Sexual function in adult male rats after prenatal modulation of the cholinergic system.

Prenatal administration of the n-cholinolytic ganglerone to pregnant female rats at different periods of gestation was found to lead to long-term changes in sexual behavior in pubescent offspring: there was a reduced dynamic of acquiring sexual experience and a very low level of sexual activity, with significant impairment to the motivational and ejaculatory components of sexual behavior. The number of males with reduced sexual activity in the experimental groups was significantly greater than that in control offspring. The results obtained here provide evidence that impairments of sexual function in adult offspring induced by prenatal administration of the n-cholinolytic ganglerone at 9-11 and 12-14 days of gestation and, to a lesser extent, the m-cholinolytic metamyzil at 9-11 days of gestation, were due to impairment to the central mechanisms regulating sexual function due to stable changes in neurotransmitter activity in the hippocampus and hypothalamus, along with a significant reduction in the blood testosterone level.

[The sexual function of mature rat males after prenatal modulation of cholinergic system].

The data obtained have shown that prenatal exposure of pregnant rat females of 9-19-day pregnancy to N-cholinolytics as compared to M-cholinolytics produce long-term behavioural changes in pubescent rat progeny. Pubescent rat progeny had low dynamics of gaining sexual experience and decreased sexual activity with equal disturbance of motivation and coitus. The number of males with absence of sexual activity was above that of the control group. We suggest that sexual dysfunction of offspring adulthood was provoked by introduction of ganglerone (N-cholinolytic) which had been injected on 9-11 and 12-14 days of gestation, and metamyzil (M-cholinolytic) injected on 9-11 days of gestation. Apparently, regulation of neuronal mechanisms for sexual function is disturbed as a consequence of lasting change in neurotransmitter activity. It is suggested that dopaminergic activity in brain limbic structures was affected the most. The significant decrease in blood testosterone values has also been elucidated.

Peripheral and central routes of administration of quaternary ammonium compound IEM-1460 are equally potent in reducing the severity of nicotine-induced seizures in mice.

Peripheral administration of nicotinic receptor antagonists with a quaternary ammonium group (hexamethonium and chlorisondamine) did not prevent the development of seizures induced by systemic treatment with nicotine in the toxic dose. The Me3N+ group with stable positive charge inhibits transport of these compounds into the brain through the blood-brain barrier. Intracerebral and peripheral (intraperitoneal) administration of compound IEM-1460 with the Me3N+ group was equally potent in reducing the severity of nicotine-induced seizures in mice. This phenomenon is related to the fact that IEM-1460 acts as a nicotinic receptor antagonist and polyamine agonist, which increases blood-brain barrier permeability for polar compounds. These features contribute to IEM-1460 transport into the brain. High anticonvulsant activity of IEM-1460 on the model of nicotine-induced seizures is associated with combined blockade of nicotinic receptors (alpha3beta4 receptors) and glutamate receptors (GluR1 AMPA receptors).

Effect of modulators of the polyamine site on the development of seizures induced by systemic and intracerebral administration of N-methyl-D-aspartate in albino mice.

Systemic intraperitoneal administration of polyamine agonist IEM-1460 containing the Me3N(+) group with a stable positive charge preventing permeation of this substance through the blood-brain barrier and polyamine antagonist arcaine had no effect on the development of seizures caused by intracerebral injection of N-methyl-D-aspartate in mice. Intraperitoneal injection of IEM-40 potentiated, while arcaine decreased the severity of seizures induced by intraperitoneal treatment with N-methyl-D-aspartate. This effect was related to modulation of the permeability of the blood-brain barrier for N-methyl-D-aspartate probably due to modulating effects of IEM-40 and arcaine on the polyamine site of N-methyl-D-aspartate receptors in the blood-brain barrier.

[Effect of vilon on neuroendocrine status and sexual function of old male rats].

The hypogonadal status of hemigonadectomised male rats has been choseh as a model of age-related sexual function decline in animals. The effect of dipeptide Vilon on parameters of sexual function and neuroendocrine status was studied. The results showed that regular introduction of Vilon in a dose of 50 microg per rat activates sexual function in old male rats. The obtained data confirm that Vilon significantly affects neuroendocrine status of animals, as well as the level of LH, prolactin and ACTH and changes the content of neurotransmitters in hypothalamus. We consider the changes in sexual function caused by Vilon not relate to change in one parameter only, but are mediated by a set of neuroendocrine and neuromediatorial factors. Significant decrease in prolactin content in blood is worthy of notice, as age-related hypersecretion of this hormone is one of the main factors leading to age-related sexual function decline.

[Effect of some imidazole-4,5-dicarboxylic acid derivatives on the activity of N-methyl-D-aspartate (NMDA) receptors].

The results of experiments on mice showed that some imidazole-4,5-dicarboxylic acid derivatives injected into lateral cerebral ventricles produce a dose-dependent convulsant or anticonvulsant effects, that is, possess the properties of partial NMDA receptor agonists. The most promising partial NMDA receptor agonist selected for further investigation is 2-propylimidazole-4,5-dicarboxylic acid.

[Interleukin-1beta and depressive states]. / Interleikin-1beta i depressivnye sostoianiia.

Administration of Interleukin-1 beta (IL-1 beta) in pyrogenic and subpyrogenic doses induced a depression of social and exploratory behaviour in rats. A reduction in locomotor activity only occurred with pyrogenic doses of the IL-1 beta. The low dose induced the reduction whereas the high dose the increase of anxiety in elevated plus maze. The opposite effects of two doses of IL-1 beta were observed also in a test with saccharine.

Pyrogenic activity of human native and human recombinant interleukins-1 beta: stabilization with albumin enhances the pyrogenic action of recombinant IL-1 beta delivered into the rabbit brain.

The pyrogenic potential of natural and recombinant human IL-1 beta in rabbits was found to be very similar when the substances were given intravenously. Under these conditions, stabilization of rIL-1 beta with human serum albumin (HSA) failed to affect the pyrogenic activity of recombinant IL-1 beta. When the two preparations were administered directly into the PO/AH area of the brain, recombinant IL-1 beta was less pyrogenic than its natural counterpart. This lower pyrogenicity of recombinant IL-1 beta was corrected if the injected material contained HSA, which is known to stabilize in vitro the biological activities of IL-1 beta against slow degradation. The possibility is now considered that the central and peripheral systems for IL-1 inactivation are different. The existence of an intrabrain IL-1 pool is suggested and its significance for neuroimmunomodulation is stressed.

[The pyrogenic activity of native and recombinant human interleukin-1 beta]. / Pirogennaia aktivnost' nativnogo i rekombinantnogo interleikina-1 beta cheloveka.

Comparative doses (100-180 ng/kg) of highly purified human native interleukin-1 beta (nIL-1 beta) and human recombinant IL-1 beta (rIL-1 beta) intravenously injected were found to cause similar changes in body temperature in rabbits. Under these conditions, stabilization of rIL-1 beta by human serum albumin (HSA) fails to affect rIL-1 beta pyrogenic activity. nIL-1 beta, 0.05-2.0 ng, injected into the PO/AH region of the brain causes dose-dependent fever in the animals. With intrahypothalamic nIL-1 beta (versus i.v. injection), the pyrogenic activity of rIl-1 beta is much lower than that of nIL-1 beta. Moreover, pyrogenicity appears to be dependent on the type of rIL-1 beta, namely on free or stabilized by HSA. The former has about 100-fold and the latter a 25-fold lower activity than the native cytokine (in terms of a dose-pyrogenic effect relationship). The findings are discussed in the light of the existence of various interleukin IL-1 beta pools.

Fever produced by intrahypothalamic injection of interleukin-1 and interleukin-6.

Pure human interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6), both of natural origin, were found to cause fever in rabbits when injected into the PO/AH region of the brain. The threshold dose required for this effect was between 0.4 and 4 U, equivalent to 0.04 to 0.4 ng for IL-1 beta, and around 50 U, equivalent to 0.05 ng for IL-6. From this it was estimated that this area of the brain responds to a local concentration of approximately 1 ng/ml of these cytokines, a level which can easily be reached after intravenous administration of threshold pyrogenic doses of either cytokine. The observation supports the view that fever induced by systemic endogenous production of IL-1 and IL-6 is due to a direct effect on the thermoregulatory center and may not require production of mediators, such as prostaglandins, at sites distant from the center.

[Role of cAMP in the mechanism of the fever reaction]. / O roli tsAMF v mekhanizme likhoradochnoi reaktsii.

It has been shown that accumulation of endogenous cAMP caused by theophylline increases the body sensitivity to the minimum doses of leukocytic and bacterial pyrogens and to prostaglandin E1. The increasing effect of theophylline was abolished by administering the higher doses of the pyrogenic agents. Repeated daily administration of bacterial pyrogen in conjunction with theophylline does not induce the development of tolerance. The possible reasons for enhanced fever in response to the minimum doses of the pyrogenic agents during accumulation of endogenous cAMP are discussed.

[Conditions favoring production and mechanism of action of macrophage pyrogen]. / Ob usloviiakh polucheniia i mekhanizme deistviia makrofagal'nogo pirogena.

Activation of mononuclear phagocytes by staphylococci in vitro results in the production of endogenous pyrogen. Macrophage pyrogen does not posses species pyrogenic specificity. Intracisternal injection increases pyrogen susceptibility more than 100-fold as compared to intravenous injection. Still more abrupt increase in pyrogen susceptibility was observed in the animals in the presence of elevated body cAMP concentration induced by theophylline preinjection.

[Endogenous pyrogen formation by bone marrow cells]. / Obrazovanie éndogennogo pirogena kletkami kostnogo mozga.

The cells of the rabbit bone marrow produced endogenous pyrogen in response to stimulation with bacterial lipopolysaccharide. Incubation of the cells in medium No 199 containing a 15% homologous serum is optimal for the release of pyrogen. It is supposed that the cells of the bone marrow take part in the formation of endgenous pyrogen and in the mechanism of pyrexia in the organism.

[Effect of cytostatic drugs on fever development following administration of bacterial pyrogen]. / Vliianie tsitostaticheskikh sredstv na razvitie likhoradochnoi reaktsii pri vvedenii bakterial'nogo pirogena

A study was made of the development of pyretic reaction to the administration of a bacterial lipopolysaccharide (pyrogenal) after preliminary treatment of rabbits with actinomycin D and cortisone. Such treatment failed to change the reactivity of thermoregulating centres to the endogenous pyrogen. Intravenous injection of bacterial pyrogen was followed by marked shortening of pyretic reaction; the reaction was markedly inhibited in response to its intracysternal administration. An important role played by polymorphonuclear leukocytes in the formation of endogenous pyrogens in the mechanism of pyrexia induced by bacterial pyrogens was shown in this work.