astrocyte marker GFAP in the hippocampus. Here we studied the cytology of this phenomenon. Rats were treated for 4 weeks with a lithium diet which resulted in serum Li+ concentrations of 0.6-1.2 mmol/l. GFAP immunocytochemistry of the hippocampus revealed a mild gliosis in the CA1 area and the dentate gyrus which was associated with a change in the orientation of astrocytic processes. In control animals astrocyte processes were mainly orientated perpendicular to the stratum pyramidale, whereas in treated animals the cells were predominantly stellar in appearance.

Ability of apomorphine and lithium chloride to create food aversions in cattle

Lithium chloride is the most common emetic used to create food aversions in laboratory animals and livestock. However, it is slowly excreted or metabolized, and requires several days for animals to recover. Because of its caustic nature and the large quantities required by cattle and sheep, lithium is best administered directly into the rumen and diluted by rumen fluid. The objective of this study was to evaluate apomorphine as an alternative emetic to create food aversions in cattle. A pilot study showed doses of apomorphine at 0.2 mg/kg BW caused some discomfort in cattle. Doses of 0.4 mg/kg BW and above resulted in severe intoxication and excessive discomfort. We then compared intramuscular injection of apomorphine at 0.1 and 0.2 mg/kg BW, to the standard dose of lithium chloride (200 mg/kg BW by gavage), and to a control treatment (200 ml water by gavage). Four heifers (428 kg) were randomly placed in each group. The heifers consumed flavored alfalfa pellets for 5 min, then were restrained in a chute and administered the respective treatment. The strength and longevity of the aversion was tested by offering the flavored pellets in single-choice extinction trials for six days. The Lithium group did not consume any flavored pellets, thus maintaining a total aversion. Both apomorphine groups reduced consumption to 40% of baseline intake, but the aversion extinguished by the end of the trial. There was no difference between the two apomorphine doses. Under these conditions, lithium chloride is superior to apomorphine in creating and maintaining taste aversions in cattle.

Use of Sodium Polystyrene Sulfonate for Reduction of Plasma Lithium Concentrations After Chronic Lithium Dosing in Mice

Previous studies have shown that oral sodium polystyrene sulfonate lowers plasma lithium concentrations after acutely administered oral doses of lithium chloride. However, a significant proportion of lithium overdose cases resulting in morbidity and mortality are those in which exposure to lithium is chronic. This study was designed to determine whether multiple oral doses of sodium polystyrene sulfonate are effective in reducing plasma lithium concentrations after chronic dosing. Placebo-controlled animal study. One hundred thirty mice were given 75 mM lithium chloride in their drinking water for a period of 14 days. At the end of that period, half of the animals were given orogastric sodium polystyrene sulfonate at 5 g/kg/dose 0, 60, 120, 180, and 360 minutes after the cessation of lithium chloride; the remaining half received orogastric water at equivalent times. Subgroups of each group were sacrificed at 90, 150, 330, 480, 1440, and 2880 minutes after lithium chloride cessation and plasma analyzed for lithium content. Lithium concentrations were compared by analysis of variance and single degree of freedom contrasts. Significance was set at an alpha level of 0.05. Lithium concentration was lower overall in the animals treated with sodium polystyrene sulfonate (p < .0001) and specifically at 150, 330, and 480 minutes after lithium chloride cessation (p < .05). Repetitive oral doses of sodium polystyrene sulfonate effectively lowered plasma lithium concentrations. Further study may ultimately define a role for the use of sodium polystyrene sulfonate in the treatment of patients with chronic lithium toxicity.

Effects of lithium on rat parotid and submandibulary gland functions

1. 1. Pure submandibular and parotid saliva were collected intraorally by micro polyethylene canula from anesthetized lithium treated and control rats using pilocarpine as secretagogue. 2. 2. Acute intraperitoneal injection of a single dose of lithium chloride (10 mg/kg), caused a significant decrease in protein, calcium, potassium and sodium concentrations of parotid saliva and also a significant decrease in protein, potassium and calcium concentrations of submandibular saliva. 3. 3. Chronic treatment of rats for 10 days by LiCl solution (1200 mg/l) also caused some marked changes in saliva compositions similar to those observed in acute experiment. 4. 4. The results of this study suggest that lithium as a drug used in the treatment of affective disorders can influence the secretory mechanisms of both submandibular and parotid glands. 5. 5. These effects of lithium in composition of parotid and submandibular saliva are not related to duration of treatment.