Modification, by lithium, of catalepsy induced by central cholinergic stimulants and morphine-like drugs

After unique injection LiCl enhances, in albino rat, catalepsy induced by arecoline and oxotremorine perhaps by adenylcyclase inhibition and/or decrease of acetylcholine synthesis. After repetitive injection of LiCl during 5 days, this phenomenon is not observable, probably owing to increase of acetylcholine synthesis. After unique injection of LiCl enhances catalepsy induced by dextromoramide, probably on account of cholinergic properties of this drug. In contrast catalepsy induced by morphine or pethidine is suppressed. This constatation would depend on opposite influence upon cerebral neuromediators : lithium diminishing cerebral serotonin and striatal acetylcholine levels and morphine increasing them. After repetitive injections these phenomenons are not observable.     

Seasonal changes in the behavioral effects of neuroleptics on white rats

Summarized results of the experiments (conducted in 1981-1984) demonstrate seasonal rhythms of some behavioural effects (catalepsy and depression of locomotor activity) of haloperidol (0.5 mg/kg) and levomepromazine (5 mg/kg) in white rats. In intact rats neuroleptics were more effective in depressing high than low motor activity. Catalepsy induced by single administration of neuroleptics was more pronounced in spring and autumn months. A certain negative correlation exists between seasonal variations of neuroleptic catalepsy and the speed of monoamine (dopamine and serotonin) metabolism in the brain of intact rats.     

Increased tolerance of the dopamine- and serotoninergic systems during chronic administration of haloperidol and levomepromazine

In experiments on male albino rats single administration of haloperidol produced catalepsy, increase in dopamine turnover, enhancement of main dopamine metabolite homovanilinic acid in the forebrain. After single administration of the levomepromazine the cataleptogenic effect was accompanied by an enhanced 5-hydroxyindole acetic acid level, and no influence on the dopamine metabolism was observed. During chronic administration of haloperidol and levomepromazine their ability to induce catalepsy and to increase homovanilinic acid or 5-hydroxyindoleacetic acid concentration diminished. Thus, it appears that chronic administration of haloperidol reduces the sensitivity of dopamine receptors, and chronic administration of levomepromazine--reduces the sensitivity of dopamine and serotonin receptors in the brain.     

Similarities between the akinesia induced by carbachol microinjections into the pontine reticular formation and neuroleptic catalepsy.

We reported previously that microinjections of carbachol directly into the pontine reticular formation of rats induced intense akinesia. In the present article we report results of tests for rigidity, righting, bracing and clinging which were conducted with the purpose to characterize behaviorally this type of akinesia. After injections of 5-15 micrograms/0.5 microliter of carbachol into the pontine reticular formation the rats were cataleptic, were not rigid when equilibrium was not challenged, had strong righting reflexes and strong bracing and clinging responses. This type of akinesia is different from the catatonia induced by systemic morphine (20 mg/kg IP), but similar to the catalepsy induced by systemic injections of haloperidol (5 mg/kg IP). It is thus suggested that the cataleptic state produced by topical carbachol in the pons is related to the dopaminergic mechanisms important for the cataleptic effect of the neuroleptic drugs.     

Effects of Systemically Administered Lithium on Phosphoinositide Metabolism in Rat Brain, Kidney, and Testis

A single subcutaneous dose of 10 mEq/kg LiCl gives rise to an increase in the cerebral cortex level of myo-inositol-1-P (I1P) that closely follows cortical lithium levels and, at maximum, is 40-fold above the control value. Kidney and testis show smaller increases in I1P level following LiCl administration. The I1P level is still sixfold greater than that of untreated rat cortex 72 h later. In cortex, parallel increases also occur in myo-inositol-4-P (I4P) and myo-inositol 1,2-cyclic-P (cI1,2P), whereas myo-inositol-5-P (I5P) remains unchanged. The cortical increases in I1P and I4P levels are partially reversed by administering 150 mg/kg of atropine 22 h after the LiCl, treatment that does not affect cI1,2P. When doses of LiCl from 2 to 17 mEq/kg are given, the cerebral cortex levels of I1P and myo-inositol, measured 24 h later, are found to reach a plateau at about 9 mEq/kg of LiCl, whereas cortical lithium levels continued to increase with greater LiCl doses. Levels of all three of the brain phosphoinositides are unchanged by the 10 mEq/kg LiCl dose, as is the uptake of 32Pi into these lipids. Chronic dietary administration of LiCl for 22 days showed that the effects of lithium on I1P and myo-inositol levels persist for that period. Over the course of the chronic administration of the lithium, levels of I1P, myo-inositol, and of lithium in cortex remained significantly correlated. We believe that these increases in inositol phosphates result from endogenous phosphoinositide metabolism in cerebral cortex and that lithium is capable of modulating that metabolism by reducing cellular myo-inositol levels. The size of the effect is a function of both lithium dose and the degree of stimulation of receptor-linked phosphoinositide metabolism. This property of lithium may explain part of its ability to moderate the symptoms of mania. Our chronic study suggests that prolonged administration of LiCl does not result in compensatory changes in myo-inositol-1-P synthase or myo-inositol-1-phosphatase.     

Differential Uptake of Lithium Isotopes by Rat Cerebral Cortex and Its Effect on Inositol Phosphate Metabolism

Twenty hours following the subcutaneous administration of 5 mEq/kg doses of 6LiCl and 7LiCl to two groups of rats, the cerebral cortex molar ratio of 6Li+/7Li+ is 1.5. The effects of the lithium isotopes on cortex myo-inositol and myo-inositol-l-phosphate levels are the same as we have reported earlier: a Li+ concentration-dependent lowering of myo-inositol and increase in myo-inositol-1-phosphate. Thus 6LiCl, when administered at the same dose as 7LiCl, produces the larger effect on inositol metabolism. When the 6LiCl and 7LiCl doses were adjusted to 5 mEq/kg and 7 mEq/kg, respectively, the cortical lithium myo-inositol and myo-inositol-1-phosphate levels of each group of animals became approximately equal, suggesting that the isotope effect occurs at the level of tissue uptake, but not on inositol phosphate metabolism. The inhibition of myo-inositol-1-phosphatase by the two lithium isotopes in vitro showed no differential effect. The isotope effect on cerebral cortex uptake of lithium is in the same direction as that reported by others for erythrocytes and for the CSF/plasma ratio, but of larger magnitude.     

Monoamine oxidase inhibitors and the depletion of 5-hydroxytryptamine from enterochromaffin cells by reserpine

Summary The influence of Nialamide (a monoamine oxidase inhibitor) on the depletion of 5-hydroxytryptamine from enterochromaffin cells, has been studied in rabbits. Experimental animals were given varying doses of Nialamide in N/10 HCl by single or repeated injections, followed by injections of reserpine. Control animals were given N/10 HCl followed by reserpine or by reserpine solvent. Nialamide did not prevent the depletion of enterochromaffin cell granules by reserpine in any of the experimental animals.     

Lithium-induced decrease of brain inositol and increase of brain inositol-1-phosphate is transient

The effects of a single does of LiCl (2.5 or 10 mEq/kg) on brain inositol and inositol-1-phosphate (Ins1P), intermediates of brain phosphoinositude (PI) turnover, were determinated in male Han: Wistar rats. There was a remarkable, 36–58 fold elevation of brain Li⁺ as the single does of LiCl was increased 4-fold. Moreover, the accumulation of brain lithium was slow during repeated administration of LiCl. Brain lithium did not correlate with changes in brain PI turnover either after a single or repeated doses. Thus, after a single does of LiCl the increases in brain Ins1P were much less than the decreases in brain inositol. Also, brain inositol was significantly decreased only with the high dose of LiCl whereas brain Ins1P accumulation was more prominent with the lower dose. Moreover, repeated daily doses of LiCl only transiently increased brain Ins1P at 1 and 7 d whereas inositol remained at control levels throughout the 14 d observation period. Lithium probably caused the transient decrease in brain inositol by inhibiting several enzymes, in addition to the inhibition of myo-inositol mono-phosphates, in the PI cycle. Moreover, a slow dampening down of PI turnover by lithium, possible via an inhibitory action on G-protein-coupling, may also explain the present findings.     

Effect of BR-16A (Mentat), a polyherbal formulation on drug-induced catalepsy in mice

Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The events, which trigger and/or mediate the loss of nigral DA neurons, however, remain unclear. Neuroleptic-induced catalepsy has long been used as an animal model for screening drugs for Parkinsonism. Administration of haloperidol (1 mg/kg, ip) or reserpine (2 mg/kg, ip) significantly induced catalepsy in mice. BR-16A (50 and 100 mg/kg, po), a polyherbal formulation or ashwagandha (50 and 100 mg/kg, po), significantly reversed the haloperidol or reserpine-induced catalepsy. The results indicate that BR-16A or ashwagandha has protective effect against haloperidol or reserpine-induced catalepsy and provide hope that BR-16A could be used in preventing the drug-induced extrapyramidal side effects and may offer a new therapeutic approach to the treatment of Parkinson's disease.     

Repeated Cocaine Administration Alters Extracellular Glutamate in the Ventral Tegmental Area

Abstract: The present study determined if repeated cocaine injections alter the effect of cocaine on extracellular glutamate in the ventral tegmental area (VTA). All rats were treated with daily cocaine (15 mg/kg i.p. × 2 days, 30 mg/kg i.p. × 5 days) or saline for 7 days. At 21 days after discontinuing the daily injections, a dialysis probe was placed into the VTA and the extracellular levels of glutamate were estimated. A systemic injection of cocaine (15 mg/kg i.p.) elevated extracellular glutamate in the VTA of rats pretreated with daily cocaine but not in the daily saline-pretreated subjects. No significant change in glutamate was produced by a saline injection in either pretreatment group. In a group of rats pretreated with daily cocaine, the D₁ antagonist SCH-23390 (30 µ M ) was infused through the dialysis probe prior to the acute injections of saline and cocaine. SCH-23390 prevented the increase in extracellular glutamate associated with the acute administration of cocaine. Behavioral data were collected simultaneously with the measures of extracellular glutamate. The behavioral stimulant effect of cocaine was greater in cocaine-pretreated than saline-pretreated subjects, and the behavioral augmentation in cocaine-pretreated rats was partly blocked by SCH-23390. These data support the hypotheses that repeated cocaine administration produces an increase in the capacity of D₁ receptor stimulation to release glutamate in the VTA and that this mechanism partly mediates behavioral sensitization produced in rats treated with daily cocaine injections.     

Effect of muscimol,a gaba-mimetic agent,on dopamine metabolism in the mouse brain

The intraperitoneal injection of muscimol at the dose of ranging from 0.5 to 5 mg/kg produced hypomotility, catalepsy and loss of righting reflex in mice. These effects were associated with an initial brief fall followed by a more sustained increase in homovanillic acid and dihydroxyphenylacetic acid levels, without changes in dopamine concentration. Diazepam potentiated the effect of muscimol in motor activity and on dopamine metabolism.     

Quantification of the Effects of Resperine on Gonadotroph Expression in the Pituitary of Goldfish (Carassius auratus)

In many teleosts, the control of gonadotropin II (or luteinizing hormone) secretion is under the dual control of stimulatory and inhibitory neuroendocrine factors. The principal stimulating factor is gonadotropin-releasing hormone and the main inhibitor is dopamine. Inhibiting the activities of dopamine by antidopaminergic drugs potentiates the actions of exogenous gonadotropin-releasing hormone analogs, resulting in a surge release of luteinizing hormone and ovulation and spawning in a number of different species. As the effects of blocking the inhibitory actions of dopamine on gonadotroph cytology have not been studied, goldfish were treated with 2, 4, 6 or 8 injections of reserpine (0.1 mg/kg body weight), at 48 h intervals, and the numbers of gonadotrophic cells studied at 48 h following last injection. After two injections, the number of gonadotrophic cells increased by 189% over controls; after four injections the increase was 234%; after six injections the increase was 259% and after eight injections, 288%. The results suggest that dopamine has an inhibitory influence on the numbers of gonadotrophs.     

A behavioural study of the effect of pentadecapeptide BPC 157 in Parkinson's disease models in mice and gastric lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine.

The effect of a stomach pentadecapeptide, BPC 157, on Parkinson's disease in mice was investigated, along with its salutary activity on stomach lesions induced by parkinsongenic agents. Parkinsongenic agents, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30.0 mg x kg(-1)b.w. i.p. once daily for 6d, and after 4d once 50.0 mg x kg(-1)b.w. i.p.) or reserpine (5.0 mg x kg(-1)b.w. i.p.) were applied i.p. BPC 157 (1.50 microg or 15.0 ng x kg(-1)b.w. i.p.) was applied 15 min before or alternatively 15 min after each MPTP administration. In reserpine studies, BPC 157 (10.0 microg or 10.0 ng x kg(-1)b.w. i.p.) was given either 15 min before reserpine or in the already established complete catalepsy 24 h thereafter. BPC 157 strongly improved the MPTP-impaired somatosensory orientation and reduced the MPTP-induced hyperactivity, and most importantly, MPTP-motor abnormalities (tremor, akinesia, catalepsy -otherwise very prominent in saline control), leading to almost complete abolition of otherwise regularly lethal course of MPTP treatment in controls. Likewise, in reserpine experiments, BPC 157 strongly prevented the development of otherwise very prominent catalepsy and when applied 24 h thereafter reversed the established catalepsy. In addition, a reduction of reserpine-hypothermy (BPC 157 pre-treatment) and reversal of further prominent temperature fall (BPC 157 post-treatment) have been consistently observed. Taking together these data, as the two most suitable animal models were consistently used and since the high effectiveness was demonstrated in pre- and post-treatment, microg and ng regimens, BPC 157 as an organoprotector should be further therapeutically investigated. Additionally, given in either regimen, pentadecapeptide BPC 157 strongly attenuated the stomach lesions in mice that otherwise consistently appeared in mice treated with the parkinsogenic neurotoxin MPTP.     

Increased urinary excretion of labelled deoxyribonucleosides in rats with stable pre-label led dna treated with methyl methanesulphonate or nitrogen mustard

After the DNA of newborn female rats had been labelled by repeated injections of [¹⁴C]orotate (totalling 36 μCi) during the first 3 weeks of life, approximately 1 000 000 dpm were found in the DNA of the liver, lungs, kidneys, gut, brain, heart and spleen of 8-week-old rats. Methyl methanesulphonate (MMS) (80 mg/kg) and di-(2-chloroethyl)methylamine (HN2) (5 mg/kg) injection increased the amount of ¹⁴C-labelled DNA pyrimidine nucleosides excreted in the urine to 5000 dpm from 350 dpm before injection. The effect on RNA products was much less marked.     

Modulation of luteinizing hormone(LH) release by clonidine and opioid peptides in castrated male rats

The effect of clonidine, a central alpha-adrenergic agonist, on the suppression of LH release induced by beta-endorphin or FK33-824, an endogenous opioid peptide or its synthetic analog, was investigated in castrated male rats, with or without pretreatment with reserpine. Pulsatile LH secretion was inhibited by intravenous injection of FK33-824 (400 micrograms/kg), or intraventricular injection of beta-endorphin (5 micrograms). Without pretreatment with reserpine, intraperitoneal administration of clonidine (1 mg/kg) failed to reverse the inhibition of LH release induced by these peptides. However, with pretreatment with reserpine (10 mg/kg), clonidine abolished the inhibitory effect on LH secretion induced by these peptides in castrated male rats. These data indicate that, unlike the results in ovariectomized, steroid-primed rats, pretreatment with reserpine allows the alpha-adrenergic system to act more peripherally than the opioid neuronal system in a neuronal network-regulating LH release in castrated male rats.     

FK506 as effective adjunct to L-dopa in reserpine-induced catalepsy in rats

Reserpine-induced catalepsy is a widely accepted animal model of Parkinson's disease. In the present study reserpine (2.5 mg/kg, ip) 20 hr and alpha-mehyl-para-tyrosine (AMPT; 200 mg/kg, ip), one hour before the experiment induced significant catalepsy in rats as assessed by bar test. There was a significant increase in the time spent on the bar in bar test as compared to the control untreated rats. L-dopa (100 mg/kg, ip) and carbidopa (10 mg/kg, ip) combination, a conventional therapy was less effective in reversing reserpine-induced catalepsy. Pretreatment with FK506, a neuroprotectant (0.5-2 mg/kg, po) not only dose dependently reduced the catalepsy in reserpine-treated rats but a lower dose (1 mg/kg) potentiated the motor stimulant actions of sub threshold dose of L-dopa (100 mg/kg, ip) and carbidopa (10 mg/kg, ip) combination. Anticataleptic effect of FK506 was blocked dose dependently by specific D2 receptor blocker sulpiride (25-100 mg/kg, ip). In conclusion, the findings of the present study suggest that FK506 has an indirect modulatory action on the dopamine D2 receptors. FK506 being a neuroprotectant, could be used as an effective adjunct to L-dopa for the treatment of neuroleptic-induced extrapyramidal side effects.     

Lithium-induced Hypersensitivity to Foot Shock in Rats and the Role of 5-Hydroxytryptophan

REPORTS of the behavioural effects of lithium salts on animals mainly seem to have dealt with depressant effects on spontaneous activities or with toxic symptoms (weight loss, polyuria, polydipsia, diarrhoea and so on). After prolonged lithium treatment, changes in brain 5-hydroxytryptamine (5HT) metabolism have been found to occur; 5HT turnover is decreased either in the whole brain¹ or in specific areas such as brainstem and hypothalamus^{1, 2}, where the levels are also decreased². When levels of 5HT are reduced in the whole brain of rats either by lesions³ or by parachlorophenylalanine (PCPA)⁴, an inhibitor of 5HT synthesis, motor responsiveness of rats to electrical stimulation of the feet has been found to increase. We have observed that rats treated with lithium for a few days struggle more than controls when the skin is punctured in the course of injections and after 2 weeks of treatment with lithium chloride (LiCl), foot shock “jump response” thresholds are reduced by about 10 and 25% with doses of 1 and 2 mequiv./kg respectively. With larger doses, sensitivity to foot shock is not increased further, but may even decline as toxic effects appear; after 2 weeks of administration of 3 mequiv/kg LiCl, toxic effects appeared in nearly all our rats and about 10% of animals died. Sheard⁵ has found that treatment for 5 days with a high dose of LiCl (5 mequiv/kg) had no effect on motor responsiveness to foot shock, although shock-induced aggressive behaviour decreased; no toxic effects were reported.     

Subacute and Chronic In Vivo Lithium Treatment Inhibits Agonist- and Sodium Fluoride-Stimulated Inositol Phosphate Production in Rat Cortex

We have investigated the effects of in vivo lithium treatment on cerebral inositol phospholipid metabolism. Twice-daily treatment of rats with LiCl (3 mEq/kg) for 3 or 16 days resulted in a 25-40% reduction in agonist-stimulated inositol phosphate production, compared with NaCl-treated controls, in cortical slices prelabelled with [3H]inositol. A small effect was also seen with 5-hydroxytryptamine (5-HT) 24 h after a single dose of LiCl (10 mEq/kg). Dose-response curves to carbachol and 5-HT showed that lithium treatment reduced the maximal agonist response without altering the EC50 value. This inhibition was not affected by the concentration of LiCl in the assay buffer. Stimulation of inositol phosphate formation by 10 mM NaF in membranes prepared from cortex of 3-day lithium-treated rats was also inhibited, by 35% compared with NaCl-treated controls. Lithium treatment did not alter the kinetic profile of inositol polyphosphate formation in cortical slices stimulated with carbachol. Muscarinic cholinergic and 5-HT2 bindings were unaltered by lithium, as was cortical phospholipase C activity and isoproterenol-stimulated cyclic AMP formation. [3H]Inositol labelling of phosphatidylinositol 4,5-bisphosphate was significantly enhanced by 3-day lithium treatment. The results, therefore, indicate that subacute or chronic in vivo lithium treatment reduces agonist-stimulated inositol phospholipid metabolism in cerebral cortex; this persistent inhibition appears to be at the level of G-protein-phospholipase C coupling.     

Effect of experimental elevation and decrease of thyroxine level on catalepsy in rats

Thyroid dysfunction is associated with mental disorders. The present study was aimed to reveal the effects of experimental decrease and increase of thyroxine level on expression of two types of extensive freezing: spontaneous and pinch-induced catalepsy, in Wistar rat males. Chronic administration of thyroxine synthesis inhibitor, propylthiouracil (5 mg/kg/day, 28 days), markedly decreased plasma hormone level and at the same time produced a significant increase in percentage of spontaneously cataleptic animals and immobility time, but had no effect on the expression of pinch-induced catalepsy. On the contrary, chronic thyroxin (0.1 mg/kg/day, 28 days) treatment produced no effect on spontaneous catalepsy expression, although it significantly increased percentage of cataleptic animals and immobility time of pinch-induced catalepsy. The results suggest that both the thyroid hormone deficit and excess provoke catalepsy in rats but enhance different forms of freezing reaction.