EARLY POSTNATAL DYSFUNCTIONING OF THE BRAIN MUSCARINIC CHOLINERGIC SYSTEM AND THE DISORDERS OF FEAR-MOTIVATED LEARNING AND MEMORY.

The aim of the study was to investigate the early postnatal dysfunctioning of the brain muscarinic cholinergic system as a major factor in the development of cognitive disorders similar with somewhat is noted in animal models of depression and in patients with Major Depressive Disease. The present study examined the processes of learning and long-term retention of information obtained in the two important tasks of non-declarative memory - active avoidance, motivated by foot shock-induced fear, and the elevated plus-maze, based on the natural fear.Experiments were carried out on male white wild rats (n=60). Four groups of animals (15 rats in each) were used with special procedures for each one. Early postnatal dysfunctioning of the brain muscarinic cholinergic system was produced by the new method worked out by Nachkebia and co-authors. Two-way shuttle-box and elevated plus maze devices were used for the investigation of fear-motivated non-declarative memory and anxiety.The lasting effects of early postnatal dysfunctioning of the brain muscarinic cholinergic system on non-declarative learning and memory and anxiety were studied for the first time in the present work. Following new facts were obtained: 1) This procedure produces in adult age initial impairment of learning in a non-declarative memory test that is based on the enhancement of the level of anxiety in both active avoidance and elevated plus maze tests; 2) Dysfunctioning of the brain muscarinic cholinergic system, in the period of early ontogenesis, does not change in adult animals the consolidation and long-term retention of information obtained in the two important tasks of non-declarative memory, active avoidance, motivated by foot shock-induced fear, and the elevated plus-maze, based on the natural fear; 3) Intraperitoneal injection of Scope in adult animals, subjected during early ontogenesis to the dysfunctioning of the muscarinic cholinergic system, reduce the level of anxiety and facilitates by this way learning and memory of natural fear-motivated non-declarative test. Early postnatal dysfunctioning of the brain muscarinic cholinergic system enhances the level of anxiety in adult age and complicates acquisition of information in fear-motivated non-declarative learning and memory tests, but does not change its consolidation and long-term retention.

CHARACTER OF THE CHANGES IN FEAR MOTIVATED DECLARATIVE MEMORY IN THE HIGH IMMOBILIZATION "DEPRESSIVE" RATS.

Present study investigated possible differences in the learning and memory of declarative memory task in rats selected according to the differences in immobilization response that is in high immobilization "depressive" and low immobilization "non-depressive" rats. Understanding the character of learning and memory disturbances in basal conditions of animal models of depression is still very topical for more intimate definition of the pathophysiology of major depressive disorder and appropriate searching the ways of its correction. Experiments were carried out on the adult white wild rats (with the weight 200-250 g, n=20). Selection of rats according to the level of immobilization was made by means of forced swim test. Learning and memory disturbances were studied using passive avoidance test that is fear motivated one trial declarative memory task. It was shown by us that 100% of low immobilization "non-depressive" rats remember painful stimulation and therefore they are not enter in the dark compartment during whole period of observation during testing session. Behavior of high immobilization "depressive" rats is not similar in passive avoidance camera; 50% of "depressive" rats, with long escape latency during training session (92±10 sec), remember painful stimulation during testing session and therefore they are not enter in the dark compartment during whole observation period. The remaining 50%, that are not differ significantly from the low immobility "non-depressive" rats by the latency of escape (5±1 sec) during training session, are not able to remember painful stimulation during testing session and therefore they enter in the dark compartment with shortest escape latency (6±1 sec). In conclusion, high immobility "depressive" rats perform passive avoidance declarative memory task at the chance level that is a direct indicator for the serious disturbances of declarative memory mechanisms in "depressive" rats selected in forced swim test according to the level of immobility.

HYPOTHALAMIC OREXINE SYSTEM ACCELERATES REGULATION OF SLEEP HOMEOSTASIS AND SLEEP-WAKEFULNESS CYCLE RECOVERY FROM BARBITURATE ANESTHESIA-INDUCED ARTIFICIAL SLEEP.

The work was aimed for the ascertainment of following question - whether Orexin-containing neurons of dorsal and lateral hypothalamus and brain Orexinergic system in general are those cellular targets which can accelerate recovery of disturbed sleep homeostasis and restoration of sleep-wakefulness cycle behavioral states from barbiturate anesthesia-induced artificial sleep. Investigation was carried out on 18 wild type white rats (weight 200-250gr). Different doses of Nembutal Sodium were used for the initiation of deep anesthesia. 30 min after barbiturate anesthesia induced artificial sleep serial electrical stimulations of dorsal or lateral hypothalamus were started. Stimulation period lasted for 1 hour with the 5 min intervals between subsequent stimulations applied by turn to the left and right side hypothalamic parts. EEG registration of cortical and hippocampal electrical activity was started 10 min after intra-peritoneal administration of Nembutal Sodium and continued continuously during 72 hour. According to obtained new evidences, serial electrical stimulations of dorsal and lateral hypothalamic Orexin-containing neurons significantly accelerate recovery of wakefulness, sleep homeostasis, disturbed because of barbiturate anesthesia induced artificial sleep and different behavioral states of sleep-wakefulness cycle. Hypothalamic Orexin-containing neurons can be considered as the cellular targets for regulating of sleep homeostasis through the acceleration of recovery of wakefulness, and SWC in general, from barbiturate anesthesia-induced deep sleep.

Influence of serial electrical stimulations of perifornical and posterior hypothalamic orexin-containing neurons on regulation of sleep homeostasis and sleep-wakefulness cycle recovery from experimental comatose state and anesthesia-induced deep sleep.

The work was aimed for the ascertainment of following question - whether Orexin-containing neurons of dorsal and lateral hypothalamic, and brain Orexinergic system in general, are those cellular targets which can speed up recovery of disturbed sleep homeostasis and accelerate restoration of sleep-wakefulness cycle phases during some pathological conditions - experimental comatose state and/or deep anesthesia-induced sleep. Study was carried out on white rats. Modeling of experimental comatose state was made by midbrain cytotoxic lesions at intra-collicular level.Animals were under artificial respiration and special care. Different doses of Sodium Ethaminal were used for deep anesthesia. 30 min after comatose state and/or deep anesthesia induced sleep serial electrical stimulations of posterior and/or perifornical hypothalamus were started. Stimulation period lasted for 1 hour with the 5 min intervals between subsequent stimulations applied by turn to the left and right side hypothalamic parts.EEG registration of cortical and hippocampal electrical activity was started immediately after experimental comatose state and deep anesthesia induced sleep and continued continuously during 72 hour. According to obtained new evidences, serial electrical stimulations of posterior and perifornical hypothalamic Orexin-containing neurons significantly accelerate recovery of sleep homeostasis, disturbed because of comatose state and/or deep anesthesia induced sleep. Speed up recovery of sleep homeostasis was manifested in acceleration of coming out from comatose state and deep anesthesia induced sleep and significant early restoration of sleep-wakefulness cycle behavioral states.

Changes of open field behavior in animal model of depression.

Animal model of depression was developed by means of chronic exposure of rat pups to anticholinergic drugs (Atropine, Scopolamine) during the early life period from postnatal day 7 (P7) and/or 14 (P14) to P21 and/or P28, respectively. Such procedure resulted in lasting behavioral changes that were evident long after drug discontinuation and persisted at mature age (2-3 month period). Behavioral changes included most indices of open field behavior. Modeled animals exhibited significant depression of locomotor activity certified by sharp reduction of the number of crossed squares, rising of a head and vertical standings. Grooming behavior was also significantly decreased. Frequency of center entrance and the time of staying in the center of open field were sharply shortened. Modeled animals exhibited complete loss of exploratory motivation which wasn't related to the enhancement of fear emotion so far as values of incidence of urination and defecation remained unchangeable. These findings indicate that postnatal exposure of rat pups to Atropine and/or Scopolamine induces lasting behavioral "despai"' or "refractory loss of interest" at mature age. In sum animal model of depression which are characterized by super sensitivity of brain muscarinic cholinergic system exhibit more depressed behavioral items in open field than other types of animal models of depression. These data imply the preference of muscarinic cholinergic super sensitivity for the development of depressive state and therefore they are very significant for both basic science and clinical research issues.

[The role of opioid system in the regulation of the sleep-wakefulness cycle].

In chronic experiments influence of single administration of various doses of morphine (0.5, 2.0 and 3.0 mg/kg) on general behavior, structural organization of the sleep-waking cycle and some EEG and somato-vegetative parameters was studied in the cats. Intraperitoneal administration of morphine elicits numerous autonomic disorders, psychic derangement and complete deterioration of the sleep-waking cycle structure. The result certify that single administration of morphine induces activation of the opiate receptors in various structures of the brain, which entails deviations of behavioral and EEG parameters, activation of the structures responsible for initiation of behavioral waking, suppression of activity in those structure, which control the slow wave sleep triggering mechanisms, deterioration of the sleep quality and significant elevation of emotional tension against the baseline. On the basis of obtained data it is suggested that the opioid system plays an important role in the sleep-waking cycle regulatory mechanisms and other forms of brain integrative activity in general.