Influence of a Nitric Oxide Synthase Inhibitor on the Anxiolytic, Stimulating, and Analgesic Effects of Long-Term Perinatal Caffeine Exposure in Rats.

We studied the effect of inducible NO synthase (iNOS) inhibitor aminoguanidine on the behavioral effects of chronic perinatal caffeine exposure. Administration of caffeine in the prenatal and early postnatal periods led to the development of anxiolytic, stimulating, and analgesic effects. Administration of aminoguanidine attenuated the anxiolytic and stimulating effects and potentiated the analgesic effect of perinatal administration of caffeine. Chronic perinatal administration of caffeine leads to significant changes in the level of anxiety, motor activity, and pain sensitivity, and inhibition of iNOS has a pronounced multidirectional effect on these effects.

Features of the Effects of Glutamatergic System Modulators in the Model of Hyperthermal Seizures in Rat Pups.

We studied the effect of lamotrigine, an anticonvulsant inhibiting the presynaptic release of glutamate, and LY341495, an antagonist of metabotropic glutamate 2/3 receptors, on the development of hyperthermic seizures and the content of LPO products in the brain of 8-10-day-old Wistar rats. Rat pups in the early postnatal period demonstrated pronounced seizures in response to thermal exposure, which was accompanied by an increase in the level of LPO products in the cerebral cortex. It was shown that the latency of generalized seizures increased after administration of both lamotrigine and LY341495. The most pronounced effect was observed in animals treated with lamotrigine. Both test substances prevented LPO intensification induced by hyperthermic exposure to varying degrees.

Effect of Nitric Oxide Synthase Inhibitor on the Learning and Spatial Memory in Rats Subjected to Long-Term Perinatal Administration of Caffeine.

We studied the effect of inducible nitric oxide synthase inhibitor aminoguanidine on learning and spatial memory in rats exposed to long-term administration to caffeine during the prenatal and early postnatal periods. The rats perinatally receiving caffeine demonstrated high learning ability in the Morris water maze. At the same time, the ability to remember the location of the hidden platform in the trial probe in these rats was reduced in comparison with that of the control group rats perinatally receiving water. Administration of aminoguanidine to rats under conditions of perinatal exposure to caffeine significantly improved the parameters of spatial learning and memory. Thus, inhibition of inducible nitric oxide synthase has a beneficial effect on the cognitive functions in offspring perinatally receiving caffeine.

Influence of Caffeine Consumption by Pregnant Rats on Behavior and Learning in Their Offspring.

We studied the effect of long-term prenatal administration of caffeine on the behavior and learning of rats in postnatal ontogeny. Experiments were carried out on male rats born by females receiving caffeine solution as the only source of fluid throughout gestation. The control group consisted of pups obtained from females receiving drinking water throughout pregnancy. It was found that long-term caffeine intake by female rats during pregnancy determined increased locomotor activity of the offspring. Rat pups born from mothers treated with caffeine during pregnancy faster reached the underwater platform in the Morris maze, i.e. demonstrated better spatial memory formation than control animals.

Antagonists of Metabotropic Glutamate Receptors Prevent the Development of Audiogenic Seizures.

Pretreatment with mGluR1 antagonist AIDA (1 mg/kg) nearly completely prevented the onset of tonic-clonic seizures and increased generation of NO in the cerebral cortex of rats with genetically determined audiogenic reaction to acoustic stimulation. Administration of mGluR5 antagonist MPEP (10 mg/kg) before audiogenic exposure was followed by a significant decrease in the degree of seizure and partially prevented increased generation of NO due to acoustic stimulation. These data indicate that mGlu receptors and NO play an important role in the pathogenetic mechanisms of audiogenic seizures.

Effect of peripheral opioid receptor agonists on depressive activity of ethanol.

We studied the effect of peripheral µ- and κ-opioid receptor agonists (not crossing the bloodbrain barrier) on locomotor activity and metabolism in rats after acute administration of ethanol. Intraperitoneal injection of ethanol in a single dose of 2 g/kg had a strong depressive effect manifested in a decrease in horizontal locomotor activity and suppression of metabolism. µ-Opioid receptor agonist DAMGO and κ-opioid receptor agonist ICI 204,448 partly abolished the effect of ethanol on locomotor activity of rats. ICI 204,448 was most potent in this respect. In contrast to µ-opioid receptor agonist DAMGO, κ-opioid receptor agonist ICI 204,448 prevented metabolism suppression induced by ethanol. Our results indicate that ICI 204,448 significantly inhibits the depressive effect of ethanol. DAMGO showed only partial effectiveness under these experimental conditions.

Effect of peripheral D2 dopamine receptor antagonist domperidone on metabolism, feeding behavior, and locomotor activity of rats.

We studied the possibility of activation of the central dopaminergic system compartment by modulating activity of D2 dopamine receptors in the gastrointestinal tract with domperidone, an antagonist not crossing the blood-brain barrier. Intragastric administration of 0.1 mg/kg domperidone to rats was followed by a significant decrease in feeding behavior and stimulation of basal metabolism, but had no effect on locomotor activity of animals in a Phenomaster system. These effects are typical of psychostimulant agents that stimulate dopamine release from nerve endings in the nucleus accumbens and some regions of the brain cortex. Our results indicate that physiological functions associated with activity of the central dopaminergic system can be modulated through peripheral dopamine receptors.

Estimation of the level of anxiety in rats: differences in results of open-field test, elevated plus-maze test, and Vogel's conflict test.

We compared individual anxiety assessed by three standard tests, open-field test, elevated plus-maze test, and Vogel conflict drinking test, in the same animals. No significant correlations between the main anxiety parameters were found in these three experimental models. Groups of animals with high and low anxiety rats were formed by a single parameter and subsequent selection of two extreme groups (10%). It was found that none of the tests could be used for reliable estimation of individual anxiety in rats. The individual anxiety level with high degree of confidence was determined in high-anxiety and low-anxiety rats demonstrating behavioral parameters above and below the mean values in all tests used. Therefore, several tests should be used for evaluation of the individual anxiety or sensitivity to emotional stress.

Role of metabotropic glutamate receptors in the mechanisms of experimental parkinsonism development.

We studied the effects of metabotropic glutamate receptor 5 (mGluR5) antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) on the development of catalepsy and NO generation in the striatum of rats under conditions of long-term treatment with low doses of rotenone, a mitochondrial complex I inhibitor. In rats receiving single intraperitoneal injection of rotenone (1.5 mg/kg), NO concentration in the striatum did not differ from that in animals receiving sunflower oil. No signs of catalepsy were observed at these terms in both animal groups. It was demonstrated that long-term rotenone treatment induced catalepsy associated with enhanced NO production in the rat striatum. mGluR5 antagonist MPEP alleviated catalepsy caused by long-term rotenone treatment and prevented rotenone-induced stimulation of NO generation.

Loperamide effects on anxiety level and feeding behavior in rats. Role of vagal afferentation.

We investigated the role of vagal afferentation in the interaction of the peripheral and central parts of the endogenous opioid system, in the mechanisms of sensorial satiation and anxiety in rats. It has been established that vagotomized rats spent less time in open arm of the plus-maze in comparison with sham-operated animals. Peripheral administration of µ-opioid receptor agonist loperamide was shown to reduce anxiety level in sham-operated rats and had no effect on this parameter in vagotomized animals. Testing in a PhenoMaster module system showed that loperamide administration suppressed feeding behavior in sham-operated animals and partially suppressed it in vagotomized animals. Vagotomy virtually completely blocked the anxiolytic effect of loperamide and partially blocked the anorexigenic effect of the µ-opioid receptor agonist.

[Central and peripheral mu-opioid systems in the mechanisms of emotional stress].

The aim of the work was to study effect of peripheral administration of mu-opioid receptor ligands unable to penetrate through the hematoencephalic barrier on the measures of emotionality in rats and on the release of beta-endorphins from nerve endings of the anterior cingulate cortex during emotional stress. The mu-opioid receptor agonist loperimide mostly acted as an anxiolytic whereas the receptor antagonist methylnaloxon showed depressive activity. Lifetime microdialysis and subsequent immunoenzyme assay demonstrated that intraventricular infusion of loperamide and methylnaloxon decreased and increased respectively the surge of beta-endorphin into the intercellular space. Immobilization-induced emotional stress insignificantly increased the beta-endorphin level in the cingulate cortex. Peripheral administration of loperamide but not methylnaloxon markedly increased the release of the neuropeptide during stress. These findings confirm the hypothesis of the authors about reciprocal interaction of central and peripheral components of the endogenous opioid system and explain the mechanism of antistress action of loperamide.

Effect of peripheral administration of peptide ligands of δ-opioid receptors on anxiety level and locomotor activity of rats.

We studied the effect of intragastric administration of a peptide δ-opioid receptor agonist DADLE and peptide δ-opioid receptor antagonist ICI 174.864 on anxiety and locomotor activity of rats. Peripheral administration of ICI 174.864 produced an anxiolytic effect, but did not modulate locomotor activity of rats. Agonist DADLE in doses of 50 and 100 µg/kg increased anxiety, but decreased locomotor activity of rats. Our results indicate that ICI 174.864 and DADLE produce opposite effects on anxiety in rats. These data support our hypothesis on the interaction between the central and peripheral compartments of the endogenous opioid system.

Changes in feeding behavior after peripheral loperamide administration in rats.

Changes in the parameters of operant feeding behavior and body weight were studied in rats after intragastric administration of µ-opioid receptor agonist loperamide. Loperamide administration significantly suppressed foraging behavior in rats and reduced their body weight. Our findings suggest that peripheral loperamide administration, according to the hypothesis of reciprocal interactions between the central and peripheral parts of the endogenous opioid system, suppresses activity of central opioid mechanisms of feeding behavior organization. Changes in feeding behavior can appear due to disturbances in the mechanisms of assessment of food reward. We hypothesized that natural activation of µ-opioid receptors of the stomach with food-derived peptides can be associated with "sensory satiation" mechanism limiting excessive food intake.

Peripheral administration of loperamide and methylnaloxone decreases the degree of anxiety in rats.

We studied the effect of µ-opioid receptor ligands on anxious and depressive behavior of rats. Intragastric administration of loperamide and methylnaloxone reduced animal anxiety evaluated by an increase in the number of entries into and time spent in open arms of the elevated plus-maze. µ-Opioid receptor agonist loperamide had the most pronounced anxiolytic effect. Analysis of animal behavior in the forced swimming test showed that administration of µ-opioid receptor antagonist methylnaloxone reduced the latency of the first submersion, increased the total time of submersion episodes, and shortened the time of active swimming, which attested to depressive properties of this agent. Loperamide had little effect on behavior of rats in the forced swimming test. Thus, µ-opioid receptor agonist loperamide has the antianxiety properties and produced no sedative effect. Therefore, this agent holds much promise as an anxiolytic drug.

Modulation of peripheral opioid receptors affects the concentration of mu-opioid receptors in rat brain.

Radioligand binding assay was used to evaluate characteristics of central mu-opioid receptors after peripheral administration of mu-opioid receptor agonist loperamide and antagonist methylnaloxone. These substances do not cross the blood-brain barrier. Loperamide and methylnaloxone produced opposite effects on the density of mu-opioid receptors in the frontal cortex of rat brain. These data confirm our hypothesis on reciprocal interactions between central and peripheral compartments of the endogenous opioid system.

Modulating role of NO in haloperidol-induced catalepsy.

Injection of haloperidol during catalepsy modeling decreased the content of NO in rat cerebral cortex. NO precursor L-arginine arrested catalepsy and prevented the decrease in NO content.

Role of nitric oxide and lipid peroxidation in pathophysiological mechanisms of audiogenic seizures in GEP Rats and DBA/2 mice.

We evaluated the role of nitric oxide and lipid peroxidation in the pathophysiological mechanisms of seizures in genetically epilepsy prone (GEP) rats and DBA/2 mice with genetically determined audiogenic epilepsy. In rats and mice acoustic stimulation led to locomotor activation followed by clonic-tonic seizures. The contents of nitric oxide and lipid peroxidation products at the peak of seizures markedly surpassed the control level.

[Model corasol-induced seizures are followed by increase of nitric oxide generation and are abolished by mexidol and alpha-tocopherol]. / Model'nye korazolovye sudorogi soprovozhdaiutsia usileniem generatsii okisi azota i ustraniaiutsia meksidolom i al'fa-tokoferolom.

The effect of mexidol and alpha-tocopherol on the onset and development of acute epilepsy model was studied in Wistar rats using penthylenetetrazole induced convulsions. The intensity of the nitric oxide (NO) production in the cerebral cortex was determined by a direct method using electron paramagnetic resonance. The rate of lipid peroxidation (LPO) was estimated by measuring the level of secondary products (thiobarbituric acid reactive species). The peak of penthylene-tetrazole convulsions is accompanied by a significant increase in the levels of both NO and LPO products. Mexidol (150 mg/kg) and alpha-tocopherol (100 mg/kg) hindered the development of model convulsions, prevented NO buildup, and inhibited LPO growth. It is suggested that suppression of the excess NO production in the cortex and inhibition of the LPO enhancement can be involved in the mechanism of action of antiepileptic drugs.

[Semax prevents elevation of nitric oxide generation caused by incomplete global ischemia in the rat brain]. / Semaks preduprezhdaet povyshenie generatsii oksida azota v mozge krys, obuslovlennoe nepolnoi global'noi ishemiei.

A twofold increase in the nitric oxide (NO) production and a moderate increase in the content of secondary products of lipid peroxidation was observed in Wistar rats with incomplete global ischemia model induced by the bilateral occlusion of common carotid arteries. A clear correlation was observed between the NO content in the rat brain and the level of neurological disturbance manifestations in the ischemized animals. The synthetic peptide semax (a fragment of ACTH4-7 Pro-Gly-Pro) in a dose of 0.3 mg/kg prevented from the development of both neurological disturbances and excess NO production in the rat brain cortex.

Role of nitric oxide and lipid peroxidation in mechanisms of febrile convulsions in Wistar rat pups.

Generation of nitric oxide and the content of lipid peroxidation products in the brain are increased in rat pups during febrile convulsions. NO-synthase inhibitor N-nitro-L-arginine in a dose of 250 mg/kg prevented hyperthermia-induced accumulation of nitric oxide, increased the latency febrile convulsions, and had no effect on the content of lipid peroxidation products.