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The review describes the influence of serotonin (5-HT) and its receptor, transporter SERT and nuclear factor Nf-kB on the immune function of the body, particularly in the digestive tract. The mechanisms of the synthesis, metabolism and catab. olism of 5-HT are characterized. The targets for serotonin on cell level are immunoactive cells--neutrophils, eosinophils, leukocytes, monocytes and dendritic cells. Receptor and non-receptor described mechanisms of action of peripheral serotonin are described. immunoactive cells express on their membrane 5 HT1A-5-HT1E-5-HT2A-5-HT3-, 5-HT4- and 5-HT7-serotonin receptor subtypes. Activation of these receptors modulate the release of TNF-α, secretion of interleukins IL-1β, IL-6, IL-8/CXCL8, IL-12p40. Mediators of the non-receptor mechanisms are transporter SERT, tryptophan hydroxylase-1 and nuclear factor Nf-kB. Target-genes for Nf-kB are genes encoding cytokines. The cooperation of non/receptory pathways involved 5-HT1A- and 5-HT3 receptors. It is concluded that the diversity of ways of peripheral serotonin on the immune function of the body are existed.

We have found that activation of 5-HT1A receptor with 8-OH-DPAT (0.1, 0.5 and 1.0 mg/kg, i. p.) considerably and dose-dependently reduced the number of 5-HT2A receptor-mediated head-twitches, whereas 5-HT1A receptor blockade with WAY-100635 (0.5 and 1.0 mg/kg, i. p.), on the contrary, pro- duced significant enhancement of this 5-HT2A receptor functional response. At the same time 5-HTA receptor activation with DOI (0.5 and 1.0 mg/kg, i. p.) abolished the 5-HT1A receptor-mediated hypothermic reaction, whereas 5-HT2A receptor blockade with ketanserin (1.0 and 2.0 mg/kg, i. p.) increased this 5-HT1A receptor functional response. Moreover, we revealed that 5-HT2A receptor antagonist ketanserin (1.0 and 2.0 mg/kg, i. p.; or 20 and 40 nmol, i. c. v.) produced the considerable dose-dependent hypothermia. This ketanserin-induced (40 nmol, i. c. v.) hypothermic reaction was significantly attenuated by pretreatment with 5-HT1A receptor antagonist WAY-100635 (1.0 mg/kg, i. p.), indicating that 5-HT2A receptor-related hypothermic response is mediated, at least partially, via activation of 5-HT1A receptors. The obtained data indicate that 5-HTA and 5-HT2A receptors are able to modulate each other functional activity by means of bilateral functional cross-talk.

The effects of serotonin receptor activation (by serotonin) and inhibition (by mianserin) on the properties of the α1-, α2-adrenoreceptors, and muscarinic cholinergic receptors in subcellular membrane fractions from the rat cerebral cortex were studied. Experimental data on the kinetics of specific antagonists binding to adrenergic and muscarinic receptors were analyzed by graphical and mathematical methods. The results suggest the presence of allosteric (cross-talk) interaction. In the control, α1- and α2-adrenoreceptors were represented by a single pool, and muscarinic receptors, by two pools. Two pools of adrenoreceptors with different affinity were detected against the background of serotonin. It was found that mianserin induces the formation of two pools of only (α2-receptors and muscarinic receptors are represented by two pools differing in the main parameters, such as dissociation constants and adrenoreceptor concentrations, in the control and experimental groups. It was shown that the allosteric effect of serotonin and mianserin is manifested in the inhibition of muscarinic receptors. It was assumed that the adrenergic and cholinergic receptors exist as dimers. The interaction between the adrenergic, cholinergic, and serotonergic systems is likely to be implemented at the cell membrane level.

The aim of the present work was to perform a comparative analysis of 5-HT(1A)- and 5-HT(2A/2C)-receptors blockade effects on depression-like behavior of the adult ovariectomized (OVX) female offspring at estrogen deficiency delivered from their prenatally stressed mothers. The adult prenatally stressed OVX female offspring were chronically (during 14 days) treated by 5-HT(1A)-receptors antagonist--NAN-190 (0.1 mg/kg, s. c.) or 5-HT(2A/2C)-receptors antagonist--ketanserine (0.1 mg/kg, i. p.) alone, or in a combination with its preparartions a low dose of 17β-estradiol (5.0 μg/rat, s. c.). All drugs were administered in 2 weeks after overiectomy during 14 days before and for all period of behavioral testing procedure. The prenatally stressed QVX female offspring were tested in the forced swimming test (FST) and the open field test (OFT). Treatment with NAN-190 alone induced marked depressant-like effect, while NAN-190 administered in a combination with a low dose of 17β-estradiol resulted in an antidepressant-like effect in the FST in the prenatally stressed OVX females as compared to the control prenatally stressed female offspring. Administration ofNAN-190 plus 17β-estradiol led to decreased frequency of rearing, exploratory and grooming behavior in prenatally stressed OVX female offspring in the OFT. Treatment with ketanserine resulted in an antidepressant-like effect in prenatally stressed OVX females in the FST as compared to the control group. However, co-administration of ketanserine with a low dose of 17β-E2 to the prenatally stressed OVX female offspring failed to modify depressant-like behavior in the FST.

The review contains an analysis of literature data on enhancement mechanisms of duodenum contractions arising during stimulation of the sympathetic trunk in the right thoracic cavity in dogs. It is established in experiments that There are mostly enhancement, not relaxation of the organ contraction occured. In this case the stimulatory effect due to the excitation of the parasympathetic fibers is excluded. The trimeperedin inhibit the serotonin receptors of autonomic ganglia neurons stimulatory activity during the nerve stimulation. It is concluded that the sympathetic trunk contain the preganglionic serotonergic nerve fibers, whose activation leads to increased bowel contractions. Direct adipinate-serotonin administration increased the bowel contraction that confirm the preganglionic serotonergic nerve fibers presence in the sympathetic trunk. The practical significance of these studies is that the new approach to the development of pharmacological agents to stimulate the motility of the gastrointestinal tract was found. The trimeperedin may inhibit the serotoninergic nerves activity that resulted in the perioperative constipation in surgical patients. Practical recommendation to exclude trimeperedin in preparing the patient for surgery to prevent perioperative constipation is formulated.

The review is devoted to the mechanism of duodenal motility activation caused by sympathetic nerves. The authors havefound that stimulation of the sympathetic trunk in the thoracic cavity in dogs in most cases provide not inhibitory but excitatory motor responses of the duodenum. Excitatory effects were eliminated during 5HT-receptors blockade by promedol and lysergol. Analysis ofpublications showed that sympathetic trunk contains serotoninergic fibers, providing excitatory motor responses of the duodenum to electrical nerve stimulation. According to histochemical and physiological studies, amount of serotonergic fibers in the sympathetic trunk is several times more than the adrenergic. This means that the body has sertoninergic nerves. Serotoninergic nerve as well as the sympathetic is a collective notion. There are: sympathetic trunks, their ramifications and branches that innervate the internal organs. Since promedol blocks serotonergic nerves, this is plausible cause of constipation in patients after surgical treatment along with the application of this drug.

Here we investigated whether the 5-HT3 receptor and the 5-HT3/5-HT(1A) receptors coaction play essential role in the regulation of locomotion, depressive-like and social behavior. It was found that central administration of selective agonist of 5-HT3 receptor m-CPBG (2.5, 5.0, 10.0 nmol) produced significant decrease of horizontal and vertical locomotor activity in the open field (OF) test. Selective antagonist of 5-HT(1A) receptor WAY-100635 (2.0 mg/kg (3.7 μmol/kg), i.p.) attenuated the effect of m-CPBG on behavior in the OF test. Selective 5-HT(1A) receptor agonist 8-OH-DPAT (0.25, 0.5, 1.0 mg/kg (0.76, 1.5 and 3.0 μmol/kg correspondingly), i.p.) significantly decreased horizontal and vertical locomotor activity in the OF test as well. The activation of 5-HT3 receptors failed to affect immobility time in the tail suspension test, whereas the activation 5-HT(1A) receptors significantly decreased the immobility time. Administration of m-CPBG also did not produced considerable effect on social behavior. At the same time, 8-OH-DPAT significantly decreased time and number of social contacts. Thus it was shown for the first time that 5-HT3 receptor-induced behavioral response observed in the OF realized mainly via 5-MHT(1A) receptor. Obtained results provide new evidence on the role of 5-HT3 receptors and 5-HT3/5-HT(1A) receptors coaction in the regulation of locomotor activity but not in the depressive-like and social behavior.

Serotonergic mechanisms are involved in many, if not all digestive functions of the gastrointestinal tract. A special role is played by serotoninergic structures in the neuronal control of motor activity. The study of these structures is of particular interest due to the widespread occurrence of irritable bowel syndrome, covering up to 20% of the adult population, which makes the research in this area up to date and in demand. Acute experiments were performed on 102 Wistar rats in 6 series. Experiments were carried out under general anesthesia (Nembutal, 60 mg/kg) and mechanical lung ventilation. Motor responses of the stomach, duodenum and ascending colon were studied to i.a. Serotonin adipate infusion (1 mg/kg) during joint blockade of sympathetic and parasympathetic chains of ANS, as well as on the background of the blockade of various 5-HT-receptors. Infusions of 5-HT-blockers reduce the magnitude of motor responses in stomach, duodenum and colon in varying degrees. Based on these data found 5-HT(1b)-receptors are mainly located in enteric neurons. The distribution of 5-HT(2b-4)-receptor is heterogeneous: 5-HT(2b)-receptors are located in enteric neurons of the stomach and intestinal myocytes; 5-HT3-receptors localized in the ganglia supplying the stomach and colon and 5-HT4-receptors are mainly located in the smooth muscle of the stomach, duodenal and ascendent colon enteric neurons.

The paper contain the literature and own experimental data on peptid/serotoninergic regulation of pancreatic activity. Peptid- and serotoninergic mechanisms of regulation of pancreas activity are described. The experimental data on serotonin influence on pancreatic duct motility under pancreatitis are given.

We have studied the effect of stimulation or blockade of the 5-HT(1A) receptors on the passive avoidance performance and open-field test behavior in gonadectomized (GDX) male rats of middle age treated with a low dose of testosterone propionate. of The 5-HT(1A) receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) or 5-HT(1A) receptor antagonist NAN-190 (0.1 mg/kg, i.p.) were chronically (for 14 days) administered alone and in a combination with low dose of testosterone propionate (0.5 mg/kg, s.c.) in GDX rats of middle age (12 - 15 months). The co-administration of NAN-190 with low dose of testosterone propionate completely restored impaired passive avoidance performance in GDX males of middle age. Moreover, GDX rats of middle age treated with NAN-190 and low dose of testosterone propionate demonstrated increased exploratory and grooming behavior in the open-field test. Both 8-OH-DPAT alone and in combination with low dose of testosterone propionate markedly impaired passive avoidance learning and failed to modify behavior in the open-field test in GDX rats of middle age. The results of the present study are indicative of a positive effect of NAN-190 in combination with low dose of testosterone propionate on the passive avoidance learning at androgen deficiency in male rats of middle age.

Different mediator systems including serotoninergic one can influence animal's locomotor behavior. It has been shown that the spinal cord in the absence of supraspinal control is able to induce the locomotor activity in hindlimbs and afferent system can activate this mechanism. In behavioral studies on the rats with complete transection of the spinal cord it has been demonstrated that the pharmacological blocking of serotoninergic system results in depression of motor activity mediated by activation of support reactions. Histological studies did not reveal any effects of activation of support reactions on the safety of neurons as well as on the distribution of synaptic contacts within L2-L4 spinal segments. At the same time it has been shown that blockade of the serotoninergic system results in alterations of cells located in 1-3 laminae of dorsal horns, and in 7 Rexed's lamina as well as in redistribution of synaptic contacts in 1-4 Rexed laminae of the spinal cord dorsal horns.

In this study, we investigated the influence of serotonin on the development and functioning of T- and B-cell-mediated immunity during ontogenesis using the pharmacological model of serotonin depletion in rat fetuses. It has been demonstrated that prenatal serotonin deficiency resulted in a decrease in thymus and spleen weights, changes in their cellular composition, and long-lasting disturbances in cell-mediated and humoral immunity in postnatal ontogenesis. The data obtained suggest that serotonin may be considered a morphogenic factor in development of the immune system.

Comparative study of the effects of chronic administration of 5-HT(2A/2C)-receptors agonist (m-CPP, 0.5 mg/kg, i.p.) and 5-HT(2A/2C)-receptors antagonist (ketanserine, 0.1 mg/kg, i.p.) for 14 days on the anxiety- and depression-like behavior in adult prenatally stressed female rats showed that prenatal stress increased the anxiety level in female rats. Chronic administration of ketanserine produced anxiolytic and antidepressant effects, which inhibited the negative action of prenatal stress on the emotional behavior, whereas chronic administration of m-CPP did not change the emotional behavior.

In stimulation of preganglionic and postganglionic nervous fibres of the trachea and stimulation of preganglionic nervous fibres of the bronchi, serotonin strengthened reduction of a smooth muscle to 114 %. Methysergide (1.0 mkg) reduced responses to serotonin to 74-77 % on the trachea and practically didn't influence the bronchi. Against ketanserinum (1.0 mkg) serotonin is dose-dependent and reduced trachea's amplitude of the constriction to 60-63% and bronchi's amplitude of the constriction to 75-79%. Hexamethonium (100.0 mkg) reduced the serotonin amplitude of the constriction of the trachea at stimulation of postganglionic nerve to 64% and the bronchi at all kinds of irritation to 82-84%. Atropine (1.0 mkg) reduced effect of serotonin in stimulation of postganglionic nerve and tracheal smooth muscles to 75-77%. On preparations of bronchi, atropine reduced the serotonin effects in stimulation of preganglionic nervous fibres to 83% and strengthened to 117% in smooth muscles in stimulation of preganglionic nerve. Thus, there is heterogeneity of responses of smooth muscles of different sites of the tracheal-bronchial pathways of the rat to serotonin.

In the current paper a role of the serotinergic system in organization of impulsive behaviour in animals was considered. The results of influence of antagonists and agonists of the different types and subtypes of 5-HT receptors (1A, B; 2A, B, C; 7) and the effects of the dorsal raphe nuclei lesions on characteristics of impulsivity related with a motor control, mechanisms of attention, reinforcement and decision making were summarized. The data on knock-out animals and the experiments with microdialysis have been also considered. There was emphasized the important role of interaction of 5-HT-, dopamine- and glutamatergic systems in mediation of impulsive behaviour.

Data on the pharmacological properties, mechanism of action, and clinical advantages of the new antidepressant drug valdoxan capable of selectively stimulating melatonin receptors are presented. The drug effect is compared to the action of epiphyseal hormone melatonin and traditional antidepressants.

It has been shown that the agonist of 5HT1A-receptors 8-OH-DPAT induces contraction of aortic rings in the presence of angiotensin II. This effect is not associated with activation of alpha1-adrenoceptors by 8-OH-DPAT as it is reproduced in the presence of prazosin which completely suppresses the nonspecific vasoconstrictive effect of 8-OH-DPAT via alpha1-adrenoceptors on the aorta incubated without angiotensin II. Synergism in the action of angiotensin II and 8-OH-DPAT is completely preserved after partial desensitization of the receptors of angiotensin II. It has been found that 8-OH-DPAT increases the free cytoplasmic calcium concentration in cultured smooth muscle cells from the rat aorta. The data obtained support the hypothesis about the existence of "silent" vasoconstrictive 5HT1A-receptors. It has been suggested that activation of these receptors underlies synergism in vasoconstrictive action of serotonin and angiotensin II.

The present study indicates involvement of serotoninergic (5-HTergic) mechanisms in immunosuppression by DSLET (100 mkg/kg), a selective agonist of the delta2-opioid receptors, in CBA mice. 8-OH-DPAT (0.1 mg/kg), a selective agonist of the 5-HT(1A)-autoreceptors, WAY-100635 (1, 3 mg/kg) and ketanserin (1, 3 mg/kg), a selective antagonists of the postsynaptic 5-HT(1A)- and 5-HT(2A)-receptors, respectively, prevented immunosuppressive effect of DSLET. A possible differential role for 5-HT-receptors in delta-opioid immunosuppression is suggested.

Experiments on CBA mice showed that selective stimulation of 2A serotonin receptors with DOI agonist (1 mg/kg) led to suppression of the immune response and reduction of the spleen and peripheral blood CD8(+)T cell counts with the cytotoxic/suppressor function. Selective blockade of these receptors with ketanserin (1 mg/kg) had an opposite effect: immunostimulation with an increase in CD8(+)T cell count in the spleen. These data indicate the involvement of 2A serotonin receptors in immunosuppressive mechanisms of serotoninergic system.

Effects of DNQX (ionotropic AMPA/cainate glutamate receptor antagonist) and metiotepin (serotonin receptor antagonist) and cycloheximide (protein synthesis inhibitor) on long-term memory reconsolidation processes were studied in snail Helix lucorum with definite type of food aversion conditioned reflex. DNQX or cycloheximide injected immediately before reminding disrupt retrieval of the food aversion 24 hours after conditioning, and repeated trials of learning with the same food as at initial trials did not form the food aversion 2 weeks later. Metiotepin + reminding also discrupt recalling of food aversion 24 hours after conditioning, while food aversion was repaired after repeated trials 2 weeks later. Simultaneous injections of DNQX + cycloheximide or metiotepin + cycloheximide immediately before reminding do not discrupt the food aversion. We suggest that unrecovered and recovered forms of amnesia induced by AMPA/cainate glutamate receptor antagonists or serotonin receptor antagonist, respectively, need specific protein molecules de novo.

We have previously found two stages of amnesia evoked by disruption of memory reconsolidation with MK-801 (NMDA glutamate receptors antagonists) application in food aversion conditioned snails. Repeated conditioning restored the food aversion at early stage of amnesia development (<10 days), whereas repeated conditioning 10 days after MK-801 application did not restore the food aversion. In present work, amnesia was induced with MK-801/reminding 24 hours after food aversion conditioning, and antiamnestic effects of NMDA receptor glycine site agonist d-cycloserine were studied at early (3rd day) or late (12th day) stages of amnesia development. D-cycloserine injection and reminding restored memory only 3 days after amnesia induction whereas d-cycloserine injection without reminding was ineffective. D-cycloserine injection and reminding as well as repeated learning 12 days after amnesia induction were also ineffective in memory restoration. Thus, for the first time, it is revealed that NMDA receptor agonist d-cycloserine influences the memory restoration processes only at early but not the later stages of amnesia development.

We studied the effect of chronic administration of 5-HT(1A)-receptor agonist 8-OH-DPAT (0.05 mg/kg subcutaneously) or antagonist NAN-190 (0.1 mg/kg intraperitoneally) for 14 days on anxious-depressive-like behavior of female rats during the key phases of the estrous cycle. Chronic administration of NAN-190 during the estrus phase produced an anxiogenic effect, while its administration during proestrus phase induced an anxiolytic effect. Administration of 8-OH-DPAT had no effect on anxiety level, but produced a pronounced antidepressive effect irrespective of the phase of the estrous cycle.

A comparative analysis of the influence of chronic administration of the 5-HT2B/2C receptor agonist, m-CPP (0.5 mg/kg, i.p.), and the 5-HT2A/2C receptor antagonist, ketanserine (0.1 mg/kg, i.p.) for 14 days on the anxiety and depressive-like behavior in the adult female rats was performed. The depression in rats was modeled using the Porsolt test. The anxiety level was assessed in the elevated plus maze test. It was established that ketanserine induced antidepressive and anxiolytic effects in females during estrous and proestrous periods. The m-CPP administration also resulted in antidepressive effect in both estrous and proestrous periods. A clear modulation was observed in the anxiety behavior as dependent on the ovarian cycle phases in rats treated with m-CPP: the anxiolytic effect was manifested at an increased level of estrogens, while anxiogenic effect was manifested at a reduced level of estrogens. It is suggested that 5-HT subtype receptors are involved to different extent in the mechanisms of anxiety-depressive-like behavior depending on the alterations of hormonal balance during the ovarian cycle. The data obtained are indicative of a close interaction between the ovarian hormonal and serotonergic systems of the brain in the mechanisms of anxiety and depression.

The third intracellular loops of hormonal receptors play the main role in the interaction of majority of the serpentine type receptors with heterotrimeric G-proteins. In recent years, it was shown that synthetic peptides corresponding to membrane-proximal regions of these loops could be selectively influenced with hormonal signal transduction via the receptors homologous to them and trigger signalling cascade in absence of the hormone. For the first time, we succeeded in synthesizing the peptides derived from C-terminal region of the third intracellular loop of the IB-subtype serotonin receptor and studied their influence on serotonin-sensitive adenylyl cyclase system in the rat brain. The peptides 300-316 and 306-316 (the numbers correspond to amino acid positions in the rat IB-subtype serotonin receptor) at micromolar concentrations in absence of hormone-stimulated GTP-binding of Gi,-proteins coupled with the IB-subtype serotonin receptors and inhibited forskolin-stimulated adenylyl cyclase activity. Using selective agonists and antagonists of serotonin receptors it was shown that the peptides 300-316 and 306--316 inhibited serotonin signal transduction via homologous to them receptor and weakly influenced other types of serotonin receptors. The peptide 300-316 is more active compared with its shorter analogue 306-316 in the selectivity and efficiency of action on adenylyl cyclase signalling system regulated via the IB-subtype serotonin receptors. These findings indicate that the regions 300-316 of the IB-subtype serotonin receptor are involved in interaction with Grproteins and consist of the main molecular determinants responsible for serotonin signal transduction to adenylyl cyclase.

The extracellular level of neurotransmitter amino acids and total content of serotonin and its metabolite 5-HIAA were estimated by microdialysis in cerebellar vermis at different stages of habituation of the acoustic startle reaction (ASR) and conditioned freezing in a startle chamber prior to acoustic stimulation. An increase in GABA and serotonin levels was observed 10 min after training. Twenty four hours after training, glycine and glutamate levels increased, whereas serotonin and 5-HIAA contents decreased. Positive correlations were revealed between the GABA and glycine levels during training and characteristics of the freezing behavior during testing. Glutamate level during the test session positively correlated with the index of long-term habituation of the ASR orienting component. NMDA receptor antagonist APV applied on cerebellar vermis before training suppressed, whereas AM PA receptor antagonist CNQX enhanced the long-term habituation of the ASR orienting component. Under the same conditions, GABA receptor antagonists bicuculline and phaclofen suppressed the long-term habituation of the defensive ASR component and formation of the conditioned freezing behavior. Applied before training 5-HT antagonist ritanserin impaired long-term habituation of defensive ASR component and formation of conditioned freezing behavior, but its application 1 h before testing enhanced the habituation of the defensive ASR component without any effect on conditioned fear. The results testify to the involvement of glutamatergic cerebellar system activity predominantly in long-term habituation of orienting ASR component and participation of GABA interneurons and serotoninergic projections to cerebellum in the mechanisms of the long-term habituation of the defensive ASR component and formation of conditioned freezing behavior.

It has been shown that the isolation of sea urchin blastomeres before "pos-division adhesion" leads mainly to the formation of similar blastomeres at the stage of the 4th cleavage division, whereas after adhesion it results in the formation of micromeres simultaneously with intact embryos. Similar results were obtained in five sea urchin species. It has been concluded that there exists a critical point in the cleavage process, when blastomeres exchange information that determines further pattern of cleavage. It has been shown on this "micromere model" that serotonin and its analogues influence the cleavage pattern of half embryos. These data served as a basis for the hypothesis of "protosynapse", a double-sided symmetric structure in which both blastomeres are not only source and a target of the signal but also a passive obstacle for the leakage of the signal substance from the interblastomere cleft to the milieu. Such a structure is also able to provide the primary asymmetry of blastomeres. The micromere model may be useful in specific pharmacological screening.

The aim of the present work was an estimation of influence of chronic administration of 5-receptors antagonist--NAN-190 (0.1 mg/kg, i. p.) and 5-HT2A/2C receptors antagonist--ketanzerine (0.1 mg/kg, i. p.) for 14 days on anxiety and depressive-like behavior in the adult female rats. Model of depression in rats was carried out in Porsolt test. Anxiety level was assessed in the elevated plus maze. It was established that chronic ketanzerine administration rendered antidepressive and anxiolytic effects in females during estrous and proestrous cycles. On the contrary, NAN-190 administration induced a more profound effect on depressive-like behavior in estrous and proestrous cycles. Also, a definite modulation of anxiety behaviour in connection with ovary cycle phases was noted: at increased level of estrogens exerted anxiolytic effect while at reduced level of estrogen--anxiogenic effect. Different extent of 5-HT subtypes receptors involvement in the mechanisms of anxiety-depressive-like behaviur at alterations of hormonal balance during ovary cycle was found. The data obtained indicate a close interaction between ovary hormonal and serotonergic systems of the brain in mechanisms of anxiety and depression.

Effect of the antiserotonin drug cyproheptadine on the erythropoiesis has been studied under conditions of the administration of cytostatics (fluoropyrimidine antimetabolite 5-fluorouracil (5-FU), alkylating agent cyclophosphane) with different mechanisms of action. It is established that the antiserotonin drug significantly accelerates regeneration of the erythroid hemopoietic branch, especially in the case of 5-FU. The depression of erythron under the conditions of cyclophosphane injections was retained. The erythropoiesis-stimulating effect of cyproheptadine is based on the restoration of the structural and functional organization of the bone marrow (formation of erythroid hemopoietic islets).

The effect of serotonin on the formation of neurons producing gonadotropin-releasing hormone (GnRH) during embryogenesis of Wistar rats was studied. The neurons producing GnRH were detected immunocytochemically on days 18 and 21 of embryonic development and on day 15 of postnatal development of rats with normal serotonin metabolism and rats in which the synthesis of serotonin was inhibited by p-chlorophenylalanine. The total number of GnRH neurons in serotonin deficiency was larger than in the case of its normal metabolism at all developmental stages studied. This is an indirect evidence for the inhibitory effect of serotonin on the formation ofGnRH neurons. To confirm the morphogenetic effect of serotonin, we studied the rate of formation of GnRH neurons by injecting bromodeoxyuridine in the formation period of these neurons. It was found that serotonin deficiency had no effect on the time of formation of GnRH neurons: over 97% of neurons formed on days 11 to 15 of embryonic development both in the experimental and control groups. Note that, in serotonin deficiency, the maximum number of GnRH neurons formed one day later than in the normal state. Thus, serotonin inhibits the proliferation of GnRH neuron progenitor cells and thereby has a morphogenetic effect on the development of these neurons.

Effects of the peptide drugs selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) and tuftsin (Thr-Lys-Pro-Arg) on the metabolism of serotonin (5-hydroxytryptamine, 5-HT) in the brain of Wistar rats preliminarily treated with the 5-HT-synthesis inhibitor p-chlorophenylalanine (PCPA, 320 mg/kg, i.p., 4 days before experiment) have been studied on a group of 87 matured rats. It is established that selank enhances the 5-HT metabolism in the brain stem 30 min after injection to animals pretreated with PCPA. In contrast to selank, tuftsin induced no changes in the 5-HT metabolism in the brain stem and decreased it in the neocortex on the same time scale. The data obtained suggest that the peptide drug selank can be used for the correction of disturbances induced by a decrease in 5-HT metabolism.

The goal of this work was to study possible mechanisms underlying the potentiation of vasopressor response to serotonin observed in traumatic shock. Experiments with isolated aorta and mesenteric artery of the rat showed that vasoconstriction is caused by the activation of 5HT2A receptors. Agonists of 5HT1B, 5HT1D, 5HT2B, and 5HT4 receptors induced vasodilation. Agonists of 5HT1A receptors had a dual effect determined by interaction with alpha1-adrenergic receptors and 5HT1A receptors. Plasma membrane depolarization with 15 mM KCl increased the vasoconstrictive force in response to serotonin. This effect was determined by the ability of KCl to activate voltage-gated calcium channels, as a result of which the intracellular calcium stores are replenished. Inhibition of serotonin response by ketanserin, a 5HT2A receptor blocker, did not depend on the presence of 15 mM KCl. Constriction in response to serotonin was potentiated after its addition to vessels preconstricted with noradrenaline or endothelin-1. The constriction response partially retained in the presence of 2 x 10(-7) M ketanserin, which completely suppressed the serotonin-induced constriction of dilated vessels both at normal membrane potential and after plasma membrane depolarization. It can be assumed that noradrenalin and endothelin-1 alter the characteristics of 5HT2A receptors and possibly 5HT1A receptors as a result of their heterodimerization with the receptors for these vasoconstrictive hormones or interreceptor interaction at the level of signaling systems. Along with the potentiating effect of KCl, this mechanism may underlie the enhancement of vasopressor response to serotonin in shock.

The aim of this study was to test our hypothesis that the brain functions as an endocrine organ before the blood-brain barrier is formed. A model of drug-inhibited serotonin synthesis in the brain using a single stereotactic administration of p-chlorophenylalanine, an inhibitor of serotonin synthesis, was developed. The inhibitor dose inducing the maximum effect in the brain and no effect on serotonin synthesis in the periphery was experimentally selected. The concentration of serotonin and its metabolites (5-hydroxytryptophan and 5-hydroxy-indoleacetic acid) was studied by high performance liquid chromatography in the brain, duodenum, and blood (separately in plasma and platelets). The optimal p-chlorophenylalanine dose (200 mg/kg) was shown to induce a sharp decrease in the brain level of serotonin (70%), a moderate decrease in plasma (16%) and platelets (26%), and an insignificant decrease in the duodenum (12%). At the same time, this dose did not decrease the 5-hydroxytryptophan level in the intestine. This suggests that the decrease in the blood level of serotonin was due to the inhibition of its synthesis in the brain, whereas the decrease in the duodenum level of serotonin was due to the compensatory release to blood while its synthetic rate remained unaltered. Thus, the developing brain before the blood-brain barrier formation was shown to secrete serotonin into blood.

Effects of cycloheximide, protein synthesis inhibitors, as well as serotonin receptor antagonist and NMDA receptor antagonist on food aversion conditioning consolidation were studied in snail Helix lucorum. Food aversion conditioning was absent in snails after application of cycloheximide. Repeated produced no food aversion conditioning for the same type of food in these snails without cycloheximide application. Food aversion conditioning was absent in snails after applications of metiotepin, nonselective serotonin receptors antagonist, or after MK-801, NMDA glutamate receptors antagonist. At the same time, repeated training produced facilitated food aversion conditioning for the same type of food in these snails. Our experiments were the first which showed that effect on different molecular mechanisms evoked reversible or irreversible disruption of long-term memory consolidation during the same learning. It was suggested that suppression of retrieval produced reversible effect, whereas disruption of memory storage initiated irreversible effect on long-term memory consolidation.

Effects of cycloheximide, protein synthesis inhibitor as well as serotonin receptor antagonist and NMDA receptor antagonist, on food aversion conditioning consolidation were studied in snail Helix lucorum. Food aversion conditioning was absent in snails after application of cycloheximide. Repeated training produced no food aversion conditioning for the same type of food in these snails without cycloheximide application. Food aversion conditioning was absent in snails after metiotepin, nonselective serotonin receptors antagonist, or after MK-801, NMDA glutamate receptors antagonist, applications. At the same time, repeated training produced facilitated food aversion conditioning for the same type of food in these snails. Our experiments were the first which showed that effect on different molecular mechanisms evoked reversible or irreversible disruption of long-term memory consolidation during the same learning. It was suggested that suppression of retrieval produced reversible effect whereas disruption of memory storage initiated irreversible effect on long-term memory consolidation.

A series of new tropan derivatives have been synthesized and investigated, which can both weaken and potentiate the serotonin-induced cerebrovascular constrictory reactions. The compound LK-728 produces a pronounced antiserotonin cerebrovascular action comparable to that of tropoxin, but being superior to the reference drug in the effect duration. On the contrary, another tropan derivative LK-769 enhances the cerebrovascular response to serotonin. A similar effect was demonstrated with the well-known antimigraine agent sumatriptan, which is an agonist of 5HT1B/1D receptors. The ability of sumatriptan to increase the local cerebral blood flow which was observed in our experiments, may also play an important role in the mechanism of the antimigraine action produced by this serotonin receptor agonist.

A comparative study has been performed of dynamics of development of ectopic transplants of embryonal (E14) neocortex anlages obtained from intact rats and from the rats administered with serotonin inhibitor para-chlorophenylalanine (PCPA) at the 11th day of pregnancy as well as after incubation of such anlages in the serotonin-containing medium. The goal of this work was to elucidate effect of serotonin on division and differentiation of embryonal neocortex cells. Study of degeneration, mitotic activity, and differentiation (by using immunohistochemical detection of nerve cell nuclear protein--NeuN) of transplanted cells has allowed establishing that serotonin promotes survival and differentiation of transplant neuroepithelial cells as well as participates in regulation of their proliferation. It is suggested that serotonin produces stimulation effect on the cell cycle rate of transplantated cells to thereby accelerate neuronal differentiation.

Effects of serotonin or glutamate receptors antagonists on reactivation of food aversion conditioning were studied in snail Helix lucorum. Metiotepin (nonselective serotonin receptor antagonist, 0.1 mg/snail) or MK-801 (NMDA glutamate receptor antagonist, 0.005 mg/snail) were injected 24 hours after 3 days of food aversion conditioning, then reminding stimulus (banana, "conditioned" food) was presented and food aversion conditioning was tested. Long-term impairing (more then 2 weeks) of food aversion conditioning was found 3 hours after concurrent reminding and inhibitors injection. Injection of receptor antagonists without reminding stimulus did not influence on food aversion conditioning retrieval. Besides, in snails with amnesia after metiotepin/reminder, facilitation of repeated elaboration aversion conditioning on banana is revealed. The repeated training of snails with amnesia caused by MK-801/reminder did not result in food aversion conditioning. It is was suggested that 5-HT5,6,7 serotonin receptors are involved in mechanisms of memory "trace" extraction of food aversion conditioning, whereas NMDA glutamate receptor - in processes of its storage in snail.

Effect of serotonin (5-HT) deficit produced by administration ofp-chlorophenylalanine at a dose of 400 mg/kg to pregnant female mice on the day 8 of gestation and on the subsequent behavior of their offspring (hybrids F1 (C57BL/CBA)) was studied. The 5-HT deficit in prenatal ontogenesis leads to the following changes of behavior: 1) females and males of the experimental group show a higher level of the explorative activity in the "open field" than control animals; 2) in females of the experimental group at the age of 90 days, unlike control females and males of experimental and control groups, the explorative activity is extinguished at the threefold testing in the "open field"; 3) females of the experimental group have a decreased level of anxiety in tests "elevated plus-maze" and the "dark-light chamber". Males of the experimental group, on the contrary, have an elevated level of anxiety. The obtained data show that the 5-HT deficit at the prenatal period affects various aspects of behavior. The degree of the changes produced by the prenatal 5-HT deficit can have different manifestation depending on sex of the animals.

Intraperitoneal injection of para-chlorophenylanine (pCPA) (400 mg/rg) causes changes in the quantitative distribution of biogenic amines (BA), in olfactory bulbs, amygdaloid complex, hippocampus, and hypothalamus of the rats. Following 18 hours after injection of pCPA content of serotonine (5-HT) in olfactory bulbs drops and noradrenaline (NA) - 5-HT ratio increases. Abrupt decrease of 5-HT in all the studied structures and increase of NA - 5-HT ratio was also observed 36 hours after the pCPA injection. After 54 hours the drug effect decreased and by 72 hours the ratio was balanced. The biochemical changes taking place 36 hours after the intraperitoneal injection of pCPA in olfactory bulbs and hypothalamus probably cause concentration and ratio changes of BA, within the limits of which rats display their aggressive behavior and become "killers".

The role of peripheral 5-HT3 receptors in the nociceptive behavioral response and the effect of the 5-HT3 antagonist ondansetron on indices of acute and tonic pain were investigated in the formalin test in 25- and 90-day-old Wistar male rats. The experimental rats were prenatally exposed to 5-HT depletion (a single injection ofparachlorophenilalanine 400 mg/kg/2 ml, i. p.; ICN, USA to the dams on day 9 of pregnancy) and to stress (dams immobilization during the last week of pregnancy). Antinociceptive effects of ondansetron in the rats with both prenatal 5-HT deficiency and stress (experimental rats) and prenatal injection of saline solution and stress (control rats) were more obvious in the younger animals. Prenatal 5-HT deficiency attenuated the antinociceptive effect of ondansetron in licking patterns in the younder age group in acute pain, and in adults--in tonic pain. Thus, the data obtained in the rats with prenatal 5-HT deficiency and stress indicate involvement of 5-HT3 receptors in mediation of prolonged pain in the formalin test, and antinociceptive effect of ondansetron which is attenuated in animals with prenatal 5-HT deficiency and specifically depends on rat's age.

Selective dopamine (D) receptor agonists either slightly improve (D2 and D3) or do not affect (D1 and D4) the tolerance of the brain to global ischemia. As for D and 5-HT (hydroxytryptamine) antagonists, only D1 antagonist SCH 23390 and 5-HT2 antagonist ketanserin produce a small neuroprotective effect, while D2, D4, 5-HT(2B) and 5-HT(2C) antagonists are not active. Simultaneous injection of D2 (raclopride), D3 (GR 103691), and D4 (L 745870) receptor blockers also does not protect the brain. These results are not at variance with a widespread hypothesis that the accumulation of extracellular 5-HT and especially D in the brain causes the neuron damage. The effect of ketanserine is not increased by D2 or D4 blockers, but the introduction of D3 blocker GR 103691 (+88%) and especially the simultaneous injection of D2,3,4 antagonists improve the effect of ketanserine (+134%). The neuroprotective effect of the last combination is not lower but even exceeds that of some neuroleptics. This fact shows the possibility to increase the tolerance to cerebral ischemia by simultaneously blocking D and 5-HT-receptors.

The influence of chronic (14 days) administration of 5-HTIA receptors agonist--8-OH-DPAT (0.05 mg/kg, s.c.) and 5-HT(1A) receptors antagonist NAN-190 (0.1 mg/kg, i.p.) alone or in a combination with 17beta-estradiol (0.5 mg on each animal, i.m.) for on depressive behavior and expression of 5-HT(1A)-, 5-HT(2A)-, 17beta- estradiol receptors mRNAs was estimated in hippocampus in adult ovariectomized (OVX) female rats. The model of depression in rats was carried out in Porsolt test. The measurement of expression of 5-HT(1A)-, 5-HT(2A)-, 17beta-estradiol receptors mRNAs in the hippocampus was performed by semiquantitative RT-PCR. In Porsolt test 17beta-estradiol in OVX rats reduced time immobility to some extent. 8-OH-DPAT alone significantly decreased time immobility in OVX rats. Chronic 8-OH-DPAT administration in a combination with 17beta-estradiol in OVX females resulted in potentiated antidepressive effect. Simultaneously, 8-OH-DPAT induced significant increase of 5-HT(1A)-, 5-HT(2A)-receptors mRNAs expression and decrease of 17beta-estradiol receptor mRNA expression in hippocampus in OVX rats as compared to the control. The data obtained indicate a close interaction of the ovary hormonal and serotonergic systems of the brain in mechanisms of depression.

The effect of chronic (14 days) administration of the serotonin 5-HT(1A) receptors agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and the 5-HT(1A) receptors antagonist NAN-190 (0.1 mg/kg, i.p.) alone or in combination with the acetylcholinesterase inhibitor galantamine (1.0 mg/kg, i.p.) on depression and anxiety was studied in old (24 months) male rats with dementia of Alzheimer's type. The results indicated that chronic combined administration of 8-OH-DPAT with galantamine resulted in pronounced antidepressant and anxiolytic action.

The influence of the chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and the 5-HT1A receptor antagonist NAN-190 (0.1 mg/kg, i.p.) alone or in combination with 17beta-estradiol (0.5 microg per animal, i.m.) for 14 days on the depression behavior and the monoamine level in hippocampus has been studied in adult ovariectomized (OVX) female rats. The model of depression in rats was realized under the Porsolt test conditions. The levels of monoamine and its metabolites were determined using HPLC. It was established that the chronic administration of 8-OH-DPAT alone produces an antidepressant effect in OVX rats. The chronic administration of 8-OH-DPAT in combination with 17beta-estradiol potentiated the antidepressant action of both preparations. The antidepressant effect of 8-OH-DPAT in OVX rats was correlated with the restoration of noradrenergic, serotoninergic, and dopaminergic neurotransmission in the hippocampus. The obtained data are indicative of a close interaction between the ovarian hormonal system and the cerebral serotoninergic system in the realization of depression mechanisms.

Selective agonist of 5-HT1A receptors--8-OH-DPAT (1 mg/kg) induced a suppression of the immune reaction in aggressive male CBA mice immunized with SRBC (5 x 10(8)). In submissive mice with 10-day defeat experience in confrontation tests, the activation of 5-HT1A receptors with 8-OH-DPAT did not alter the immune response, whereas the application of selective antagonist of 5-HT1A receptors WAY-100635 increased the immune reaction only in submissive mice. It is concluded that activation or blockade of 5-HT1A receptors produced different effects on the immune function of CBA mice depending on the initial emotional state which is known to be provided in aggressive and submissive animals by different activities of the brain neurotransmitter systems including the 5-HTergic system.

Tetanic electric stimulation of Helix foot evokes sensitization of escape reaction. This behavioral sensitization and posttetanic potentiation (PTP) of acetylcholine-induced inward current (ACh-current) in command Helix neurons of escape behavior were similar. Antagonist of serotonin receptors methiothepin prevents the PTP of the ACh-current and behavioral sensitization. Serotonin disrupts the PTP of the ACh-current. It is suggested that the increase in cholinosensitivity of the command neurons with the involvement of methiothepin-sensitive serotonin receptors may be the cellular postsynaptic mechanism of behavioral sensitization of Helix escape reaction.

The effect of the new antimigraine drug tropoxin - the serotonin receptor (5-HT2) antagonist - on the human platelet aggregation in vitro induced by ADP (1 x 10(-5) M) and epinephrine (2.5 x 10(-6) M) was studied. Tropoxin reliably inhibited the ADP-induced platelet aggregation in a concentration range of 0.01 - 7 mg/ml. A significant inhibition effect with respect to the epinephrine-induced platelet aggregation was observed in a drug concentration range of 2 - 7 mg/ml, although a reliable antiaggregant activity was also observed below 2 mg/ml. A bolus administration of tropoxin (10 mg/kg) in rabbits decreased the ADP-induced platelet aggregation ex vivo by a factor of 1.2 - 1.4. The effect appeared 45 min after treatment and was observed during subsequent 30 min.

Experiments were performed on nembutal-narcotized rabbits. To study motor activity of the large intestine stimulation was applied to the right vagus nerve and left sympathetic trunk, as well as to the right pelvic nerve and left sympathetic trunk. We found a decreasing gradient of serotoninergic innervation from the ascending colon to the transverse colon and rectum (45-50, 30-35, and 25-30%, respectively) during simultaneous stimulation of the sympathetic trunk and vagus nerve and an increasing gradient of serotoninergic innervation in the large intestine during simultaneous stimulation of the sympathetic trunk and pelvic nerve. Stimulation of serotoninergic fibers was accompanied by arterial spasm in the microcirculatory bed and venous congestion.

We studied functional asymmetry in the innervation of smooth muscle organs (right and left ureter, and right and left fallopian tubes). Asymmetry in the innervation of the right and left ureter is provided by activation of the purinergic system. Asymmetry in the innervation of the fallopian tubes is determined by the purinergic and serotoninergic mechanisms.

Time-course of astrocyte appearance in the neocortex of F1 (CBA/C57B1) mice after prenatal serotonin depletion was studied. To suppress serotonin synthesis, para-chlorophenylalanine was administered to females once at the early postimplantation stage of gestation. To visualize differentiating astrocytes, the immunohistochemical method for demonstration of astrocyte intermediate filament protein--glial fibrillary acidic protein (GFAP) was used, which allowed not only to label the cells, but also to evaluate the starting point, extent and time-course of their differentiation. The results obtained have shown that in all the neocortical areas studied (area cingularis, area occipitalis, area parietalis, area insularis, area praepiriformis, area piriformis, area entorhinalis and area subiculum), normally, GFAP-positive cells appeared in the layer I at postnatal week 1. In the course of development, the process of astrocyte differentiation was shown to become progressively more intensive. At the same time, the process of barrier structures formation took place. During the first days of postnatal development astrocytes and their processes were shown to appear close to the blood vessels and lateral ventricle walls. In the neocortex of animals that developed during the serotonin depletion, GFAP-positive cells were formed in decreased numbers, in particular, in the white matter, at all the stages of postnatal development studied.