lithium-chloride and Body-Weight

This analysis was conducted to compare the effects of adjunctive ziprasidone or placebo on metabolic parameters among patients receiving maintenance treatment with lithium or valproate. We also tested whether metabolic syndrome (MetS) and other risk factors were associated with baseline characteristics and treatment response. In the stabilization phase (Phase 1), 584 bipolar I disorder (DSM-IV) patients received 2.5-4 months of open label ziprasidone (80-160 mg/d) plus lithium or valproic acid (ZIP+MS). Patients who achieved at least 8 weeks of clinical stability were subsequently randomized into Phase 2 to 6-months of double-blind treatment with ZIP+MS (n=127) vs. placebo+MS (n=113). At baseline of Phase 1, MetS was found in 111 participants (23%). Participants with MetS (vs. non-MetS participants) were more likely to be aged 40 years or older, had significantly more severe manic symptoms, higher abdominal obesity, and higher BMI. Increase in abdominal obesity was associated with lower manic symptom improvement (p<0.05, as assessed by MRS change score) during Phase 1, while symptom improvement differed across racial groups. In the Phase 2 double-blind phase, the ZIP+MS group had similar weight and metabolic profiles compared to the placebo+MS group across visits. These results corroborate existing findings on ziprasidone which exhibits a neutral weight and metabolic profile in the treatment of schizophrenia and bipolar patients. Our findings suggest that MetS is highly prevalent in patients with bipolar disorder, may be associated with greater manic symptom severity, and may predict treatment outcomes.

Topics: Adjuvants, Immunologic; Antipsychotic Agents; Bipolar Disorder; Body Weight; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Longitudinal Studies; Male; Metabolic Diseases; Metabolome; Piperazines; Psychiatric Status Rating Scales; Thiazoles; Valproic Acid

Three separate lithium chloride doses, calculated according to body weight, and a placebo were administered under double-blind conditions to 68 manic inpatients. The relationship of lithium chloride treatment dose to steady-state serum lithium levels (day 7 to 10 of treatment) and clinical response were examined. High (0.72 mEq/kg/day) and medium (0.5 mEq/kg/day) lithium chloride doses were more efficacious than placebo (P<.001 and P<.05, respectively), as determined by decrements in global mania ratings (day 7 to 10 of treatment). A low dose (0.24 mEq/kg/day) was not found to be more efficacious than placebo. The proportion of patients with improved manic ratings increased markedly as a function of increased steady-state serum lithium level(chi-squared for trend in proportions, 17.91; P<.001).

Topics: Acute Disease; Adolescent; Adult; Aged; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Body Weight; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Male; Middle Aged; Patient Dropouts; Placebos; Psychiatric Status Rating Scales; Treatment Outcome

In rodents, early-life exposure to environmental stress or antidepressant medication treatment has been shown to induce similar long-term consequences on memory- and depression-related behavior in adulthood. To expand on this line of work, we evaluated how juvenile exposure to chronic variable stress (CVS) or the selective serotonin reuptake inhibitor fluoxetine (FLX) influences conditioned taste aversion (CTA) learning in adulthood. To do this, in Experiment 1, we examined how adolescent CVS alone (postnatal day [PND] 35-48), or with prenatal stress (PNS) history (PNS + CVS), influenced the acquisition and extinction of CTA in adult male Sprague Dawley rats. Specifically, at PND70+ (adulthood), rats were presented with 0.15 % saccharin followed by an intraperitoneal (i.p.) injection of lithium chloride (LiCl) to induce visceral malaise. A total of four saccharin (conditioned stimulus) and LiCl (unconditioned stimulus) pairings occurred across the CTA acquisition phase. Next, saccharin was presented without aversive consequences, and intake was measured across consecutive days of the extinction phase. No differences in body weight gain across the experimental days, rate of CTA acquisition, or extinction of CTA, were observed among the experimental groups (control, n = 7; CVS, n = 12; PNS + CVS, n = 9). In Experiment 2, we evaluated if early-life FLX exposure alters CTA learning in adulthood. Specifically, adolescent stress naïve male and female rats received FLX (0 or 20 mg/kg/i.p) once daily for 15 consecutive days (PND35-49). During antidepressant exposure, FLX decreased body weight gain in both male (n = 7) and female rats (n = 7), when compared to respective controls (male control, n = 8; female control, n = 8). However, juvenile FLX exposure decreased body weight-gain in adult male, but not female, rats. Lastly, adolescent FLX history had no effect on CTA acquisition or extinction in adulthood (PND70), in neither male nor female rats. Together, the data indicate that juvenile FLX exposure results in a long-term decrease of body weight-gain in a male-specific manner. Yet, independent of sex, neither early-life stress nor FLX exposure alters CTA learning in adulthood.

Topics: Animals; Avoidance Learning; Body Weight; Female; Fluoxetine; Lithium Chloride; Male; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Saccharin; Stress, Psychological; Taste

Inflammation-mediated skeletal muscle wasting occurs in patients with sepsis and cancer cachexia. Both conditions severely affect patient morbidity and mortality. Lithium chloride has previously been shown to enhance myogenesis and prevent certain forms of muscular dystrophy. However, to our knowledge, the effect of lithium chloride treatment on sepsis-induced muscle atrophy and cancer cachexia has not yet been investigated. In this study, we aimed to examine the effects of lithium chloride using in vitro and in vivo models of cancer cachexia and sepsis. Lithium chloride prevented wasting in myotubes cultured with cancer cell-conditioned media, maintained the expression of the muscle fiber contractile protein, myosin heavy chain 2, and inhibited the upregulation of the E3 ubiquitin ligase, Atrogin-1. In addition, it inhibited the upregulation of inflammation-associated cytokines in macrophages treated with lipopolysaccharide. In the animal model of sepsis, lithium chloride treatment improved body weight, increased muscle mass, preserved the survival of larger fibers, and decreased the expression of muscle-wasting effector genes. In a model of cancer cachexia, lithium chloride increased muscle mass, enhanced muscle strength, and increased fiber cross-sectional area, with no significant effect on tumor mass. These results indicate that lithium chloride exerts therapeutic effects on inflammation-mediated skeletal muscle wasting, such as sepsis-induced muscle atrophy and cancer cachexia.

Topics: Animals; Body Weight; Cachexia; Cell Differentiation; Cell Proliferation; Culture Media, Conditioned; Glycogen Synthase Kinase 3 beta; Inflammation; Lipopolysaccharides; Lithium Chloride; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Muscle Contraction; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Neoplasms; RAW 264.7 Cells; RNA, Small Interfering; Sepsis; SKP Cullin F-Box Protein Ligases; Tetrazolium Salts; Thiazoles

The aim of this work was to clarify whether maternal lithium chloride (LiCl) exposure disrupts the neonatal neuroendocrine-cytokine axis. Pregnant Wistar rats were orally administrated 50 mg LiCl/kg b.wt. from gestational day (GD) 1 to postpartum day 28. Maternal administration of LiCl induced a hypothyroid state in both dams and their neonates compared to the control dams and neonates at lactation days (LDs) 14, 21 and 28, where the levels of serum free triiodothyronine (FT3) and free thyroxin (FT4) were decreased and the level of serum thyrotropin (TSH) level was increased. A noticeable depression in maternal body weight gain, neonatal body weight and neonatal serum growth hormone (GH) was observed on all examined postnatal days (PNDs; 14, 21 and 28). A single abortion case was recorded at GD 17, and three dead neonates were noted at birth in the LiCl-treated group. Maternal administration of LiCl disturbed the levels of neonatal serum tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), interleukin-1 beta (IL-1β), interferon-gamma (INF-γ), leptin, adiponectin and resistin at all tested PNDs compared to the control group. This administration produced a stimulatory action on the level of neonatal cerebral serotonin (5-HT) at PND 14 and on the level of neonatal cerebral norepinephrine (NE) at PNDs 21 and 28. However, this administration produced an inhibitory action on the level of neonatal cerebral dopamine (DA) at all examined PNDs and on the level of neonatal cerebral NE at PND 14 and the level of neonatal cerebral 5-HT at PNDs 21 and 28 compared to the corresponding control group. Thus, maternal LiCl exposure-induced hypothyroidism disrupts the neonatal neuroendocrine-cytokine system, which delay cerebral development.

Topics: Animals; Animals, Newborn; Antimanic Agents; Biogenic Monoamines; Body Weight; Brain Chemistry; Cytokines; Female; Growth Hormone; Hypothyroidism; Lithium Chloride; Maternal Exposure; Neurosecretory Systems; Pregnancy; Rats; Rats, Wistar; Thyrotropin; Thyroxine; Triiodothyronine

Kaolin clay eating has been considered as a marker of nausea in rats, because a variety of treatments, which evoke nausea in humans, generate consumption of kaolin clay in rats. The present study with two experiments replicated kaolin clay ingestion induced by an injection of emetic lithium chloride (LiCl). The LiCl injection, however, did not generate eating of wooden objects in rats. The present study also provides a new finding that consumption of kaolin clay alleviates rats' taste aversion learning caused by an LiCl injection. This finding is congruent with the contention that consumption of kaolin clay is not only a useful index of, but also an effective remedy for, drug-induced nausea in rats.

Topics: Analysis of Variance; Animals; Antidiarrheals; Antimanic Agents; Avoidance Learning; Body Weight; Eating; Kaolin; Lithium Chloride; Male; Nausea; Rats; Rats, Wistar; Taste

This study examined sex differences in the establishment of lithium chloride (LiCl)-induced conditioned disgust behavior (anticipatory nausea) to a distinct context in adult male and female rats. Also examined were potential sex differences in response to treatment with the bacterial endotoxin, lipopolysaccharide (LPS), and its effect on learning and memory. Twenty-nine male and 31 female naïve Long-Evans rats were injected (intraperitoneally; i.p.) with either 200μg/kg LPS or 0.9% (NaCl), 90min prior to i.p. injections of either 128mg/kg LiCl or 0.9% NaCl, and immediately placed into a distinctive context for 30min (repeated over 4 conditioning days, spaced 72h apart). 72h following the final conditioning day, each subject was re-exposed to the context on a drug-free test day where orofacial and somatic behaviors were recorded. Results showed that LiCl-treated females conditioned stronger disgust reactions, relative to LiCl-treated males, as evidenced by significantly higher frequencies of conditioned "gaping" behavior (p<0.02) and forelimb flailing (p<0.01) in females. Pre-treatment with LPS during conditioning led to strong inhibition of conditioned disgust behavior, to levels that did not significantly differ from controls. Although there was no apparent sex difference in the degree of inhibition produced by LPS in this context-based rodent disgust model, males did exhibit significantly greater 24h body weight losses following LPS injections on the first two conditioning days, relative to females. The results of the current study provide strong evidence for a sex difference in the establishment of anticipatory nausea, as well as, evidence for a sex difference in the acute-phase response to endotoxin treatment.

Topics: Animals; Avoidance Learning; Behavior, Animal; Body Weight; Conditioning, Psychological; Emotions; Female; Immune System; Lipopolysaccharides; Lithium Chloride; Male; Nausea; Rats; Sex Characteristics

We have recently demonstrated that adaptation of the hypothalamic-pituitary-adrenal (HPA) axis to repeated exposure to a stressor does not follow the rules of habituation and can be fully expressed after a single experience with severe stressors. In the present work we tested the hypothesis that adaptation could be impaired if animals experience malaise during initial exposure to the stressor. To this end, animals were allowed to drink saccharin for 30min before being exposed for 3h to immobilization on boards (IMO), a severe stressor; then they were given either saline or lithium ip after the first hour of IMO. Stress-naïve rats followed exactly the same procedure except IMO. Exposure to IMO caused a strong activation of the HPA axis whereas the effect of lithium was modest. Both IMO and lithium administration resulted in conditioned taste aversion to saccharin when evaluated 4days later. When all animals were exposed to IMO 6days later, reduced HPA response and less impact on body weight was observed in the two groups previously exposed to IMO as compared with stress-naïve rats. Therefore, lithium administration during the first IMO exposure did not affect adaptation of the HPA axis and weight gain. These results indicate that malaise per se only weakly activated the HPA axis and argue against the hypothesis that signs of physical malaise during exposure to the stressor could impair HPA adaptation.

Topics: Adaptation, Physiological; Adrenocorticotropic Hormone; Animals; Antimanic Agents; Body Weight; Corticosterone; Disease Models, Animal; Hypothalamo-Hypophyseal System; Lithium Chloride; Male; Pituitary-Adrenal System; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Saccharin; Stress, Psychological; Time Factors

Nausea and aversive food responses are commonly reported following bariatric surgery, along with post-surgical reduction in meal size. This study investigates whether a meal size limit can be conditioned by associating large meals with aversive outcomes.. In rats, the intake of meals exceeding a pre-defined size threshold was paired with lithium chloride-induced gastric illness, and the effects on self-determined food intakes and body weight were measured.. Rats given LiCl contingent on the intake of a large meal learned to reliably reduce intake below this meal size threshold, while post-meal saline or LiCl before meals did not change meal size. It was further demonstrated that this is not a conditioned taste aversion and that this effect transferred to foods not explicitly trained. Finally, when rats received LiCl following all large meals, the number of small meals increased, but total food intake and body weight decreased.. While further work is needed, this is the first demonstration that meal size may be conditioned, using an aversion procedure, to remain under a target threshold and that this effect is distinct from taste avoidance. Corresponding reduction in food intake and body weight suggests that this phenomenon may have implications for developing weight loss strategies and understanding the efficacy of bariatric surgery.

Topics: Adjuvants, Immunologic; Animals; Avoidance Learning; Behavior, Animal; Body Weight; Eating; Lithium Chloride; Rats; Taste

Lithium, a well-known drug for the treatment of bipolar disorder, may also have the ability to reduce neurodegeneration and stimulate cell proliferation. Systemic injection of mitochondrial toxin 3-nitropropionic acid (3NPA) is known to induce a relatively selective, Huntington disease-like brain injury. The aim of this study was to determine the effect of lithium chloride (LiCl) on brain injury caused by 3NPA. Female adult Wistar rats were pre-treated with LiCl (127 mg/kg) 1 day before the first injection of 3NPA (28 mg/kg), and then for 8 days with the same treatment but receiving LiCl 1 hour before 3NPA. Control groups were pre-treated accordingly, with LiCl or with normal saline, but were not treated with 3NPA. Staining for cytochrome c oxidase activity and in situ hybridization autoradiography of synaptotagmin-4 and -7 mRNAs were used to evaluate brain injury caused by 3NPA. There was a significant reduction of body weight in the 3NPA+LiCl group (79%) compared to the 3NPA group (90%, p = 0.031) and both control groups (100%, p = 0.000). Densitometric evaluation of cytochrome c oxidase staining and in situ hybridization autoradiograms revealed that the pre-treatment with LiCl caused an increase in striatal lesion for about 40% (p = 0.049). Moreover, the lesion was observed also in the hippocampus of three animals from the 3NPA+LiCl group and in two animals from the 3NPA group. However, there were no differences between the LiCl and saline group in any of the measured parameters. We concluded that the pre-treatment with a relatively nontoxic dose of LiCl could aggravate brain injury caused by 3NPA.

Topics: Animals; Body Weight; Brain Chemistry; Brain Diseases; Electron Transport Complex IV; Female; Hippocampus; Lithium Chloride; Neostriatum; Nitro Compounds; Propionates; Rats; Rats, Wistar; Synaptotagmins

Flavour aversion learning (FAL) and conditioned flavour preference (CFP) facilitate animal survival and play a major role in food selection, but the neurobiological mechanisms involved are not completely understood. Neuroanatomical bases of CFP were examined by using Fos immunohistochemistry to record neuronal activity. Rats were trained over eight alternating one-bottle sessions to acquire a CFP induced by pairing a flavour with saccharin (grape was CS+ in Group 1; cherry in Group 2; in Group 3, grape/cherry in half of animals; Group 4, grape/cherry in water). Animals were offered the grape flavour on the day immediately after the training and their brains were processed for c-Fos. Neurons evidencing Fos-like immunoreactivity were counted in the infralimbic cortex, nucleus accumbens core, and anterior piriform cortex (aPC). Analysis showed a significantly larger number of activated cells after learning in the aPC alone, suggesting that the learning process might have produced a change in this cortical region. Ibotenic lesions in the aPC blocked flavour-taste preference but did not interrupt flavour-toxin FAL by LiCl. These data suggest that aPC cells may be involved in the formation of flavour preferences and that the integrity of this region may be specifically necessary for the acquisition of a CFP.

Topics: Animals; Avoidance Learning; Body Weight; Choice Behavior; Conditioning, Psychological; Lithium Chloride; Male; Piriform Cortex; Proto-Oncogene Proteins c-fos; Rats, Wistar; Taste

The present study has been designed to explore the possible interaction between hemeoxygenase-1 (HO-1) and glycogen synthase kinase-3β (GSK-3β) pathway in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats. 3-NP produces neurotoxicity by inhibition of the mitochondrial complex II (enzyme succinate dehydrogenase) and by sensitizing the N-methyl-D-aspartate receptor. Recent studies have reported the therapeutic potential of HO-1/GSK-3β modulators in different neurodegenerative disorders. However, their exact role is yet to be explored. The present study is an attempt to investigate the effect of pharmacological modulation of HO-1/GSK-3β pathway against 3-NP-induced behavioral, biochemical and molecular alterations in rat. Behavioral observation, oxidative stress, pro-inflammatory [tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)], HO-1 and GSK-3β activity were evaluated post 3-NP treatment. Findings of the present study demonstrate a significant alteration in the locomotor activity, motor coordination, oxidative burden (increased lipid peroxidation, nitrite concentration and decreased endogenous antioxidants), pro-inflammatory mediators [TNF-α, IL-1β], HO-1 and GSK-3β activity in 3-NP-treated animals. Further, administration of hemin (10- and 30-mg/kg; i.p.) and lithium chloride (LiCl) (25- and 50-mg/kg; i.p.) prevented the alteration in body weight, motor impairments, oxidative stress and cellular markers. In addition, combined administration of hemin (10-mg/kg) and LiCl (25-mg/kg) showed synergistic effect on 3-NP-treated rats. Pretreatment with Tin (IV) protoporphyrin (40 μM/kg), HO-1 inhibitor reversed the beneficial effect of LiCl and hemin. Outcomes of the present study suggest that HO-1 and GSK-3β enzymes are involved in the pathophysiology of HD. The modulators of both the pathways might be used as adjuvants or prophylactic therapy for the treatment of HD-like symptoms.

Topics: Animals; Body Weight; Corpus Striatum; Encephalitis; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heme Oxygenase-1; Hemin; Lipid Peroxidation; Lithium Chloride; Male; Metalloporphyrins; Motor Activity; Neuroprotective Agents; Neurotoxicity Syndromes; Nitrites; Nitro Compounds; Oxidative Stress; Propionates; Protoporphyrins; Rats; Rats, Wistar; Rotarod Performance Test; Signal Transduction

Previous studies of central diabetes insipidus suggested that thiazides acutely exerted a paradoxical antidiuresis by either indirectly activating volume-homeostatic reflexes to decrease distal fluid-delivery, or directly stimulating distal water-reabsorption. This study investigated whether the direct and indirect actions of bendroflumethiazide (BFTZ) simultaneously cooperated and also whether the renal nerves were involved in inducing long-term antidiuresis in nephrogenic diabetes insipidus (NDI). BFTZ or vehicle was gavaged into bilateral renal denervated and innervated rats with lithium-induced NDI for 10 days, constituting four groups. At one day before (D0) and one, five and ten days after starting administration of BFTZ or vehicle, rats were placed in metabolic cages to collect urine for 6 hours. BFTZ-treatment in both renal innervated and denervated rats caused equivalent reductions in urine-flow, creatinine clearance, lithium clearance and free-water clearance, but rises in urine-osmolality, fractional proximal reabsorption and fractional distal reabsorption at all days compared to D0, as well as to those of their relevant vehicle-received group. Therefore, the chronic antidiuretic response to BFTZ in conscious NDI rats was exerted through a concomitant cooperation of its direct distal effect of stimulating water-reabsorption and its indirect effect of reducing distal fluid-delivery by activating volume-homeostatic mechanisms, which appeared independent of the renal nerves.

Topics: Animals; Antidiuretic Agents; Autonomic Denervation; Bendroflumethiazide; Biomarkers; Blood Pressure; Blood Urea Nitrogen; Body Weight; Creatinine; Diabetes Insipidus, Nephrogenic; Disease Models, Animal; Diuresis; Drinking; Kidney; Lithium Chloride; Male; Natriuresis; Osmolar Concentration; Rats; Rats, Sprague-Dawley; Time Factors; Urodynamics; Water-Electrolyte Balance

Diphtheria toxin-mediated, acute ablation of hypothalamic neurons expressing agouti-related protein (AgRP) in adult mice leads to anorexia and starvation within 7 d that is caused by hyperactivity of neurons within the parabrachial nucleus (PBN). Because NMDA glutamate receptors are involved in various synaptic plasticity-based behavioral modifications, we hypothesized that modulation of the NR2A and NR2B subunits of the NMDA receptor in PBN neurons could contribute to the anorexia phenotype. We observed by Western blot analyses that ablation of AgRP neurons results in enhanced expression of NR2B along with a modest suppression of NR2A. Interestingly, systemic administration of LiCl in a critical time window before AgRP neuron ablation abolished the anorectic response. LiCl treatment suppressed NR2B levels in the PBN and ameliorated the local Fos induction that is associated with anorexia. This protective role of LiCl on feeding was blunted in vagotomized mice. Chronic infusion of RO25-6981, a selective NR2B inhibitor, into the PBN recapitulated the role of LiCl in maintaining feeding after AgRP neuron ablation. We suggest that the accumulation of NR2B subunits in the PBN contributes to aphagia in response to AgRP neuron ablation and may be involved in other forms of anorexia.

Topics: Adjuvants, Immunologic; Agouti-Related Protein; Animals; Anorexia; Appetite; Blotting, Western; Body Weight; Deglutition Disorders; Eating; Lithium Chloride; Male; Mice; Mice, Knockout; Neurons; Phenols; Piperidines; Pons; Receptors, N-Methyl-D-Aspartate; Rhombencephalon; Time Factors; Vagotomy

Glycogen synthase kinase 3 (GSK-3) plays a central role in cellular energy metabolism, and dysregulation of GSK-3 activity is implicated in a variety of metabolic disorders, including obesity, type 2 diabetes, and cancer. Hence, GSK-3 has emerged as an attractive target molecule for the treatment of metabolic disorders. Therefore, this research focused on identification and characterization of a novel small-molecule GSK-3 inhibitor. Compound 1a, a structure based on 3-hydroxychromone bearing isothiazolidine-1,1-dione, was identified from chemical library as a highly potent GSK-3 inhibitor. An in vitro kinase assay utilizing a panel of kinases demonstrated that compound 1a strongly inhibits GSK-3β. The potential effects of compound 1a on the inactivation of GSK-3 were confirmed in human liver HepG2 and human embryonic kidney HEK293 cells. Stabilization of glycogen synthase and β-catenin, which are direct targets of GSK-3, by compound 1a was assessed in comparison with two other GSK-3 inhibitors: LiCl and SB-415286. In mouse 3T3-L1 preadipocytes, compound 1a markedly blocked adipocyte differentiation. Consistently, intraperitoneal administration of compound 1a to diet-induced obese mice significantly ameliorated their key symptoms such as body weight gain, increased adiposity, dyslipidemia, and hepatic steatosis due to the marked reduction of whole-body lipid level. In vitro and in vivo effects were accompanied by upregulation of β-catenin stability and downregulation of the expression of several critical genes related to lipid metabolism. From these results, it can be concluded that compound 1a, a novel small-molecule inhibitor of GSK-3, has potential as a new class of therapeutic agent for obesity treatment.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adiposity; Aminophenols; Animals; Anti-Obesity Agents; beta Catenin; Body Weight; Cell Differentiation; Chromones; Glycogen Synthase Kinase 3; HEK293 Cells; Hep G2 Cells; Humans; Lipid Metabolism; Lithium Chloride; Male; Maleimides; Mice; Mice, Inbred C57BL; Obesity; Protein Stability; Thiazoles

Stress activates the hypothalamus-pituitary-adrenal (HPA) axis leading to the release of glucocorticoids (GC). Increased activity of the HPA axis and GC exposure has been suggested to facilitate the development of obesity and metabolic syndrome. Nonetheless, different stressors can produce distinct effects on food intake and may support different directions of food learning e.g. avoidance or acceptance. This study examined whether interoceptive (LiCl and exendin-4) and restraint stress (RS) support similar or distinct food learning. Female rats were exposed to different stressors after their consumption of a palatable food (butter icing). After four palatable food-stress pairings, distinct intakes of the butter icing were observed in rats treated with different stressors. Rats that received butter icing followed by intraperitoneal injections of LiCl (42.3mg/kg) and exendin-4 (10μg/kg) completely avoided the palatable food with subsequent presentations. In contrast, rats experiencing RS paired with the palatable food increased their consumption of butter icing across trials and did so to a greater degree than rats receiving saline injections. These data indicate that interoceptive and psychosocial stressors support conditioned food avoidance and acceptance, respectively. Examination of c-Fos immunoreactivity revealed distinct neural activation by interoceptive and psychosocial stressors that could provide the neural basis underlying opposite direction of food acceptance learning.

Topics: Animals; Antimanic Agents; Avoidance Learning; Binge-Eating Disorder; Body Weight; Conditioning, Operant; Data Interpretation, Statistical; Eating; Exenatide; Female; Food Preferences; Immunohistochemistry; Lithium Chloride; Peptides; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stress, Psychological; Venoms

Adult hippocampal neurogenesis is an important process in the regulation of cognition, stress responsivity, and sensitivity to antidepressant and mood stabiliser drugs. Increasing evidence suggests that the hippocampus is functionally divided along its axis with the ventral hippocampus (vHi) playing a preferential role in stress- and anxiety-related processes, while the dorsal hippocampus (dHi) is crucial for spatial learning and memory. However, it is currently unclear whether stress or the medications used to treat stress-related disorders, preferentially affect neurogenesis in the vHi rather than dHi. The aim of this study was to determine whether the mood stabiliser, lithium, preferentially affects cell proliferation and survival in the vHi rather than dHi under stress conditions. To this end, mice of the stress-sensitive strain, BALB/c, underwent chronic exposure to immobilisation stress plus lithium treatment (0.2% lithium-supplemented diet), and the rates of cell proliferation and survival were compared in the dHi and vHi. Lithium preferentially increased cell proliferation in the vHi under stress conditions only. This increase in cell proliferation was secondary to reductions in the survival of newly-born cells. Moreover, lithium-induced decreases in cell survival in the vHi were only observed under stress conditions. Taken together, the data suggest that the turnover of newly-born cells in response to chronic stress and lithium treatment occurs predominantly in the vHi rather than the dHi. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Topics: Analysis of Variance; Animals; Antimanic Agents; Body Weight; Bromodeoxyuridine; Cell Proliferation; Cell Survival; Disease Models, Animal; Hippocampus; Lithium Chloride; Male; Mice; Mice, Inbred BALB C; Neurogenesis; Neurons; Stress, Psychological

Psychological stress is a major risk factor for mood and anxiety disorders. However, the phenotypic manifestation of stress effects varies across individuals, likely due, in part, to genetic variation. Modeling the behavioral and neural consequences of stress across genetically diverse inbred mouse strains is a valuable approach to studying gene × stress interactions. Recent work has shown that C57BL/6J mice exposed to ten daily sessions of restraint stress exhibited increased exploration of the aversive light compartment in the light/dark exploration (LDE) test. Here we sought to clarify the nature of this stress-induced phenotype by testing the ability of treatment with various clinically efficacious drugs of different therapeutic classes to rescue it. Ten days of restraint increased light compartment exploration, reduced body weight and sensitized the corticosterone response to swim stress. Subchronic administration (during stress and LDE testing) of fluoxetine, and to a lesser extent, lithium chloride, rescued stress-induced LDE behavior. Chronic fluoxetine treatment prior to (plus during stress and testing) failed to block the LDE stress effect. Acute administration of antipsychotic haloperidol, anti-ADHD medication methylphenidate or anxiolytic drug chlordiazepoxide, prior to LDE testing, was also unable to normalize the LDE stress effect. Collectively, these data demonstrate a treatment-selective prophylactic rescue of a restraint stress-induced behavioral abnormality in the C57BL/6J inbred strain. Further work with this novel model could help elucidate genetic and neural mechanisms mediating stress-induced changes in mouse 'emotion-relevant' behaviors and, ultimately, further understanding of the pathophysiology of stress-related neuropsychiatric disorders. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Body Weight; Central Nervous System Stimulants; Chlordiazepoxide; Corticosterone; Disease Models, Animal; Emotions; Exploratory Behavior; Fluoxetine; Light; Lithium Chloride; Male; Methylphenidate; Mice; Mice, Inbred C57BL; Restraint, Physical; Stress, Psychological; Swimming

The effects of the bacterial endotoxins, lipopolysaccharide (LPS) and muramyl dipeptide (MDP; Experiment 1), and the viral mimetic, polyinosinic: polycytidylic acid (poly I:C; Experiment 2), on the acquisition of "conditioned gaping" behavior in the rodent model of LiCl-induced anticipatory nausea were examined. Experimentally naïve adult male Long-Evans rats were injected (intraperitoneal, i.p.) with either 200 μg/kg LPS, 1.6 mg/kg MDP, or 0.9% saline (Experiment 1), or 4.0 mg/kg poly I:C or 0.9% saline (Experiment 2), 90 min prior to treatment with 127 mg/kg LiCl or saline control and immediately placed into a distinctive context for 30 min (repeated over 4 conditioning days, spaced 72 h apart). On a drug-free test day (72 h following conditioning day 4), each animal was re-exposed to the context for 10 min, and orofacial and aversive behavioral responses were video recorded and analyzed. The results showed that pre-treatment with LPS, MDP (Experiment 1), or poly I:C (Experiment 2) prior to LiCl+context conditioning significantly impaired the establishment of conditioned gaping behavior, thus blocking the acquisition of anticipatory nausea. Results varied in regards to peripheral acute-phase response sickness behaviors, with significantly reduced weight loss in LPS-treated animals, less robust weight loss in poly I:C-treated animals, and no significant reductions in body weight in MDP-treated animals. The learning impairments observed in the current study suggest that endotoxin treatment with bacterial and viral endotoxin may have stronger central effects on learning and memory behavior, relative to peripheral effects on body weight and other sickness-related responses.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Acute-Phase Reaction; Animals; Behavior, Animal; Body Weight; Conditioning, Classical; Lipopolysaccharides; Lithium Chloride; Male; Nausea; Poly I-C; Rats; Rats, Long-Evans

This study examined the effects of the bacterial endotoxin, lipopolysaccharide (LPS), on the establishment of anticipatory nausea and conditioned taste avoidance in a simultaneous conditioning paradigm using an intravascular/intraperitoneal saccharin taste. 83 naïve adult male Long-Evans rats were injected (intraperitoneal) with either 200 μg/kg LPS or 0.9% saline (NaCl), 90 min prior to ip treatment with either 64 mg/kg LiCl, 64 mg/kg LiCl+2.0% saccharin, 0.9% NaCl, or 0.9% NaCl+2.0% saccharin, and immediately placed into a distinctive context for 30 min (repeated over 4 conditioning days, spaced 72 h apart). 72 h following the final conditioning day, each animal was re-exposed to the context on a drug-free test day where orofacial responding was recorded. The next day, animals received a 24 h 2-bottle preference test with a choice between water and a palatable 0.2% saccharin solution. Results showed that LPS exposure, prior to LiCl or LiCl+Saccharin treatment, inhibited the establishment of anticipatory nausea, as evidenced by significantly lower conditioned gaping frequencies relative to animals pre-treated with NaCl followed by LiCl or LiCl+Saccharin. LPS pre-treatment also inhibited the formation of LiCl-induced taste avoidance, as evidence by significantly higher saccharin preferences in Group LPS-LiCl+Saccharin relative to Group NaCl-LiCl+Saccharin. The results of the current study provide additional evidence for the deleterious effects of LPS on learning and memory in aversive conditioning.

Topics: Analysis of Variance; Animals; Anticipation, Psychological; Avoidance Learning; Behavior, Animal; Body Weight; Face; Fear; Lipopolysaccharides; Lithium Chloride; Male; Mouth; Nausea; Rats; Rats, Long-Evans; Saccharin; Sweetening Agents; Taste

Bipolar disorder (BPD) is a devastating long-term disease for which a significant symptom is mania. Rodent models for mania include psychostimulant-induced hyperactivity and single gene alterations, such as in the Clock or DAT genes, but there is still a pressing need for additional models. Recently, our lab isolated a line of mice, termed Madison (MSN), that exhibit behavioral characteristics that may be analogous to symptoms of mania. In this study we quantified possible traits for mania and tested the response to common anti-BPD drugs in altering the behavioral profiles observed in this strain. Relative to other mouse lines, MSN mice showed significant elevations of in-cage hyperactivity levels, significant decreases in daytime sleep, and significant increases in time swimming in the forced swim test. In terms of sexual behavior, the MSN mice showed significantly higher number of mounts and a trend toward higher time mounting. In separate studies, olanzapine and lithium (or respective controls) were administered to MSN mice for at least 2weeks and response to treatments was evaluated. Olanzapine (1mg/kg/day) significantly decreased in-cage hyperactivity and significantly increased time sleeping. Lithium (0.2-0.4% in food) significantly decreased in-cage hyperactivity. Given the behavioral phenotypes and the response to anti-BPD treatments, we propose that MSN mice may provide a possible new model for understanding the neural and genetic basis of phenotypes related to mania and for developing pharmaceutical treatments.

Topics: Animals; Antimanic Agents; Behavior, Animal; Benzodiazepines; Bipolar Disorder; Body Weight; Dark Adaptation; Disease Models, Animal; Exploratory Behavior; Lithium Chloride; Mice; Olanzapine; Sexual Behavior, Animal; Sleep; Swimming

The NR2E1 region on Chromosome 6q21-22 has been repeatedly linked to bipolar disorder (BP) and NR2E1 has been associated with BP, and more specifically bipolar I disorder (BPI). In addition, patient sequencing has shown an enrichment of rare candidate-regulatory variants. Interestingly, mice carrying either spontaneous (Nr2e1(frc) ) or targeted (Tlx(-) ) deletions of Nr2e1 (here collectively known as Nr2e1-null) show similar neurological and behavioral anomalies, including hypoplasia of the cerebrum, reduced neural stem cell proliferation, extreme aggression and deficits in fear conditioning; these are the traits that have been observed in some patients with BP. Thus, NR2E1 is a positional and functional candidate for a role in BP. However, no Nr2e1-null mice have been fully evaluated for behaviors used to model BP in rodents or pharmacological responses to drugs effective in treating BP symptoms. In this study we examine Nr2e1(frc/frc) mice, homozygous for the spontaneous deletion, for abnormalities in activity, learning and information processing, and cell proliferation; these are the phenotypes that are either affected in patients with BP or commonly assessed in rodent models of BP. The effect of lithium, a drug used to treat BP, was also evaluated for its ability to attenuate Nr2e1(frc/frc) behavioral and neural stem cell-proliferation phenotypes. We show for the first time that Nr2e1-null mice exhibit extreme hyperactivity in the open field as early as postnatal day 18 and in the home cage, deficits in open-field habituation and passive avoidance, and surprisingly, an absence of acoustic startle. We observed a reduction in neural stem/progenitor cell proliferation in Nr2e1(frc/frc) mice, similar to that seen in other Nr2e1-null strains. These behavioral and cell-proliferation phenotypes were resistant to chronic-adult-lithium treatment. Thus, Nr2e1(frc/frc) mice exhibit behavioral traits used to model BP in rodents, but our results do not support Nr2e1(frc/frc) mice as pharmacological models for BP.

Topics: Animals; Antimanic Agents; Avoidance Learning; Body Weight; Cell Proliferation; Eating; Evoked Potentials, Auditory, Brain Stem; Female; Genotype; Habituation, Psychophysiologic; Hindlimb Suspension; Hot Temperature; Hyperkinesis; Immunohistochemistry; Lithium Chloride; Male; Memory; Mice; Mice, Knockout; Motor Activity; Pain Measurement; Receptors, Cytoplasmic and Nuclear; Reflex, Startle; Reverse Transcriptase Polymerase Chain Reaction

The underlying mechanisms of the ketogenic diet (KD) remain unknown. Involvement of peroxisome proliferator-activated receptor-alpha (PPARalpha) has been suggested. The aim of this study was to assess the anticonvulsant properties of fenofibrate, a PPARalpha agonist. Wistar rats were fed at libitum during 14 days by regular diet, KD, regular diet containing 0.2% fenofibrate (F), or KD containing 0.2% fenofibrate (KD + F). Pentylenetetrazol (PTZ) threshold and latencies to the onset of status epilepticus induced by lithium-pilocarpine were used to assess diet treatments with anticonvulsive effects. Myoclonic and generalized seizure PTZ thresholds were increased in F- and KD-treated animals in comparison to control. No difference was observed between KD + F group and the others groups (control, F, KD). Latencies to the onset of status epilepticus were increased in F and KD groups compared to control. Fenofibrate exerts anticonvulsive properties comparable to KD in adult rats using PTZ and lithium-pilocarpine models. The underlying mechanisms such as PPARalpha activation and others should be investigated. These findings may provide insights into future directions to simplify KD protocols.

Topics: 3-Hydroxybutyric Acid; Analysis of Variance; Animals; Body Weight; Diet, Ketogenic; Disease Models, Animal; Electroencephalography; Epilepsy; Fenofibrate; Hypolipidemic Agents; Ketone Bodies; Lithium Chloride; Liver; Male; Organ Size; Pentylenetetrazole; Pilocarpine; PPAR alpha; Rats; Rats, Wistar; Reaction Time

Extreme obesity slowly develops in female rats over the months following seizures induced by a single systemic injection of lithium and pilocarpine if the resulting limbic seizures are treated with the atypical neuroleptic acepromazine (but not with ketamine). To discern the contributions from food consumption, water consumption, and (daytime and nighttime) activity to this weight gain, these behaviors were monitored for 4 months, about 2 months after seizure induction. The results indicated that the rats that underwent the obesity procedure exhibited 50% heavier body weights and consumed 42% more food than the reference group, which included rats that had been induced to seize but treated with ketamine. There were no statistically significant differences between groups with respect to either water consumption or (daytime or nighttime) activity. Factor analyses of data for individual rats verified the dissociation between activity and weight gain for the obese rats. The results suggest that the progressive weight gains are centrally mediated and are not secondary to diminished activity or altered fluid consumption.

Topics: Acepromazine; Analysis of Variance; Animals; Antipsychotic Agents; Body Weight; Disease Models, Animal; Drinking; Eating; Epilepsy; Female; Lithium Chloride; Obesity; Pilocarpine; Rats; Rats, Wistar; Weight Gain

Glucose transporter type 1 (Glut-1) facilitates glucose flux across the blood-brain-barrier. In humans, Glut-1 deficiency causes acquired microcephaly, seizures and ataxia, which are recapitulated in our Glut-1 haploinsufficient mouse model. Postnatal brain weight deceleration and development of reactive astrogliosis were significant by P21 in Glut-1(+/-) mice. The brain weight differences remained constant after P21 whereas the reactive astrocytosis continued to increase and peaked at P90. Brain immunoblots showed increased phospho-mTOR and decreased phospho-GSK3-beta by P14. After fasting, the mature Glut-1(+/-) females showed a trend towards elevated phospho-GSK3-beta, a possible neuroprotective response. Lithium chloride treatment of human skin fibroblasts from control and Glut-1 DS patients produced a 45% increase in glucose uptake. Brain imaging of mature Glut-1(+/-) mice revealed a significantly decreased hippocampal volume. These subtle immunochemical changes reflect chronic nutrient deficiency during brain development and represent the experimental correlates to the human neurological phenotype associated with Glut-1 DS.

Topics: Age Factors; Animals; Animals, Newborn; Apoptosis; Astrocytes; Body Weight; Brain; Carbohydrate Metabolism, Inborn Errors; Carrier Proteins; Cell Proliferation; Cell Size; Cells, Cultured; Dendrites; Disease Models, Animal; Female; Fibroblasts; Gene Expression Regulation, Developmental; Glial Fibrillary Acidic Protein; Gliosis; Glucose Transporter Type 1; Humans; Hypoglycemia; In Situ Nick-End Labeling; Lithium Chloride; Magnetic Resonance Imaging; Male; Mice; Mice, Knockout; Neurons; Organ Size; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Skin; TOR Serine-Threonine Kinases

The worldwide prevalence of obesity is increasing at an alarming rate, along with the associated increased rates of type 2 diabetes, heart disease, and some cancers. While efforts to address environmental factors responsible for the recent epidemic must continue, investigation into the anorectic functions of potential molecules we present here, such as apolipoprotein (apo)E, offers exciting possibilities for future development of successful anti-obesity therapies.. Changes in feeding behavior after intracerebroventricular injection of apoE, the regulation of hypothalamic apoE gene expression by energy status, and the interaction of hypothalamic apoE with other neuropeptides were studied.. Intracerebroventricular apoE significantly decreased food intake without causing malaise, whereas intracerebroventricular infusion of apoE antiserum stimulated feeding, implying that endogenous apoE tonically inhibits food intake. Consistent with this, apoE was present in the hypothalamus, a brain site intimately involved in the integration of signals for energy homeostasis. Fasted rats exhibited significantly decreased apoE gene expression in the hypothalamus, and refeeding of these rats for 4 h evoked a significant increase of hypothalamic apoE mRNA levels. Both genetically obese (ob/ob) mice and rats with high-fat diet-induced obesity had significantly reduced hypothalamic apoE mRNA levels compared with their lean control counterparts, suggesting that decreased apoE may contribute to hyperphagia in these obese animals. Additionally, apoE-stimulated hypothalamic proopiomelanocortin gene expression and SHU9119, a melanocortin 3/4 receptor antagonist, attenuated the inhibitory function of apoE on feeding.. These data demonstrate that apoE suppresses food intake via a mechanism enhancing melanocortin signaling in the hypothalamus.

Topics: Animals; Antibodies; Apolipoproteins E; Blotting, Western; Body Weight; Brain; Dietary Fats; Eating; Fasting; Hypothalamus; Immunohistochemistry; Injections, Intraventricular; Lithium Chloride; Male; Melanocyte-Stimulating Hormones; Mice; Mice, Obese; Neuropeptides; Obesity; Rats; Rats, Long-Evans; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Lithium treatment of patients and laboratory animals causes increased body weight but no single organ or system has been found responsible. In the present work, we showed that lithium increased the weight of the female rat's gastrointestinal (GI) tract including its contents. The weight gain of the female rat GI tract was the same order of magnitude as the weight gain of the whole body of the females. All three parts of the GI tract (stomach, small intestine, colon) participated in the weight gain. Lithium treatment of male rats also increased GI tract weight, but lithium did not increase their overall body weight because of loss of weight at other sites.

Topics: Animals; Antimanic Agents; Body Weight; Female; Gastrointestinal Tract; Lithium Chloride; Male; Organ Size; Rats; Sex Characteristics

Mutations in the tyrosine kinase receptor trkB or in one of its natural ligands, brain-derived neurotrophic factor (BDNF), lead to severe hyperphagia and obesity in rodents and/or humans. Here, we show that peripheral administration of neurotrophin-4 (NT4), the second natural ligand for trkB, suppresses appetite and body weight in a dose-dependent manner in several murine models of obesity. NT4 treatment increased lipolysis, reduced body fat content and leptin, and elicited long-lasting amelioration of hypertriglyceridemia and hyperglycemia. After treatment termination, body weight gradually recovered to control levels in obese mice with functional leptin receptor. A single intrahypothalamic application of minute amounts of NT4 or an agonist trkB antibody also reduced food intake and body weight in mice. Taken together with the genetic evidence, our findings support the concept that trkB signaling, which originates in the hypothalamus, directly modulates appetite, metabolism, and taste preference downstream of the leptin and melanocortin 4 receptor. The trkB agonists mediate anorexic and weight-reducing effects independent of stress induction, visceral discomfort, or pain sensitization and thus emerge as a potential therapeutic for metabolic disorders.

Topics: Animals; Body Weight; Disease Models, Animal; Eating; Energy Metabolism; Glucose; Homeostasis; Leptin; Lithium Chloride; Male; Melanocortins; Mice; Mice, Inbred C57BL; Mice, Obese; Nerve Growth Factors; Obesity; Rats; Rats, Sprague-Dawley; Receptor, trkB; Receptors, Leptin; Taste; Triglycerides

Mood disorders are the most common psychiatric disorders. Although the mechanisms implicated in the genesis of mood disorders are still unclear, stress is known to predispose to depression, and recently, studies have related hippocampal neurogenesis and apoptosis to depression. In the present study we first examined the balance between cell birth-death in the hippocampus and subventricular zone (SVZ) of pre-pubertal and adult rats subjected to chronic-mild-stress (CMS). CMS led to increased corticosterone secretion and induced depressive-like symptoms (assessed in the forced-swimming test); these endocrine and behavioral effects were paralleled by decreased hippocampal, but not SVZ, cell proliferation/differentiation and by increased apoptotic rate. In order to determine if lithium, a known mood stabilizer with antidepressant properties, could prevent the stress-induced events, we analyzed the same parameters in a group of rats treated with lithium during the stress exposure period (CMS+Li) and observed that the hormonal, behavioral and cell turnover effects of CMS were abrogated in these animals. Subsequently, to search for possible pathways through which CMS and lithium influence behavior, cell fate and synaptic plasticity, we analyzed the expression of glycogen-synthase-kinase-3beta (GSK-3beta), as well as some of its downstream targets (B-cell-CLL/lymphoma2-associated athanonege (BAG-1) and synapsin-I). CMS increased GSK-3beta and decreased synapsin-I and BAG-1 expression in the hippocampus. Interestingly, co-administration of lithium precluded the CMS-induced effects in GSK-3beta, synapsin-I and BAG-1 expression. Our observation that specific inhibition of this kinase with AR-A014418 blocked the effects of CMS in depressive-like behavior and in BAG-1 and synapsin-I expression confirmed the involvement of the GSK-3beta pathway in stress-induced effects. In summary, these results reveal that lithium, by regulating the activity of GSK-3beta, prevents the deleterious effects of stress on behavior and cellular functions.

Topics: Adrenal Glands; Animals; Antimanic Agents; Behavior, Animal; Body Weight; Cell Proliferation; Cell Survival; Corticosterone; Depressive Disorder; Disease Models, Animal; DNA-Binding Proteins; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Lithium Chloride; Male; Neuronal Plasticity; Neurons; Rats; Rats, Wistar; Stem Cells; Stress, Psychological; Synapsins; Synaptic Transmission; Transcription Factors; Up-Regulation

The systemic treatment with angiogenesis inhibitor has been shown to result in weight reduction and adipose tissue loss in various models of obesity. To verify the mechanism of CKD-732 (TNP-470 analog) against obesity, we evaluated CKD-732's peripheral and central anti-obesity effects. CKD-732 was injected subcutaneously (s.c.) for 7 days in various animal models and intracerebroventricularly (i.c.v.) in arcuate nucleus (ARC) lesion mice, ob/ob mice, and normal littermates. Modulation of the hypothalamic neuropeptide mRNAs after i.c.v. injection was evaluated in ARC lesion mice and normal littermates. A conditioned taste aversion (CTA) was performed using lithium chloride (LiCl) as a positive control agent in Long-Evans Tokushima Otsuka and Otsuka Long-Evans Tokushima fatty (OLETF) rats. As a result, 7 days of CKD-732 s.c. injection reduced the cumulative food intake and the body weight significantly in both treated obese (e.g. 114.8 +/- 13.4 g vs 170.7 +/- 20.6 g, 7.9 +/- 0.5% decrease vs 0.3 +/- 2.2% decrease; in treated OLETF rat versus control OLETF rat, P < 0.01 respectively) and non-obese models. Epididymal and mesenteric fat pads, and the size of adipocytes were significantly decreased in treated rats. A single i.c.v. injection decreased food intake and body weight in ARC lesion mice and ob/ob mice but not in normal littermates. Unexpectedly, the hypothalamic neuropeptide mRNAs were not altered by single i.c.v. injection. CKD-732 also induced a dose-dependent CTA comparable with LiCl injection, which is a commonly used agent to produce a CTA. In conclusion, CKD-732 causes significant body weight and appetite reduction, possibly by decreasing adiposity directly and inducing central anorexia, which is partly explained by a CTA. These results should be carefully verified to assess the utility of CKD-732 as an anti-obesity drug.

Topics: Adipocytes; Adipose Tissue; Animals; Anti-Obesity Agents; Arcuate Nucleus of Hypothalamus; Body Weight; Cell Size; Cinnamates; Cyclohexanes; Eating; Epoxy Compounds; Hypothalamus; Lithium Chloride; Male; Mice; Mice, Obese; Neuropeptides; O-(Chloroacetylcarbamoyl)fumagillol; Obesity; Rats; Rats, Inbred OLETF; Sesquiterpenes; Taste

Lithium treatment of patients and laboratory animals causes increased body weight. Lithium also elevates the plasma corticosterone levels of rats. Our purpose was to correlate the gain of body weight with the effects of lithium on the thymus gland, the organ most susceptible to stress and to elevated corticosterone levels. Toward this end, it was also necessary to establish a reliable and reproducible model by use of an inbred strain of rats. Female rats of the inbred Lewis strain were injected subcutaneously with lithium chloride or saline for an 18-day period. Necropsies were performed one day after the last treatment or at intervals during the treatment period. Lithium increased body weight gain compared to controls in all the experiments on Lewis rats. Contrary to the body as a whole, lithium caused loss of weight of the thymus gland. The spleen lost less weight than the thymus. Both lithium and nonspecific stress elevate plasma corticosterone and cause thymolysis. Mild nonspecific stress is known to cause increased weight gain in rats as well as in humans. Our data suggest that lithium acts like nonspecific stress to increase weight gain as a consequence of elevated glucocorticoids, manifested in our experiments by thymolysis. This mechanism has not been proposed previously.

Topics: Animals; Antimanic Agents; Body Weight; Corticosterone; Female; Lithium Chloride; Rats; Rats, Inbred Lew; Thymus Gland

Assessment of cognition and information processing in mice is an important tool in preclinical research that focuses on the development of cognitive enhancing drugs. Analysis of transgenic (TG) and knockout (KO) mice is usually performed on a F2 B6x 129 background. In the present study, we have compared performance of F2 B6x 129 hybrid mice (F2 mice) with that of the two parental inbred strains (C57Bl/6J and 129sv mice), and a wild-type (WT) strain (with a combined B6x 129 background) in three cognitive/information processing paradigms. It was found that the F2 mice outperformed either of the parental strains and provide a control sample with good baseline performance in the Morris water maze (MWM). Reliable deficits could be obtained in learning and memory in this paradigm following injections with scopolamine (0.16 mg/kg) in the F2 mice, which can potentially be used to test effects of reference and novel compounds in order to develop cognitive enhancing drugs. Furthermore, it was shown that the four genotypes showed normal latent inhibition (LI) using the conditioned taste aversion (CTA) paradigm and exhibited no differences in prepulse inhibition (PPI) levels. Following the setup of these procedures in mice, we are now able to compare the effects of gene knockout/mutations used for target validation with results in the present study as a frame of reference.

Topics: Animals; Antimanic Agents; Body Weight; Conditioning, Psychological; Genotype; Lithium Chloride; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Motor Activity; Muscarinic Antagonists; Reflex, Startle; Reward; Scopolamine; Space Perception; Species Specificity; Sucrose; Taste

Neuromedin U 2 receptor (NMU2R) plays important roles for the regulation of food intake and body weight. However, the molecular mechanism underlying the action of NMU2R has not been clearly defined. We have taken chemical genetic approach to examine the involvement of peptides in the regulation of NMU2R effects. A cell-based reporter gene assay has been developed and used for the screening of human NMU2R agonist. Three natural product compounds, EUK2010, EUK2011 and EUK2012, were identified that could activate the reporter gene expression in the cell-based functional assay. Although these compounds showed high EC50 at hundreds micro-molar range, in vitro pharmacological analysis suggested that they were specific agonists for the human NMU2R. The natural compounds could decrease food intake and lead to the reduction of body weight in different animal models. To understand the molecular basis of the NMU2R regulation of food intake and body weight, we examined the expression of a number of key genes in hypothalamus and adipose tissues after oral administration of EUK2010 in mice. Our results demonstrated that the expression levels of a number of neuropeptide genes were altered after the treatment of EUK2010. Interestingly, EUK2010 increased the expression of Leptin in white fat. These results suggested that these peptides may participate in the regulation of NMU2R effects in mice.

Topics: Animals; Body Weight; DNA Primers; Energy Intake; Gene Expression Regulation; Genes, Reporter; Humans; Lithium Chloride; Membrane Proteins; Mice; Mice, Inbred C57BL; Peptide Hormones; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Receptors, Neurotransmitter

To evaluate the effectiveness of lithium augmentation of topiramate on mood symptoms, binge eating behavior, and body weight in obese bipolar patients with binge eating disorder (BED) seeking weight management.. We conducted a naturalistic study of 12 consecutive outpatients with bipolar disorders, BED, and obesity who received lithium augmentation for mood instability during the course of topiramate-based pharmacotherapy for obesity and BED. Lithium was added to topiramate (mean dose 514 mg i.d.) and titrated to a mean dose of 1009 mg i.d. (mean plasma concentration 0.7 mmol/L). Treatment response was assessed by comparing changes in clinical severity scales for mood and eating disorders, weekly binge eating frequency, and weight for the 2 months before and the first 2 months during lithium treatment.. A statistically significant improvement in global severity of mood symptoms was observed after as compared to before lithium augmentation. Statistically insignificant reductions in weight and in binge frequency and severity were also observed after lithium addition.. Optimal weight loss treatment in obese patients with comorbid bipolar and BEDs may require stabilization of mood. The combination of lithium and topiramate may have a role in the management of this difficult-to-treat population.

Topics: Adult; Anti-Obesity Agents; Antimanic Agents; Bipolar Disorder; Body Mass Index; Body Weight; Bulimia Nervosa; Comorbidity; Drug Interactions; Female; Follow-Up Studies; Fructose; Humans; Lithium Chloride; Male; Middle Aged; Obesity; Severity of Illness Index; Statistics, Nonparametric; Surveys and Questionnaires; Topiramate

To test effects of paraldehyde on behavioral outcome of status epilepticus (SE) in developing rats.. Motor SE was induced by LiCl-pilocarpine in rats on postnatal (P) day 12 or 25. Two hours after SE onset, animals were injected with a single dose of paraldehyde (0.07 and 0.3 ml/kg in the P12 group and 0.3 and 0.6 ml/kg in the P25 group). Effects on seizure severity and mortality were evaluated. Growth of animals and their motor abilities were monitored until the adulthood. Three months after SE, cognitive abilities were tested by using the Morris water maze.. Both tested doses of paraldehyde equally affected motor seizures. Convulsions continued until the paraldehyde administration, but then they quickly subsided in all groups. During the subsequent 24 h, occasional clonic seizures occurred in P25 animals treated with the lower dose of paraldehyde. Only hyperactivity and/or automatisms were observed in the other experimental groups. Mortality was not affected by the dosage of paraldehyde. The higher dosage of paraldehyde improved recovery after SE in both age groups. No difference was found in motor abilities between controls and SE animals, except shortening of time spent on the rod in the rotarod test in the P12 group. In P25 rats, treatment with a higher dosage of paraldehyde improved learning abilities compared with the lower dosage. In the P12 group, animals treated with the lower dosage exhibited slightly impaired learning compared with controls and animals receiving the higher dosage.. Paraldehyde injected 2 h after SE onset modulates long-term outcome in immature rats in a dose-related manner.

Topics: Animals; Animals, Newborn; Anticonvulsants; Behavior, Animal; Body Weight; Dose-Response Relationship, Drug; Exploratory Behavior; Lithium Chloride; Male; Maze Learning; Motor Activity; Paraldehyde; Pilocarpine; Rats; Rats, Wistar; Status Epilepticus

Feeding and drinking typically involve both appetitive and consummatory behaviors. Appetitive behaviors include those behaviors produced by an animal prior to the actual consumption, such as approach movements, whereas consummatory behaviors (such as licking and chewing) are involved in the actual consumption of food. The present research compared the gustatory conditioning effects of bacterial lipopolysaccharide (LPS) and lithium chloride (LiCl) in two different paradigms, conditioned taste avoidance and conditioned taste aversion which differentially affect the appetitive and consummatory components of feeding. Male rats were implanted with intraoral cannulae and habituated to a water deprivation schedule and afterwards received two conditioning days (Days 1 and 4). Each conditioning day consisted of 1 h access to a novel sucrose solution (0.3 M) immediately followed by a systemic injection of LPS (200 microg/kg), LiCl (0.15 M, 3 meq) or NaCl vehicle. Conditioned taste aversion was assessed using the taste reactivity test on Day 7, where orofacial and somatic responses were videotaped and analyzed during 3 brief (1 min) exposures to the sucrose solution. Conditioned taste avoidance was assessed on Days 8 and 9 using a two-bottle preference test (sucrose versus water). Animals conditioned with LiCl displayed typical aversive-like responses in the taste reactivity paradigm evidenced by significant reductions in positive ingestive responses (P<0.05) and an increase in active aversive responses (P<0.05) relative to controls. Furthermore, LiCl treatment resulted in conditioned avoidance of sucrose in the two-bottle preference test characterized by a decreased sucrose preference (P<0.05). Conditioning with LPS produced a reduced sucrose preference (P<0.05) relative to controls, comparable to the avoidance seen in LiCl-treated rats. In contrast, conditioning with LPS resulted in similar positive ingestive responses to intraorally infused sucrose as seen in controls. The present results demonstrate that LPS treatment produces conditioned avoidance but not aversion and suggest that LPS can selectively condition the appetitive aspects of feeding whereas the consummatory behaviors remain unaffected.

Topics: Adjuvants, Immunologic; Administration, Oral; Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Body Weight; Conditioning, Operant; Drinking; Eating; Food Preferences; Habituation, Psychophysiologic; Lipopolysaccharides; Lithium Chloride; Male; Rats; Rats, Long-Evans; Sucrose; Time Factors; Water Deprivation

Recent studies have shown that acute systemic administration of the selective orexin-1 receptor antagonist SB-334867 significantly reduces food intake in rats. Although this anorectic action of orexin-1 receptor blockade is associated with an acceleration in the transition from eating to resting, it is widely recognised that the behavioural indices of satiety are not dissimilar to those of illness. In this context, Experiment 1 confirmed a significant anorectic effect of 90 (but not 60) mg/kg lithium chloride (LiCl) in male rats presented with palatable mash in the home-cage environment. Experiment 2 employed a continuous monitoring technique to contrast the effects of LiCl (90 mg/kg) and SB-334867 (10 and 30 mg/kg) on food intake and behaviour during a 1-h test with palatable mash. SB-334867 dose-dependently inhibited food intake, with the higher dose producing a comparable degree of appetite suppression (approximately 40%) to that seen with LiCl. Despite equivalent anorectic action, the two compounds produced very different effects on behaviour. LiCl reduced active behaviours (locomotion, rearing, grooming and sniffing), slowed the rate of eating and disrupted the behavioural satiety sequence (BSS). In contrast, SB-334867 (30 mg/kg) decreased the duration of feeding and grooming, and modestly accelerated the transition between eating and resting. Furthermore, whereas LiCl failed to alter posttreatment bodyweight gain, SB-334867 (30 mg/kg) produced a significant weight loss in the 24-h period immediately following injection. Overall, the divergent profiles obtained with equianorectic doses of LiCl and SB-334867 provide convincing evidence for the behavioural selectivity of SB-334867-induced anorexia.

Topics: Animals; Appetite; Appetite Depressants; Benzoxazoles; Body Weight; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Lithium Chloride; Male; Naphthyridines; Orexin Receptors; Rats; Rats, Inbred Strains; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Satiety Response; Urea

This paper was written to pay honor to Professor Gerard P. Smith because of his strong influence on me to study the ingestion of sweet and fat mixtures. Three experiments are reported here, in which the laboratory rat was given an emulsion of a glucose+saccharin mixture with corn oil. In the first experiment, a two-bottle, 24-h test was given comparing the emulsion with water. Over 6 weeks, the concentration of the corn oil was gradually increased. When given only food and water, or the glucose/saccharin solution, the rats regulated their caloric intake and grew at a normal rate. In contrast, when the corn oil was present, the rats significantly increased their caloric intake, resulting in a marked increase in body weight. In the second experiment, a detailed analysis of the ingestion revealed that the rate of licking the emulsion during drinking bouts increased in a linear manner as the concentration of the corn oil was increased. In the third experiment, a conditioned taste aversion to the sweet/fat emulsion generalized to the fat more than to the sweet solutions. The implications for a gustatory input are discussed.

Topics: Animals; Body Weight; Corn Oil; Dose-Response Relationship, Drug; Drinking Behavior; Drug Interactions; Emulsions; Feeding Behavior; Glucose; Lithium Chloride; Rats; Saccharin; Time Factors

To develop and use a behavioral paradigm for assessments of what nutrient properties are detected by intestinal chemoreceptors, we combined features of the "electronic esophagus" preparation (Elizalde G and Sclafani A. Physiol Behav 47: 63-77, 1990) and the conditioned taste aversion protocol (Garcia J and Koelling RA. Psychon Sci 4: 123-124, 1966). In four experiments, separate groups of food-deprived rats with gastric (experiments 1-4) or duodenal (experiment 4) catheters were infused with either carbohydrates (maltodextrin) or fats (corn oil) into their stomachs or small intestines, either while they consumed nonnutritive flavored solutions (experiments 1 and 2) or in the absence of any intake (experiments 3 and 4). For some animals, one of the macronutrient infusions was paired with lithium chloride injections shown to support conventional conditioned aversions. After training, in various oral preference test trials, animals were given opportunities to taste and consume the nonnutritive solutions that had served as oropharyngeal conditioned stimuli as well as the nutrients that had been infused intragastrically, with or without poisoning, but never sampled by mouth. As previously established, preferences for the nonnutritive flavors were enhanced by association with intragastric infusions of macronutrients, with carbohydrates producing the greater preference. On first exposure to the two macronutrients for oral consumption, animals reduced their intake of the nutrient that had been previously poisoned when it was infused into the gastrointestinal tract. These results, along with additional controls, suggest that nutrient tastes detected in the intestines can be recognized centrally based on oropharyngeal gustatory stimulation.

Topics: Animals; Avoidance Learning; Body Weight; Chemoreceptor Cells; Conditioning, Operant; Corn Oil; Dietary Carbohydrates; Dietary Fats; Duodenum; Esophagogastric Junction; Intestines; Intubation, Gastrointestinal; Lithium Chloride; Male; Polysaccharides; Rats; Rats, Sprague-Dawley; Taste

Studies were performed to determine if the reported 'proconvulsant' action of lithium in rats given cholinergic drugs is related to receptor-initiated phospholipase A2 signaling via arachidonic acid. Regional brain incorporation coefficients k* of intravenously injected [1-14C]arachidonic acid, which represent this signaling, were measured by quantitative autoradiography in unanesthetized rats at baseline and following administration of subconvulsant doses of the cholinergic muscarinic agonist, arecoline. In rats fed LiCl for 6 weeks to produce a therapeutically relevant brain lithium concentration, the mean baseline values of k* in brain auditory and visual areas were significantly greater than in rats fed control diet. Arecoline at doses of 2 and 5 mg/kg intraperitoneally increased k* in widespread brain areas in rats fed the control diet as well as the LiCl diet. However, the arecoline-induced increments often were significantly greater in the LiCl-fed than in the control diet-fed rats. Lithium's elevation of baseline k* in auditory and visual regions may correspond to its ability in humans to increase auditory and visual evoked responses. Additionally, its augmentation of the k* responses to arecoline may underlie its reported 'proconvulsant' action with cholinergic drugs, as arachidonic acid and its eicosanoid metabolites can increase neuronal excitability and seizure propagation.

Topics: Animals; Arachidonic Acid; Arecoline; Autoradiography; Body Weight; Brain; Carbon Radioisotopes; Cholinergic Agonists; Drug Administration Routes; Drug Administration Schedule; Lithium Chloride; Male; Rats; Rats, Inbred F344; Rest; Seizures; Signal Transduction; Time; Wakefulness

Expression of the Huntington's disease (HD) mutation in mice (R6/2 line) causes a progressive neurological phenotype that includes deterioration of motor function resembling that seen in HD. The current study sought to determine whether or not chronic treatment of R6/2 mice with lithium chloride would have an effect on the progression of the phenotype, in light of lithium's reported neuroprotective and anti-depressive properties. Treatment began either before or after the onset of symptoms. Chronic treatment with lithium caused a significant improvement in rotarod performance when treatment was started post- but not pre-symptomatically. There was no overall effect on survival in either group, but further analysis revealed that in the post-symptomatic group, mice could be assigned to one of two distinct groups, depending on the effects of lithium. One subgroup of mice lost weight faster, died earlier and showed rotarod performance similar to the vehicle-treated controls. The other subgroup lost weight at a normal rate, died at a similar age, but showed greatly improved motor performance compared to controls. The improvement in rotarod performance suggests that lithium may improve motor symptoms as well as depression in some HD patients.

Topics: Aging; Animals; Antimanic Agents; Behavior, Animal; Body Weight; Disease Models, Animal; Drug Administration Routes; Female; Huntington Disease; Lithium Chloride; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Mutation; Norbornanes; Phenotype; Psychomotor Performance; Rotation; Survival; Time Factors

In the present study, the effects of orally-administered lithium on testicular morphology were examined in the spotted munia (Lonchura punctulata), a seasonally breeding sub-tropical finch. Adult males were procured from natural populations during the month of August, a time when these birds begin to show seasonal reproductive maturity in an annual cycle. Both during the period of acclimation, and throughout the subsequent experimental period, the birds were maintained in an open aviary simulating natural environmental conditions. Lithium was dissolved in distilled water and was administered via the oral route by means of a commercially available stomach-tube. A total of five experimental groups were utilized. The first group (Group A) served as control and received lithium-free distilled water in a similar manner. In the remaining four groups, lithium was administered daily as follows: Group B (2.5 mEq/Kg body weight for 5 days); Group C (2.5 mEq/Kg for 10 days); Group D (5.0 mEq/Kg for 5 days) and Group E (5.0 mEq/Kg for 10 days). All lithium administrations were carried out between 14:00 and 15:00h. Twenty-four hours after the last oral lithium, final body weights were recorded, blood samples were obtained (by brachial vein puncture for the measurement of serum lithium) and the animals were sacrificed, and testes were collected for histological studies. Our results indicated that lithium treatment led to a significant reduction in testicular weight and seminiferous tubular diameter, and a marked degenerative changes in germ cells in that most of the spermatids and mature spermatozoa showed necrotic changes and were sloughed off from the seminiferous tubular epithelium. Complete desquamation and loss of germ cells, and their clump formation were also noted within many seminiferous tubular lumen. Notably these adverse effects were observed when serum lithium levels were within the therapeutic range for human. These results confirm our earlier report on lithium's adverse effects on testicular function, and extend further to show that lithium indeed has a significant adverse effect on the histomorphology, and, thus, the function of the testis in birds.

Topics: Animals; Behavior, Animal; Body Weight; Leydig Cells; Lithium; Lithium Chloride; Male; Necrosis; Organ Size; Seasons; Seminiferous Tubules; Songbirds; Spermatids; Spermatozoa; Testis

Lithium salt has been widely used as a treatment for mania, but the mechanism of its effect remains unknown. Previously, by studying c-fos expression, we showed that the striatum was a possible target region for the antimanic effects of lithium salt. The present study focused on the effect of subchronic lithium chloride treatment on G-proteins (Golf, Ggamma7) and adenylyl cyclase type V, which are expressed specifically in the rat striatum. Subchronic lithium chloride treatment significantly increased the level of Golf protein, a stimulant alpha-subunit of G-protein, by 53.5% (P<0.01), but the levels of Ggamma7 and adenylyl cyclase type V did not change. This increased level of Golf protein was found after 2 weeks of lithium chloride treatment, but not after 1 week, and the level returned to the basal level 1 week after withdrawal of lithium chloride. This result suggests that the level of Golf protein increases to compensate for the suppression of the adenylyl cyclase system by lithium, and that this increase may account for the "rebound" phenomenon, which is the relapse observed after abrupt discontinuation of lithium salt treatment.

Topics: Adenylyl Cyclases; Animals; Blotting, Western; Body Weight; Corpus Striatum; Gene Expression Regulation; GTP-Binding Protein alpha Subunits; GTP-Binding Proteins; Heterotrimeric GTP-Binding Proteins; In Situ Hybridization; Lithium; Lithium Chloride; Male; Rats; Rats, Wistar; RNA, Messenger; Time Factors

To compare the results of cardiac output measurements obtained by lithium dilution and transpulmonary thermodilution in paediatric patients.. A prospective study.. Paediatric intensive care unit in a university teaching hospital.. Twenty patients (age 5 days-9 years; weight 2.6-28.2 kg) were studied.. Between two and four comparisons of lithium dilution cardiac output (LiDCO) and transpulmonary thermodilution (TPCO) were made in each patient.. Results from three patients were excluded: in one patient there was an unsuspected right-to-left shunt, in two patients there was a problem with blood sampling through the lithium sensor. There were 48 comparisons of LiDCO and TPCO in the remaining 17 patients over a range of 0.4-6 l/min. The mean of the differences (LiDCO-TPCO) was -0.1 +/- 0.3 (SD) l/min. Linear regression analysis gave LiDCO = 0.11 + 0.90 x TPCO l/min (r2 = 0.96). There were no adverse effects in any patient.. These results suggest that the LiDCO method can be used to provide safe and accurate measurement of cardiac output in paediatric patients. The method is simple and quick to perform, requiring only arterial and venous catheters, which will already have been inserted for other reasons in these patients.

Topics: Age Factors; Body Weight; Cardiac Output; Catheterization, Central Venous; Dye Dilution Technique; Feasibility Studies; Femoral Artery; Humans; Iliac Artery; Infant, Newborn; Intensive Care Units, Pediatric; Intensive Care, Neonatal; Linear Models; Lithium Chloride; Prospective Studies; Pulmonary Artery; Thermodilution; Time Factors

In this report, we have examined the effects of lithium on testicular morphology in a male subtropical wild avian species, the roseringed parakeet (Psittacula krameri). Adult male birds were collected during the months of February-March, a time when the testicular gametogenic activity in these seasonally breeding birds is at its peak. They were injected, intramuscularly, twice daily (07:00 and 19:00 h) with lithium chloride (Sigma Chemical Company) at a dosage of 0.5 mEq/Kg body weight either for 5 or 10 days. A significant decrease in both the absolute and relative testicular weights was evident in the lithium-treated birds as compared to those of the saline-injected control animals. Light microscopic studies of the testis in the lithium-treated animals showed a wide range of degenerative changes. These included a) a significant reduction in the diameter of seminiferous tubules; b) necrosis and exfoliation of most of the germ cells in the seminiferous tubular lumen with the exception of the spermatogonia; and c) a significant reduction in the number of mature spermatozoa in the tubular lumen. These degenerative changes were dependent on the duration of lithium treatment and were evident when the plasma lithium concentrations were well below the human therapeutic range. Leydig cell morphology was not affected by lithium however. Our results provide the first experimental evidence of lithium's adverse reproductive function in an avian species. These data provide further support to the view that lithium adversely affects the male reproductive system and that these effects extend beyond mammalian species.

Topics: Animals; Antimanic Agents; Body Weight; Lithium; Lithium Chloride; Male; Organ Size; Parakeets; Seminiferous Tubules; Spermatogenesis; Testis

Lithium chloride was injected into rats by the intraperitoneal or intravenous route. The dose was proportional to body weight, in the conventional manner. Lithium levels in blood serum and organs were determined after 3-24 h. Within a given strain, large rats had higher levels than small rats. The size of the rats, and not their age, was the determining factor. The large rats had more adipose tissue than the small rats. Inasmuch as lithium distributes in body water, the excess fat in large rats reduces its volume of distribution, which may be responsible for raising the lithium levels in aqueous compartments, including serum. Male and female rats of equal body size developed equal lithium levels in serum.

Topics: Age Factors; Animals; Body Weight; Female; Lithium Chloride; Male; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Sex Factors

We explored the possibility that quantitative analysis of the relationship between sucrose concentration and sham intake differentiated how various treatments affected the intake of sweet solutions. Rats were sham fed sucrose solutions varying in concentration from 0.03125 to 1.5 M. Under different treatment conditions, intake concentration functions were generated that plotted amount sham fed against sucrose concentration. Sucrose concentration that yielded 50% maximal sham intake were calculated to indicate the position of the concentration-intake function on the x-axis. Quinine adulteration of sucrose solutions and injection of 0.5 mg/kg i.p. of the dopamine antagonist pimozide reduced sham intake and shifted the concentration-intake function to the right. Lithium chloride (60 mg/kg i.p.) injected 30 min before sham feeding, a reduction of food deprivation from 18 to 6 h before sham feeding, and 6 micrograms/kg cholecystokinin octapeptide reduced sham intake equivalent amounts but did not shift the concentration-intake functions along the x-axis. The data indicate that of several factors that reduce sham feeding, only some also shift the position of concentration-intake curves, and these curve shifts may identify intake changes mediated by alterations in the processing of the taste input.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Drinking; Drug Combinations; Food Deprivation; Lithium Chloride; Male; Osmolar Concentration; Pimozide; Quinine; Rats; Rats, Inbred Strains; Sincalide; Solutions; Sucrose

Possums (Trichosurus vulpecula) are New Zealand's main vertebrate pest. Control practices using poisons are likely to remain the most cost effective methods for the immediate future but poisons may be avoided in the field. A series of experiments were conducted to determine whether cyanide bait avoidance involved conditioned food aversions (CFA) induced by sublethal cyanide ingestion. Food aversions were conditioned in three experiments using intraperitoneal or oral routes of administration with three different cyanide formulations over a range of doses. Across all experiments there was a direct relationship between dose and the proportion of animals developing CFAs. When administered orally, doses greater than 5 mg/kg resulted in more than 50% of surviving animals developing aversions. Route of administration or formulation appeared to have no differential effect on development of CFA. Although there was considerable variation between individuals in the degree of aversion shown this may be one mechanism that could account for poor possum kill rates in some poisoning operations.

Topics: Administration, Oral; Animals; Avoidance Learning; Body Weight; Cyanides; Dose-Response Relationship, Drug; Eating; Female; Injections, Intraperitoneal; Lithium Chloride; Male; Opossums; Sex Characteristics

When low doses of insulin are infused directly into the third ventricle, rats reduce their food intake and lose weight. To determine whether these effects could be due to malaise induced by the treatment, the effects of intraventricular insulin were compared to the effects of the emetic agent lithium chloride to condition a taste aversion, to stimulate oxytocin secretion, and to reduce sodium appetite in response to furosemide treatment. For all three of these measures, lithium chloride treatment had a predictable effect compared to controls. Specifically, lithium caused a significant taste aversion, elevated plasma oxytocin, and attenuated sodium appetite. However, lithium did not produce a significant change in food intake or body weight. On the other hand, intraventricular insulin treatment did cause a significant reduction in body weight yet had no effect on these indices of malaise in the rat. These data are consistent with the hypothesis that intraventricular insulin does not reduce food intake and body weight by producing malaise but rather serves as a negative feedback signal of body adiposity to the central nervous system.

Topics: Animals; Appetite; Avoidance Learning; Body Weight; Dose-Response Relationship, Drug; Eating; Injections, Intraperitoneal; Injections, Intraventricular; Insulin; Lithium Chloride; Male; Oxytocin; Rats; Taste; Viscera; Water-Electrolyte Balance

Status epilepticus was induced in rats by sequential injections of lithium and pilocarpine. Seizure activity was aborted by a combination of MK-801 and diazepam, with status duration ranging from 3 to 180 min. When the hearts were examined 8-12 days later, rats that had experienced an episode of status epilepticus had significantly heavier hearts than did controls. The nature of the cardiac tissue changes was not examined, and deserves further study.

Topics: Animals; Body Weight; Cardiomegaly; Diazepam; Dizocilpine Maleate; Electroencephalography; Lithium Chloride; Male; Myocardium; Organ Size; Pilocarpine; Rats; Rats, Sprague-Dawley; Status Epilepticus

The contribution of the loop segments to lithium reabsorption in sodium-replete, anesthetized Sprague-Dawley rats was examined by perfusing superficial loops of Henle between late proximal convolutions and early distal tubules. Preliminary experiments in which lithium was initially present only inside or outside the perfused loop confirmed substantial permeability of one or more of the loop segments to lithium. In subsequent experiments, in which lithium was infused intravenously and included in the perfusate so that the perfusate-to-plasma lithium concentration ratio was close to that found in late proximal tubules during lithium clearance studies, lithium reabsorption was inversely related to the perfusion rate: values for fractional lithium reabsorption (FRLi) at perfusion rates of 10, 20, and 30 nl/min were 58 +/- 3, 17 +/- 2, and 2 +/- 2%, respectively. Bumetanide (10(-6) M) markedly inhibited FRLi but also reduced water reabsorption, suggesting an effect on the pars recta at this dose; 10(-7) M bumetanide, which was without effect on water reabsorption, had only a small effect on FRLi at a perfusion rate of 10 nl/min but reduced FRLi by approximately 70% at 20 nl/min. We argue that the remarkable flow dependency of lithium reabsorption, together with its bumetanide sensitivity, provides evidence for significant voltage-driven lithium reabsorption in the thick ascending limb of Henle.

Topics: Absorption; Analysis of Variance; Animals; Blood Pressure; Body Weight; Bumetanide; Glomerular Filtration Rate; Inulin; Kinetics; Lithium Chloride; Loop of Henle; Male; Perfusion; Rats; Rats, Sprague-Dawley; Sodium; Time Factors

Ob/ob mice (OB) with B16 melanoma become anorectic, but lean mice (LN) do not. Present studies suggest that this difference reflects a greater bent for OB to form conditioned taste aversions (CTA). In Exp 1, healthy OB formed stronger CTAs than LN to a saccharin taste paired with lithium chloride (LiCl, 3 mEq/kg ip). In Exp 2, the OB-LN difference of Exp 1 was decreased by giving naltrexone (10 mg/kg sc) before LiCl, which suggested opiate involvement. Exp 3 showed that OB tumor anorexia vanishes if foods dissociated from tumor growth are given: OB fed a constant diet became anorectic 16 days after B16 inoculation; giving a new diet on Day 16 delayed anorexia onset for 8 days; a second new diet on Day 32 abolished anorexia for 24 hr. LN with tumors ate all diets at nontumor control levels. OB survived melanoma longer than LN regardless of diet, but OB fed a varied diet died first; thus, anorexia may enhance OB survival.

Topics: Animals; Anorexia; Avoidance Learning; Body Weight; Conditioning, Classical; Extinction, Psychological; Lithium Chloride; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Obese; Neoplasm Metastasis; Neoplasm Transplantation; Saccharin; Species Specificity; Taste

Two experiments are reported here. First, the effect of lithium chloride (1, 2 and 4 mEq/kg IP for 21 days) on body weight was assessed in female and male rats. Food intake was measured in the rats treated with 2 mEq/kg. All the doses tested significantly increased body weight in female rats. A linear relationship between body weight gain and lithium dose was also observed. In contrast, in male rats, the low doses of lithium (1 and 2 mEq/kg) did not affect body weight, whereas the high dose (4 mEq/kg) decreased body weight. These results confirm previous reports on a sex-dependent effect of lithium on body weight in rats. In the second experiment, body weight and food intake were assessed in female rats treated with lithium alone, or in combination with insulin or sulpiride, a D2 dopamine receptor blocker. It was found that the effect of lithium on body weight and feeding was additive to the effects of sulpiride and insulin. These findings are indirect evidence that lithium enhances body weight in rats by a different mechanism than the one described for sulpiride or insulin.

Topics: Animals; Body Weight; Chlorides; Dose-Response Relationship, Drug; Drug Interactions; Female; Insulin; Lithium; Lithium Chloride; Male; Rats; Rats, Inbred Strains; Sex Characteristics; Sulpiride

The present study was undertaken to examine whether the urinary amount of furosemide is influenced by chronic lithium treatment. LiCl at 2 mEq/kg/day in 1 ml vehicle (5% glucose solution) or 1 ml of vehicle alone was injected intraperitoneally for 8 days into Wistar rats. On day 8, 30 mg/kg of furosemide in 3% body weight of 1% NaCl was given orally, and urine was collected for 6 hr after dosage. The urinary amount of furosemide in the Li-treated rats was significantly lower than that in the control animals [Li group (n = 12): 514 +/- 75 (mean +/- S.E.) vs. control group (n = 12): 916 +/- 85 micrograms/kg/6 hr, P less than 0.01]. This finding indicates that pharmacokinetic alterations of furosemide might occur during chronic treatment with lithium.

Topics: Administration, Oral; Animals; Body Weight; Chlorides; Drinking; Furosemide; Lithium; Lithium Chloride; Male; Rats; Rats, Inbred Strains; Renin; Urine

We studied the effects of lithium chloride, given i.p. in doses of 0.05, 1, 2, 4 and 8 mEq/kg twice daily for 14 days, on preparations of guinea pig myenteric plexus. The effects of lithium added to isolated myenteric plexus preparations derived from chronically treated animals showed that relatively low lithium concentrations produced a statistically significant decrease in the force of contraction, this effect being concentration-dependent. 3-Isobutyl-1-methylxanthine (IBMX) induced a statistically significant inhibition, between 30 and 50%, of the lithium effects. cAMP levels in animals treated chronically with lithium were studied, using an isotopic displacement technique. Our results show that only the highest dose of lithium (8 mEq/kg per day) significantly decreased basal levels of cAMP. In the presence of IBMX, low doses of lithium (1 mEq/kg per day) induced a very significant decrease in cAMP levels, but the inhibition remained constant, approximately 30-35%, at doses from 2 mEq/kg per day. In guinea pig myenteric plexus preparations from acutely treated animals, our results show a direct relationship between lithium concentration and inhibition of the cAMP accumulation induced by IBMX.

Topics: Animals; Body Weight; Chlorides; Cyclic AMP; Dose-Response Relationship, Drug; Guinea Pigs; Lithium; Lithium Chloride; Male; Myenteric Plexus; Time Factors

The present study was undertaken to examine whether urinary excretions of prostaglandins increase by repeated administration of a non-toxic dose of lithium. Our previous study demonstrated that 2 mEq/kg/day of lithium chloride (LiCl) is not a toxic dose; and therefore, this dose of LiCl in 1 ml vehicle (5% glucose solution) or 1 ml of vehicle alone was injected intraperitoneally for 7 days into Wistar rats. On day 7, 3% body weight of 1% NaCl solution was given orally; and urine for the determination of PGE2 and 6-keto-PGF1 alpha, a metabolite of PGI2, was collected for 6 hr after dosage. Thereafter, blood samples for measuring plasma renin activity (PRA) were obtained. The urinary amounts of PGE2 and 6-keto-PGF1 alpha in the Li-treated rats were significantly greater than those in the control animals. The values of PRA did not significantly differ between the two groups of rats. These findings indicate that the production of prostaglandins, including those of PGE2 and PGI2, are enhanced during repeated administration of a non-toxic dose of lithium. The enhanced production of prostaglandins might not be mediated through the activated renin-angiotensin system.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Chlorides; Dinoprostone; Drug Administration Schedule; Injections, Intraperitoneal; Lithium; Lithium Chloride; Male; Rats; Rats, Inbred Strains; Renin; Sodium

The present study was performed on immature male rats aged 35 days. Subcutaneous injections of lithium chloride at a daily dose of 2.0 mg/kg for 15 days resulted in significant inhibition of spermatogenesis at stage VII of the seminiferous epithelial cycle. Spermatogonia A, preleptotene spermatocytes and step 7 spermatids were decreased in number in comparison to controls. Serum levels of FSH, LH, PRL, and testosterone were decreased. Activities of testicular delta 5-3 beta-hydroxysteroid dehydrogenase and 17 beta-hydroxysteroid dehydrogenase were suppressed along with a low caudal epididymal sperm count in comparison with controls. When the treatment was prolonged for 20 and 25 days, it showed an additional significant diminution in accessory sex organ weights and number of midpachytene spermatocytes at stage VII in comparison to control animals of corresponding age. It is concluded that lithium has an adverse effect on testicular function in immature rats by reducing serum levels of FSH, LH, PRL, and testosterone. Furthermore, since hormonal changes and altered spermatogenic activities were evident when the serum concentration of lithium was within the therapeutic range, our data may have some potential clinical implications.

Topics: 17-Hydroxysteroid Dehydrogenases; 3-Hydroxysteroid Dehydrogenases; Aging; Animals; Body Weight; Chlorides; Dose-Response Relationship, Drug; Follicle Stimulating Hormone; Lithium; Lithium Chloride; Luteinizing Hormone; Male; Organ Size; Prolactin; Prostate; Rats; Rats, Inbred Strains; Seminal Vesicles; Sperm Count; Spermatogenesis; Testis; Testosterone

Changes in the activities of acid and alkaline phosphatase were observed in the testis, prostate and seminal vesicle after the injection of lithium chloride at the doses of 100, 200 and 400 micrograms/100 g body weight/day for 7, 14 and 21 days. The studies indicate that 200 and 400 micrograms/100 g body weight for 14 days and 21 days showed a significant inhibition in the activity of acid phosphatase in all the above reproductive organs. There is a significant stimulation of alkaline phosphatase activity at the doses of 200 and 400 micrograms of lithium after 21 days of treatment in testis, prostate and seminal vesicle along with significant decrease in accessory sex organs weight in comparison to control animal. Therefore, it is evident that the effect of lithium on male reproductive organs mainly depends on the amount of the drug being injected and the duration of treatment to it.

Topics: Acid Phosphatase; Alkaline Phosphatase; Animals; Body Weight; Chlorides; Dose-Response Relationship, Drug; Genitalia, Male; Lithium; Lithium Chloride; Male; Prostate; Rats; Rats, Inbred Strains; Seminal Vesicles; Testis

European hamsters were fed LiCl-supplemented food for a long time before, during and after the hibernating season. Long-term administration of LiCl does not suppress hibernation, which occurs normally during the first part of the experiment. Moreover lithium-treated hibernating hamsters tolerate very high plasma lithium levels. This tolerance is not explained. The results are discussed in relation with the recent theories on the similarities between depression, seasonal affective disorder and hibernation.

Topics: Animals; Arousal; Body Weight; Chlorides; Cricetinae; Feeding Behavior; Female; Hibernation; Light; Lithium; Lithium Chloride; Male; Seasons; Social Environment

Changes in body weight and taste aversion in the learned helplessness paradigm were examined. In Experiment 1, adult male Sprague-Dawley rats drank saccharin or a control solution, followed by either 100 inescapable shocks or simple restraint. Rats were weighted daily and were tested for saccharin aversion two days after the stress session. Shocked rats gained less weight in the days after stress than restrained controls. Saccharin aversion was apparent only among rats that had consumed saccharin before the stress session. Experiment 2 examined whether control over shock affected body weight or taste aversion. Home-cage controls were included to assess the effects of restraint alone. In addition, the combined effects of shock and a toxin on aversion were studied. Rats drank saccharin solution, followed by escapable or inescapable shock, restraint, or no treatment. Then half of each group was injected with saline; the other half was injected with lithium chloride. As in Experiment 1, shock reduced body weight relative to restraint or no treatment, and shock produced a taste aversion among saline-treated rats. However, shock attenuated the aversion produced by lithium chloride, as did simple restraint. There were no differences in body weight or taste aversion between escapably and inescapably shocked rats. These results suggest a role for stress in the anorexia and weight loss associated with clinical depression and may have implications for theories of learning and learned helplessness.

Topics: Animals; Arousal; Avoidance Learning; Body Weight; Chlorides; Conditioning, Classical; Electroshock; Helplessness, Learned; Lithium; Lithium Chloride; Male; Rats; Taste

We have investigated the role of the area postrema (AP) in mediating the neurohypophyseal hormone response to peripheral administration of nausea-producing agents in rats. In control animals, lithium chloride (LiCl) and apomorphine (APO) caused a rise in plasma levels of immunoreactive oxytocin (OT) and arginine-vasopressin (AVP), whereas sulphated cholecystokinin octapeptide (CCK-8s) stimulated OT secretion only. Rats with AP lesions exhibited a similar OT and AVP response to LiCl and APO but the OT response to CCK-8s was significantly diminished. The results indicate that the selective stimulation of OT secretion by CCK-8s is partly mediated via the AP. Although the nausea-producing effects of LiCl and APO may involve the AP, the neuroendocrine effects of these agents may well be mediated via actions outside the AP.

Topics: Animals; Apomorphine; Arginine Vasopressin; Body Weight; Cerebral Ventricles; Chlorides; Lithium; Lithium Chloride; Male; Oxytocin; Rats; Rats, Inbred Strains; Sincalide

This study was to resolve a discrepancy in the literature as to the capability of infant rats in acquiring conditioned taste aversion. Previous studies had indicated that during the 1st postnatal week, an aversion to saccharin could be conditioned when paired with lithium chloride (LiCl). Analogous conditioning with sucrose did not seem to occur until the end of the 2nd postnatal week, however, even though sucrose is discriminated from water and preferred before then. We observed that 5- and 9-day old pups express conditioned taste aversion to both saccharin and sucrose flavors that previously were paired with illness induced by LiCl. This learning occurred only when several hours separated cannulation and conditioning. A number of other factors that seemed likely to determine this early learning were found to have no effect. Thus it appears that rats can learn taste aversions very early in life, but only under certain circumstances. The results are discussed with reference to Vogt and Rudy's (1984) conclusions on the ontogeny of taste guided behaviors in the rat.

Topics: Age Factors; Animals; Body Weight; Catheterization; Chlorides; Conditioning, Classical; Female; Food Preferences; Lithium; Lithium Chloride; Male; Rats; Rats, Inbred Strains; Saccharin; Sucrose; Taste; Time Factors

Lithium chloride, in common with other drugs with emetic effects, prolongs stomach emptying. In different experiments, a drug state induced by a low dose of pentobarbital in Experiment 1 and morphine in Experiment 2 or a distinctive place (Experiments 3, 4) was the conditioned stimulus paired with lithium chloride as the unconditioned stimulus. In each case, Pavlovian conditioning occurred and the conditioned response mimicked lithium's unconditioned effect on stomach emptying.

Topics: Animals; Body Weight; Chlorides; Conditioning, Classical; Eating; Gastric Emptying; Lithium; Lithium Chloride; Male; Rats; Rats, Inbred Strains

The effect of pre and postnatal maternal ingestion of 1 mEq LiCl, given ad libitum in drinking water, on neonatal development was studied in the mouse. The measurements made included evaluation of body and selected organ weights of the weaning offspring. In addition, determination of weaning mouse liver alcohol dehydrogenase (L-ADH), aldehyde dehydrogenase (L-ALDH) were performed to assess the sensitivity of the offspring to ethanol intoxication due to the clinical trials of lithium salts in alcoholism. Heart lactate dehydrogenase isoenzymes were also assayed to assess developmental aspects of the offspring. Little changes occurred in body weight and only moderate increase in spleen weight was noted without concomitant changes in brain, kidney or liver weight of the nursing dams. Maternal Li+ exposure resulted in increased kidney, liver and spleen but not brain weights from controls in the weaning animals. This effect was greater in the female than in the male offspring. The weaning mice showed an induction of L-ALDH as a consequence of maternal Li-treatment. No changes occurred in the other hepatic and cardiac enzymes studied. The results suggest sex-dependent neonatal sensitivity towards maternal ingestion of a small concentration of LiCl in drinking fluid. Hepatic changes of L-ALDH may represent an early expression of hepatic toxicity in the weaning mouse.

Topics: Alcohol Dehydrogenase; Aldehyde Dehydrogenase; Animals; Animals, Suckling; Body Weight; Chlorides; Female; Growth; Isoenzymes; L-Lactate Dehydrogenase; Lithium; Lithium Chloride; Male; Mice; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects

Daily uptake of lithium salt (LiCl) in the drinking water at a rate of over 100 micrograms/g b.wt (or 2.4 mEq/kg) reduced or suppressed natural torpidity (hibernation) in the Turkish hamster (Mesocricetus brandti). The data indicate a direct influence of lithium on clock-related functions controlling the hibernation process rather than indirect effects by preventing gonadal regression and thereby also hibernation.

Topics: Animals; Biological Clocks; Body Weight; Chlorides; Circadian Rhythm; Cricetinae; Female; Hibernation; Lithium; Lithium Chloride; Male; Mesocricetus; Testis

The development of a conditioned taste aversion (CTA) was assessed in rats made hyperphagic with parasagittal knife cuts in the ventromedial hypothalamus (VMH). The animals were water deprived and presented with a .1% saccharin solution paired with injections of either lithium chloride or sodium chloride. In Experiment 1, VMH rats tested at a nonobese weight level did not differ from sham-operated control rats in the acquisition and extinction of the CTA. In Experiment 2, moderately obese VMH rats displayed a stronger CTA than did sham-operated control rats as evidenced by a slower rate of extinction. This effect was not due to the higher absolute dose of LiCl given to the obese VMH rats. A second group of obese VMH rats given an amount of LiCl equivalent to that given to the control rats also displayed retarded extinction of the CTA. The results of these experiments demonstrate that hyperphagia-inducing knife cuts do not alter aversive taste conditioning in rats but that hypothalamic obesity does enhance conditioned taste aversions. This may reflect an obesity-induced suppression in appetitive motivation.

Topics: Animals; Body Weight; Chlorides; Conditioning, Classical; Extinction, Psychological; Female; Hypothalamus, Middle; Lithium; Lithium Chloride; Obesity; Rats; Rats, Inbred Strains; Saccharin; Sodium Chloride; Taste; Water Deprivation

Three experiments were done to compare effects of LiCl and carbamazepine (CBZ) on behaviors known to be influenced by LiCl in rats. The first experiment showed acute treatment with either LiCl (0.3-1.5 mmol/kg) or CBZ (0.13-0.42 mmol/kg) to produce a learned taste aversion to saccharin. The second experiment showed short-term treatment (once daily for 5 days) with LiCl (1.5 mmol/kg/day) to suppress open field activity in otherwise untreated rats and to cause a behavioral syndrome when given together with pargyline. In contrast, short-term treatment with CBZ (0.42 mmol/kg/day) failed to influence open field behavior. The third experiment compared effects of LiCl (1.5 mmol/kg) and CBZ given at a dose (1.68 mmol/kg) higher than that used in Experiments 1 and 2. LiCl or CBZ had similar suppressant effects on locomotor activity in otherwise untreated rats, but only LiCl led to a behavioral syndrome in rats given pargyline. The findings suggest that LiCl and CBZ may have some similar mechanisms of action on behavior, as well as some different ones.

Topics: Animals; Avoidance Learning; Behavior, Animal; Body Weight; Carbamazepine; Chlorides; Lithium; Lithium Chloride; Male; Rats; Rats, Inbred Strains; Taste

Intraperitoneal injections of epinephrine (20, 40, 80, and 160 microgram/kg) and amphetamine (.1, .2, and .4 mg/kg) were administered to rats with various forms of hepatic denervation. In Experiment 1, destruction of the esophageal trunks of the vagus attenuated epinephrine and amphetamine anorexia, but destruction of the hepatic vagus did not. In Experiment 2, rats with celiac ganglionectomy, subdiaphragmatic vagotomy, or the combined operation all exhibited decreased epinephrine anorexia to the same extent. However, ganglionectomized rats were less responsive to amphetamine anorexia than were vagotomized ones. Vagotomized rats were significantly more reactive to lithium chloride (10, 20, and 30 mg/kg) than were controls. These results suggest that the major component of hepatic metabolic afferent fibers travels from the liver, through the celiac ganglion, and into the esophageal vagal trunks where they ascend to the brain. The anorexic action of amphetamine appears to result from a centrally induced sympathetic action on the liver.

Topics: Afferent Pathways; Animals; Blood Glucose; Body Weight; Chlorides; Denervation; Dextroamphetamine; Drinking; Eating; Epinephrine; Ganglia, Sympathetic; Lithium; Lithium Chloride; Liver; Male; Muridae; Rats; Satiation; Vagus Nerve

Weight increase is a common side-effect after chronic lithium salt treatment in man. This effect has not always been found in animal models using the rat. The possibility that the age and sex of animals might interfere with the results was studied, using groups of male and female rats, 2, 5, and 12 months old, injected intraperitoneally twice daily for 28 days with a solution of lithium chloride, or sodium chloride as control. The dose used was 1.5 meq./kg body weight (total daily dose of 3.0 meq./kg). In 2 month old animals, lithium induced an increase in weight significantly greater than that of the controls in the female group, while the weight of the male rats in this age group remained indistinguishable from the control rats. The 5 and 12 month old lithium treated female rats showed no differentiation in weight. Lithium treatment of the males in these two age groups caused a large number of deaths and, considering only those animals which survived, average weights were significantly less than those of control in the 5 month olds rats, and equal to control in the 12 month olds. It is concluded that age and sex have to be taken into consideration when studying the effects of chronic lithium treatment on the weight of rats.

Topics: Age Factors; Animals; Body Weight; Chlorides; Female; Lithium; Lithium Chloride; Male; Rats; Rats, Inbred Strains; Sex Factors; Time Factors

This study tested the hypothesis that lithium alters the phase relationships of various 24-hour rhythms. Six point 24-hour patterns were measured throughout a 12 hour light/12 hour dark cycle from separate groups of individually housed adult male wistar rats maintained for six weeks on ad lib water and either 1) Normal lab chow, 2) Lab chow supplemented with 50mM/KG of lithium chloride, or 3) Lab chow supplemented with 50mM/KG of sodium chloride. Plasma lithium levels were 0.7-1.0 mEq/1. The sodium diet had no effect on any of the variables measured relative to normal controls. Plasma but not red blood cell lithium levels demonstrated a 24-hour rhythm with higher levels during darkness. Serum and red blood cell sodium levels did not differ among the diets and showed no 24-hour variation. Lithium treated rats weighed significantly less than controls and had significantly heavier kidneys per 100 grams of body weight than controls. Resting plasma corticosterone levels demonstrated the expected 24-hour pattern in all groups, however, the lithium group evidenced higher levels during the middle of the dark hours than either control group. Water consumption also demonstrated a 24-hour rhythm. Lithium animals consumed far greater quantities of water than controls and this behaviour became increasingly exaggerated over the duration of the study. The data are interpreted as suggesting that lithium broadens the peak of twenty four hour rhythms such that normal elevation in these measures appear earlier and last longer.

Topics: Animals; Body Weight; Chlorides; Circadian Rhythm; Corticosterone; Drinking; Erythrocytes; Kidney; Light; Lithium; Lithium Chloride; Male; Organ Size; Rats; Rats, Inbred Strains; Sodium

Spontaneous locomotor activity and dopaminergic responsivity were assessed after long-term dietary treatment with the anti-manic drug lithium. Chronic dietary Li administration was not accompanied by the toxicities often reported with other modes of administration. In addition, the diet reliably yields serum and brain Li levels in the prophylactic range for manic-depressive illness. After 4 weeks exposure to Li, spontaneous locomotor activity was reduced as compared to subjects on the control diet whether or not food intake was restricted. The depression of locomotor activity following an injection of the dopamine agonist, apomorphine, was less severe in animals that ingested Li compared to those with free access to the control diet. Finally, in confirmation of the findings of Pert et al., chronic Li administration led to a partial attenuation of apomorphine-evoked stereotyped behaviors in subjects rendered supersensitive to the drug by daily injections of haloperidol (HAL) for 3 weeks. The findings suggest that the commonly reported suppressant action of Li on spontaneous behavior is not attributable to overt toxicity or to diminished growth rate. Similarly, these health factors do not account for the ability of chronic Li treatment to suppress the behavioral manifestation of dopaminergic supersensitivity associated with long-term HAL exposure.

Topics: Animals; Apomorphine; Body Weight; Chlorides; Corpus Striatum; Eating; Haloperidol; Humans; Lithium; Lithium Chloride; Male; Motor Activity; Rats; Rats, Inbred Strains; Receptors, Dopamine; Spiperone; Stereotyped Behavior

Topics: Adrenal Glands; Animals; Ascorbic Acid; Body Weight; Chlorides; Kidney; Lithium; Lithium Chloride; Liver; Male; Organ Size; Organ Specificity; Rats