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Using the method of quantitative immunohistochemistry, the expression of antiapoptotic protein Bcl-2 and neurotrophin BDNF was studied in CA1 hippocampal field of rats that survived severe hypoxia (SH), the damaging effects of which were compensated by subsequent three postconditioning (PC) sessions of mild hypobaric hypoxia (360 mm Hg, 2 hours, three times with 24 hour intervals). It was shown that the expression of the proteins studied was decreased in rat hippocampus after SH. Hypoxic postconditioning which improved the structural and functional rehabilitation after SH, was shown to up-regulate the expression of Bcl-2 and BDNF in hippocampal CA1 neurons in rats that survived SH. These results suggest the involvement of Bcl-2 and BDNF in processes of adaptation to SH and compensation of its damaging effects.

The effects of repetitive mild hypobaric hypoxic preconditioning upon pro- and antioxidant systems in rat hippocampus were studied. It was found that three-trial preconditioning by mild hypobaric hypoxia (360 mm Hg, 2 h) induced moderate oxidative stress immediately after the last preconditioning trial. In addition, it down-regualted the levels of peptide antioxidants (Trx-1, Trx-2, Cu,Zn-SOD) and several lipid peroxidation products 24 h later.

Hypoxic postconditioning using episodes of mild hypobaric hypoxia is a new neuroprotective technique. We compared the neuroprotective efficacy of hypoxic postconditioning and cerebrolysin in a model of posthypoxic pathology in rats. Animals that survived the severe hypoxia (180 Torr, 3 h) were exposed to hypoxic postconditioning or received cerebrolysin. Postconditioning prevented the injury and loss of hippocampal (fields CA1, CA4) and neocortical neurons whereas cerebrolysin was protective only for CA4 and the neocortex. Besides that, postconditioning, unlike cerebrolysin, led to the complete functional rehabilitation from the severe hypoxia by normalizing the level of anxiety and the pituitary-adrenal axis activity. The findings demonstrate that the elaborated postconditioning technique might provide useful tool for therapy of posthypoxic pathology and stroke.

Transcription factor NF-kappaB plays a pivotal role in mechanisms of brain neuron survival and degeneration under injurious stimuli, first of all different types of hypoxia. In the present work, using quantitative immunohystochemistry, we provide analysis of expression of different subunits of NF-kappaB (p65 and c-Rel) in the rat neocortex in response to severe injurious hypobaric hypoxia (HH) or after a single or multiple sessions of mild protective HH. Severe hypoxia (SH), resulting in loss of brain neurons, has no effect on the level of expression of p65 but suppresses expression of c-Rel. Multiple (but not single one) trials of preconditioning using mild HH which reduce neuronal damage promote p65 expression and prevent suppression of c-Rel level after SH. Triple session of mild HH itself when applied as a preconditioning stimulus upregulate expression of both subunits, while single administration or sixfold trials has no effect on the level of immunoreactivity of both subunits. The revealed peculiarities of the expression of p65 and c-Rcl implies that these subunits of NF-kappaB appear to contribute to the mechanisms of brain tolerance to SH.

Gluco- and mineralocorticoid receptors are believed to play important roles in mechanisms of the hypothalamic-pituitary-adrenal axis (HPA) regulation, neuronal death/survival, as well as learning and memory processes. Imbalanced levels of MR and GR result in impairment of HPA activity and can promote neuronal injury and loss following exposures to extreme factors. In the present study, using quantitative immunohistochemistry, the comparative analysis of the effects of hypobaric hypoxia in several modes on expression profiles of GR and MR in dorsal (CA1) and ventral (dentate gyrus) hippocampus was performed. According to the data obtained, severe injurious hypoxia induced prominent disturbances of GR and MR expression in the cells of CA1 and dentate gyrus that correlated to the remarkable neuronal injury/loss in CA1 and dysregulated HPA activity. Sets of three- or six-trial (but not one-trial) preconditioning using mild hypoxia prior to severe hypoxia prevented these abnormalities.

In the review, results of the long-standing authors'studies and literature data concerning one of the underresearched aspects of actual problem of induced brain tolerance to injurious factors - "preventive" signal function of the hypoxic preconditioning, as well as molecular and hormonal mechanisms underlying its protective effects are presented. Hypoxic preconditioning by using of mild hypobaric hypoxia in special mode mobilizes evolutionary acquired genome determined defense mechanisms of brain neurons and whole organism. This process involves an activation of multiple intracellular components, as well as hypothalamic-pituitary-adrenal axis. Cascade mechanisms of intracellular signaling including receptors, mitochondrial respiratory chain, key intracellular regulatory systems, early genes, superfamilies of the inducible and activation transcription factors are sequentially engaged in the processes of initiation, induction and expression of hypoxic tolerance. The determination of optimal modes of hypoxic preconditioning appears to be of significant importance to assure the effective activation of protective signal mechanisms.

Group I of metabotropic glutamate receptors (ImGluRs) are a family of G-protein-coupled receptors which activate a multitude of signaling pathways important for modulating neuronal excitability and synaptic plasticity as well as anti- and prosurvival pathways initiated by hypoxia. However these functions are still not complete and sometimes controversial. The present work is a review of data concerning involvement of ImGluRs in mechanisms of cell response to hypoxia. We also present original data demonstrating their participation in forming pathogenic and adaptogenic intracellular events, appearing in rat neocortex during a day after severe or moderate hypobaric hypoxia, respectively. Ca2+ responses to ImGluRs stimulation in survival cortical slices and expression of ImGluRs, IP3Rs and PLCbeta1 in immunolabelled cortical preparations were estimated for these two different hypoxic models.

Protective effects of the novel technique of hypoxic postconditioning with a hypobaric hypoxia paradigm were studied in "stress-restress" model ofposttraumatic stress disorder in rats. It was shown that repeated (3 times) exposure of rats that survived after severe traumatic stress to mild hypobaric hypoxia (postconditioning mode) efficiently abolished the development of stress-induced anxiety state. Postconditioning had a clear anxiolytic effect both when it was delivered after traumatic stress and after restress, but the intensity of this effect depended on the period ofpathogenesis of the posttraumatic stress disorder, when postconditioning was given. The results indicate that suggested postconditioning model with repetitive mild hypobaric hypoxia exerts potent anxiolytic and stress-protective action.

Hypobaric hypoxia may have either detrimental or adaptive effect on structural and functional characteristics of brain neurons. In this study, the effect of different regimes of hypobaric hypoxia on the structural and functional characteristics of hippocampal and neocortical neurons was examined in rats (n = 30). It was shown that severe hypoxia (induced by pressure in the pressure chamber equal to 180 Torr) caused structural neuronal damage both in the fronto-parietal neocortex and dorsal and ventral hippocampus 3 days after the exposure. The preconditioning using mild hypobaric hypoxia (pressure equal to 360 Torr) had varied effect on the morphological characteristics of brain neurons of rats, subjected to severe hypoxia. Multiple (three-trial or six-trial) preconditioning prevents structural damage of neurons induced by subsequent severe hypoxia. On the contrary, single preconditioning trial of mild hypoxia was ineffective in terms of neuroprotection.

This review includes results of own studies and literature data on the topical problem of neurobiology and medicine: discovery of the mechanisms of increased brain resistance to extreme exposures. The emphasis is made on the molecular-cellular and hormonal mechanisms of hypoxic preconditioning-induced brain tolerance to injurious hypoxia, psychoemotional and traumatic stress. A role of basic hormonal and intracellular cascade pro-adaptive processes mediating the neuroprotective action of hypoxic preconditioning is reviewed. A dynamics of the mechanisms of development of induced susceptible brain areas (hippocampus, neocortex) tolerance which includes phases of induction, transformation and expression, is presented. New data on preconditioning-induced cross-tolerance providing increased brain resistance not only to hypoxia but also to other stresses are reported. For the first time neuroprotective effects of hypoxic postconditioning are described.

The present study has been aimed to estimate a neuroprotective effect of postconditioning (PostC) by using mild hypobaric hypoxia (360 mm Hg, 2 h) in a model of severe hypoxic brain injury (180 mm Hg, 3 h) in rats. PostC was performed by three trials of mild hypoxia with 24 h intervals, according to two different protocols--PostC was started 3 h (early PostC) or 24 h (delayed PostC) following severe hypoxia. Using histological methods and computer image analysis, loss of neurons in hippocampus and neocortex was analyzed 7 days after severe hypoxia. Severe hypoxia caused loss of 24% of neurons in layer V of the neocortex, 26% of neurons in CA1 region of hippocampus and 22% of neurons in CA4 region. Early PostC prevented loss of neurons in CA1 region of hippocampus and significantly reduced loss of neurons in neocortex (to 13%) and in CA4 region (to 10%). Delayed PostC fully prevented neuronal damage in CA4 region of hippocampus and neocortex and was to a large extent but not completely protective in CA1 region (12% of neurons were lost). The results show that PostC performed by hypobaric hypoxia has a pronounced neuroprotective effect, reducing the loss of neurons in vulnerable structures of brain (hippocampus and neocortex). The efficacy of neuroprotection depends upon the time of presentation of the first PostC session.

We have previously shown that severe acute hypobaric hypoxia (SH) increases the expression of several endogenous antioxidants including thioredoxin-1 (Trx-1) in hippocampal neurons of rats. Preconditioning by three sessions of mild hypobaric hypoxia (MH) significantly augments this increase at the early period after subsequent SH, but MH itself without subsequent SH, in contrast, decreases expression of Trx-1. The dynamics of Trx-1 expression between the first and the last (third) sessions of preconditioning remains, however, unclear. In the present work, the previously studied Trx-1 expression in different areas of the hippocampus at hours 3 and 24 after thrice-repeated MH is compared to its expression at hours 3 and 24 after a single MH. It is shown that both a single and a thrice-repeated MH have similar effects on the Trx-1 expression. Since their neuroprotective effects in subsequent SH significantly differ, it is possible to conclude that hypoxic tolerance of neurons is determined not by the "background" level of antioxidants expression itself but has rather more complex regulatory mechanisms. These mechanisms may be associated with the wave-like oscillations of Trx-1 expression during preconditioning which was described in the present study.

There was studied effect of severe hypobaric hypoxia and subsequent reoxygenation on level and dynamics of lipid peroxidation in membranes of neocortex cells and in mitochondria-enriched neocortex fraction of non-preconditioned rats and of rats preconditioned thrice with a moderate hypobaric hypoxia. The threefold hypoxic preconditioning increasing brain resistance has been shown to significantly prevent disturbance of lipid peroxidation processes in neocortex--one of the most hypoxia-sensitive brain structures--and to modify development of these processes in mitochondria.

The purpose of this work was to study the dynamics of expression of mitochondrial Mn-dependent superoxide dismutase (Mn-SOD) 3 and 24 hours after single and triple exposure to mild hypoxia. The investigation was conducted in 18 male Wistar rats using immunocytochemical method. It was shown that in various hippocampal areas the effects of single and triple hypoxia exposure on the Mn-SOD expression could be different or largely similar. The expression dynamics at four time points studied (3 and 24 hours after the first exposure, 3 and 24 hours after the third one) had a wave character which may be important for the development of moderate hypoxia-induced tolerance to subsequent more severe exposures.

Activity of the phosphoinositide system of the intracellular signalization was studied in offspring of rats exposed to severe hypobaric hypoxia at the 14-16th (group 1) or the 18-20th day (group 2) of prenatal development. At the age of 15 days, in animals of both experimental groups the basal level of triphosphoinositides in the brain cortex was shown to be elevated as compared with control. In the group 1 this parameters also remains elevated in adult animals. Application of glutamate produces a more pronounced increase of the inositephosphates in brain sections of the 15-day old rats of the group 1 than in sections of animals of the control group. In the 15-day old rats of the group 2, as compared with control, the phosphoinositide response to glutamate application was reduced. No changes in the inositephosphate levels were revealed after application of glutamate upon sections of adult (the 90-day old) control animals and of adult rats of the group 2. In sections of adult rats of the group 1, on the contrary, the glutamate application produced an increase of the inositephosphate content. The obtained data indicate essential changes of the phosphoinositide metabolism in the brain of rats exposed to action of hypoxia at the period of prenatal development. The character and the degree of these changes depend on the period of development when the action of hypoxia occurs.

Hypoxia modifies glutamatergic signaling in the brain producing an increase of intracellular Ca2+ level. Depending on the power of survived hypoxia, degres and spatial-temporal profile of posthypoxic Ca2+ accumulation induce different Ca2+-dependent processes leading cells either to death or to hypoxia tolerance. To elucidate the specificity of different glutamate receptors involvement in these alternative processes the patterns of Ca2+ responses to stimulation of different subtype of ionotropic and metabolotropic glutamate receptors by their agonists were determined in perfused slices of piriform cortex obtained from the rats surviving either severe (pathogenic) or moderate (preconditioning) hypobaric hypoxia. It was shown that hypoxia of different modality modified Ca2+ responses of all tested receptor subtypes in different manner. The greatest difference was found for Ca2+ responses to stimulation of group I metabolotropic glutamate receptors.

In this study, by an immunocytochemistry it is established that development of the depression after an inescapable stress in the learned helplessness model in rats is associated with stable induction of the transcription factor NGFI-A in the dorsal hippocampus (CA1 field) and in the paraventricular hypothalamic magnocellular nucleus (PVNm), as well as with rapid and transient stress-induced expression of NGFI-A in the dentate gyrus and, supported on high level till 5 days, in the neocortex. Hypoxic preconditioning using mild repetitive hypobaric hypoxia (360 Torr for 2 hrs each of 3 days) prevented development of the depressive state in rats, and considerably changed the dynamics of the NGFI-A immunoreactivity in the hippocampus: the stable increase of an expression in the dentate gyrus and only transitory and delayed (for 5 day) in the CA1 field was detected. In the neocortex (Layer II) the stress influence was levelled with preconditioning by preventing the prolongation of the first wave of expression NGFI-A untill 5 days, and in PVNm, on the contrary, was stimulated the second (delayed) wave of an expression of this transcription factor. The pattern of NGFI-A expression in the hippocampus, neocortex and hypothalamus of preconditioned rats revealed an obvious pathological response to aversive stress, which results in development of depressive frustration rather than the adaptation. Stress-induced modifications of early gene product NGFI-A expression in the brain caused by hypoxic preconditioning, possibly, play important role in tolerance to hard psychoemotional stresses and may be an important part of antidepressive mechanisms.

Preconditioning using threefold mild hypobaric hypoxia (HH) is known to increase the tolerance of vulnerable brain neurons to severe hypoxia and other damaging factors. In the present study, the changes of the expression of transcription factors NF-kappaB (nuclear factor kappa B) and CREB (cAMP response element binding protein) were studied in the hippocampus of rats preconditioned by mild hypoxia. Using immunocytochemical method, it was demonstrated that HH increased NF-kappaB and phosphorylated CREB (pCREB) immunoreactivity in CA1-CA4 fields of the hippocampus and gyrus dentatus. It also contributed to the up-regulation of the expression of these transcription factors in the hippocampus of preconditioned rats 3-24 h following severe HH. These findings suggest that NF-kappaB and CREB are involved in HH-activated mechanisms of brain tolerance development.

The impact of mild hypobaric hypoxia on the development of anxiety-like state in rats in experimentally simulated human post-traumatic stress disorder was studied. Three-trial exposure to mild hypobaric hypoxia (360 mm Hg for 2 hours daily, for 3 days) in preconditioning or post-conditioning mode performed, respectively, before or after exposure to severe traumatic stress in the "stress-restress" model produced a significant anxiolytic effect on the rat open-field and plus-maze behavior. Anxiolytic effect of modem antidepressant Paxil (20 mg/kg daily, for 3 days) was weaker. This drug produced side-effects on particular behavioral characteristics in the open field. The conclusion was made on the efficacy of mild hypobaric hypoxia and the possibility of its implementation as a medication-free tool for prophylaxis and correction of post-traumatic stress disorder.

It was shown recently that preconditioning by 3-time repetitive mild hypoxia significantly augmented expression of thioredoxin-1 (Trx-1) antioxidant protein at 3 h after subsequent acute severe hypoxia in rat hippocampus as compared to the expression of this protein in non-preconditioned rats. However, it was unclear whether this augmentation was due to an accumulation of Trx-1 during the preconditioning before severe hypoxia or by a modification of reaction to severe hypoxia itself. To answer this question, Trx-1 expression level after preconditioning without subsequent severe hypoxia was studied in an experiment on 12 mature male Wistar rats. Trx-1 expression was studied by immunocytochemistry 3 h and 24 h after thrice-repeated mild hypobaric hypoxia (three 2h treatments at 360 Torr spaced by 24 h intervals). 24 h after the last hypoxic treatment, Trx-1 immunoreactivity was significantly decreased in the neurons of all the hippocampal regions studied (CA1, CA2, CA3 and dentate gyrus). In CA3 it was also decreased at 3 h after hypoxia. These findings indicate that mild preconditioning hypoxia, by itself, does not increase, but on the contrary, decreases Trx-1 expression. It may be concluded that the augmentation of Trx-1 content in the preconditioned animals is due to a modified reaction to severe hypoxia, but is not the result of Trx-1 accumulation during preconditioning.

The protective effect of hypoxic preconditioning on the development of depressive states in rat experimental models has been studied. Three-trial preconditioning by repetitive hypobaric hypoxia (360 mm Hg, 2h) prevented triggering of behavioral depression, pituitary-adrenal axis hyperactivity and impairment of negative feedback in dexamethasone test in rats following inescapable aversive stress in the model of endogenous depression. Anxyolytic and antidepressant-like effect of the hypoxic preconditioning was not less than that of tetracyclic antidepressant ludiomil. The findings reveal that the preconditioning by intermittent hypobaric hypoxia increases tolerance to psychoemotional stress, possesses potent anxiolytic and antidepressant-like effects and might be applied for prevention of depressive episodes.

The purpose of this study was to determine whether mild hypobaric hypoxic preconditioning provides protection against learning deficit caused by subsequent more severe hypoxia insult. Learning was examined using a passive avoidance task. Three groups of Wistar male rats: the intact and exposed to either severe hypoxia (160 Torr, exposition 3 h) or mild hypobaric hypoxic preconditioning (360 Torr, exposition 2 h, repeated three or six times daily) followed by severe hypoxia, were included in this study. In experiment 1 a passive avoidance response was acquired in 15 min immediately after hypoxia. In experiment 2 rats were exposed to hypoxia in 60 min after the acquisition of passive avoidance response. The mild hypobaric hypoxic preconditioning significantly attenuated the hypoxia-induced learning deficit in rats in Experiments 1 and 2. In experiment 1 the mild hypobaric hypoxic preconditioning repeated six times was more effective in protection against learning deficit in hypoxia exposed rats than in the case of triple mild hypobaric hypoxic preconditioning. The amount of rats suffered irreversible respiratory arrest was also assessed in this study. It was found that 50% of rats exposed to severe hypoxia died in consequence of this pathology, whereas in rats preconditioned before the severe hypoxia only 15% died for this reason. The overall results indicate that the mild hypobaric hypoxic preconditioning significantly increases CNS resistance to severe hypoxia in rats.

The effects of severe hypobaric hypoxia and preconditioned severe hypoxia on the expression of early genes products--proteins c-Fos and NGFI-A, and structural changes in rat hippocampal and neocortical neurons were studied using Nissl staining and immunocytochemistry. Severe hypoxia was found to induce a suppression of c-Fos and NGFI-A synthesis (at 3-24 h after exposure) and delayed (by day 3-7) destructive neuronal changes, which developed according to "light" and predominantly "dark" type, that obviously reflected necrotic or apoptotic processes, respectively. The preconditioning in the regime applied abolished these pathological changes, as expressed by stimulation of early gene products expression and marked reduction of neuronal damage following severe hypoxia.

The effects of the thiol oxidative agent 5,5'-dithiobis (2-nitrobenzoic acid) (DTNB) inhibiting NMDA receptors activity on changes of the evoked focal potentials generation (the NMDA and non-NMDA components EPSP) in response to long-term (LA) and short-term (SA) anoxic exposure which induced functional disturbances or promoted increasing of neurons resistance to LA, were studied on the rat olfactory cortex slices (Wistar-Kyoto). It was revealed that DTNB (200 mkM) effectively protected the depression of the EPSP generation induced by LA in the most tested neurons. In addition, DTNB eliminates the protective effect of the SA on focal EPSP generation evoked by LA. Nevertheless this dependence concerns the NMDA component and, to a lesser extent, the non-NMDA component EPSP. A possible role of changes of the NMDA receptor modulatory redox sites in mechanisms of functional disturbances and increasing neuronal resistance induced by hypoxic influences, is discussed.

A preventive short-term hypoxia (preconditioning) increases neuronal resistance against subsequent strong hypoxic effects. Literature review and authors' own data on molecular-cellular mechanisms of the hypoxic preconditioning, are presented. Participation of intracellular signal transduction, genome, stress-proteins, and neuromodulating peptides in this process, is discussed. The role of glutamatergic as well as calcium and phosphoinositide regulatory systems and neuromodulating factors as the components of a "volume" signal transmission are analyzed in hypoxic precondition-associated induction of functional tolerance mechanisms against acute harmful effects in neurones of olfactory slices.

The participation of NMDA receptors in the changes caused by evoked EPSPs in the activity of calcium and phophoinositide intracellular regulatory systems (ICRS) bioelectric activity (evoked EPSPs) and in cell production of polypeptides was studied in rat olfactory cortical slices exposed to short-term anoxia (STA) and long-term anoxia (LTA). To determine NMDA receptor involvement in these functional and metabolic reactions, the slices were treated with the antagonists APV and MK-801 during anoxia of different duration (STA and LTA being 2 and 10 min, respectively) and subsequent reoxygenation. EPSPs were recorded extracellularly in response to lateral olfactory tract stimulation. The STA-mediated stimulation of NMDA receptors was found to promote adaptive reactions (moderate activation of IRS, long-term potentiation of synaptic transmission) in the postanoxic period. LTA induced the long-lasting stimulation of NMDA receptors that led to the hyperactivation of calcium and phosphoinositide IRS, to the suppression of generation of EPSPs and of synthesis of polypeptides probably of adaptive action. All these events induced pathological processes in the postanoxic period.

Moderate long-term activation of intracellular regulatory system (IRS) was found to be manifested as an increase in the bound calcium content and intensity of the phosphoinositide metabolism following a 30-minute re-oxygenation in the rat olfactory cortex perfused slices. The perfusate induced a similar activation in intact slices-recipients. Long-term anoxia induced a biphasic NMDA-dependent increase in intracellular free Ca2+ and pathogenic hyperactivity of the IRS. The pathogenic events could be prevented by preconditioning of the slices by either short-term anoxia (STA) or post-STA donor perfusate.

Different chemical factors of the volume transmission were found to be of importance for the latter process: peptides as possible transporting substances for adaptogenic signals as they were involved in mechanisms of the brain adaptogenic responses, particularly to tetanic stimulation of the neurones and hypoxic stress. Substances secreted by donor-slice cells following tetanic and anoxic stimulation were found to exert an obvious effect upon synaptic transmission inducing a long-term potentiation and protecting it against functional disturbances. Mechanisms of interaction between synaptic and volume transmission signals, are discussed.

In the article literature data and results of our studying of long-term potentiation (LTP) are analyzed the position of the proposed hypothesis that cells secrete during their activation into extracellular space a neuromodulatory factors, affecting on cell population and promoting the transformation of short-terms excitability in long-term one. It is considered the possible molecular-messengers particulated in development LTP. The neurophysiological and neurochemical evidences of the involvement neuropeptides as the key retrograde messengers are presented. It is analyzed the biological assay method as the adequate approach for study the role of endogenous neuropeptide in the LTP and analogous models. The possible mechanisms acting of neuropeptide by cells in LTP genesis are discussed.

Serotonin (5-HT) application (10 mcM) onto L-PPl1 neurons of the pleural ganglia of land snail Helix lucorum produced the synaptic facilitation of the neuronal response evoked by sensory stimulation. At the same time, it did not change the parameters of the neuronal membrane (resting potential and membrane excitability). In addition to synaptic facilitation, the higher 5-HT concentration (100 mcM) produced an increase in membrane excitability and a slight membrane depolarization. The 5-HT effects were modality-dependent: the duration of facilitation of the response evoked by tactile stimulation of the snail head was about 1 h while that of the response evoked by quinine application (0.3% solution) onto the snail lip was 2-3 h. The 5-HT effects were site-specific: its application facilitated only the neuronal responses evoked by tactile stimulation of the snail head but not other body sites. The dynamics of the electrophysiological effects and the level of bound calcium were similar in L-PPl1 neurons. The described neuronal effects resemble those observed after the nociceptive sensitization of these neurons. The data obtained suggest the 5-HT involvement in the mechanisms of short-term changes and consolidation of long-term plasticity underlying the sensitization in Helix L-PPl1 neurons.

The review of literature data is presented on the problem molecular and cellular mechanisms of learning which is intensely studied for last decade using the long-term potentiation (LTP) model in the brain slices in vitro. The main attention is paid for molecular mechanisms of LTP induction and supporting phases in hippocampal structures on the pre- and postsynaptic levels especially for the involvement of transmitters and retrograde messengers in these processes. The role of protein kinase-dependent proteins phosphorylation and of peptides synthesis expression in the LTP development is discussed. The perspective directions of complex investigation of LTP molecular mechanisms are outlined which are useful for understanding the whole picture of neuronal plasticity lying it the basis of learning and memory processes.

Stimulation of glytamate- and cholinoreceptors by the agonists induced a prolonged calcium and phosphoinositide responses to short-term anoxia or administration of an antioxidant agent in cortical structures. Processes of adaptation essentially modified these responses.

Responses to a 5-min anoxia were studied in cats with different taste sensitivity for phenilthiocarbamide (PTC). The sensitive animals were more resistant against hypoxia. The difference in the cats seems to be determined by the condition of the cAMP system involved in adaptive responses.

Recovery of unit activity was studied after a 5-min anoxia following a short-term anoxia in the cat brain cortex. The short-term anoxia's protective effect was only revealed in case when it had induced the phenomenon of asphyxic hyperactivity. The protective effect seems to be due to the short-term anoxia-induced changes in the calcium, polyphosphoinositide and cAMP regulatory systems' activity.

During a 2.5-min. hypoxia in monkeys, a rearrangement of the unit activity occurred in the visual and prefrontal cortex. Following this, the motor response in delayed visual spatial reaction tack did not restore during several hours. The rearrangement involved appearing of sequential phases of hyperactivation and inhibition. Duration of the posthypoxic inhibition and ratio of posthypoxic hyperactivation frequencies to the background one were significantly greater in the prefrontal cortex than in the visual one.

Changes in the intracellular bound calcium, polyphosphoinositides and cAMP were studied during 60 min. of recovery after 50-90 s of anoxia in the cat cerebral cortex. Different changes of the intracellular regulatory system's components were revealed in the reoxygenation period.

The effects of paraoxon (1.5-4.5 LD50) on the levels of intracellular regulatory components, such as membrane-bound calcium (Ca(b)) and polyphosphoinositides (PPI) were studied along with microcirculation and neuronal bioelectric activity control in the feline cerebral cortex. There was a relation between these parameters, which supports the important role of Ca(b) and PPI in the mechanism of paraoxon's neurotoxic action. Taking into account the findings, it is advisable to use a complex of drugs in organophosphate intoxication, which will correct the mechanisms of intracellular signal transduction.