ACQUISITION AND CONSOLIDATION OF TWO-WAY ACTIVE AVOIDANCE IN THE HIGH IMMOBILIZATION "DEPRESSIVE" RATS.

Present study investigated possible changes in acquisition and consolidation of associative memory in high immobilization "depressive" and low immobilization "non-depressive" rats. Question is very topical because understanding the character of learning and memory disturbances, one of symptoms of major depressive disease, is very significant for more intimate definition of the pathophysiology of major depressive disorder and appropriate searching the ways of its correction. Selection of rats according to the level of immobilization was made by means of forced swim test. Learning and memory disturbances were studied using two-way active avoidance test that is fear motivated multi trial associative memory task. It was shown that ability to avoid/escape an aversive event by learning to perform a specific behavior, in response to a stimulus cue, is retained at the high level in high immobility "depressive" rats, selected by forced swim test. Acquisition of new information about an aversive stimulus is significantly facilitated and processes of consolidation are realized without any impairment. Thus, acquisition and consolidation of associative learning and memory is not impaired in high immobility "depressive" rats in two-way active avoidance task.

The character of sleep disturbances produced by multiple administrations of atropine the antagonist of brain muscarinic cholinergic system.

Modification of brain muscarinic cholinergic system normal functioning can be considered as an appropriate strategy for the study of its role in sleep-wakefulness cycle basic mechanisms in general and in the course/maintenance of PS in particular. For this aim systemic application of muscarinic cholinoreceptors antagonists is significant because it gives possibility to modify functioning all of known five sub-types of muscarinic cholinoreceptors and to study the character of sleep disturbances in these conditions. Problem is very topical because the question about the intimate aspects of BMChS involvement in PS maintaining mechanisms still remains unsolved. In cats Atropine systemic administration was made once daily at 10:00 a.m. and continuous EEG registration of sleep-wakefulness cycle ultradian structure, lasting for 10 hour daily, was started immediately. In sum each animal received anti-muscarinic drugs for 12 times. Thereafter drug administrations were ceased and EEG registration of sleep-wakefulness cycle ultradian structure was continued during 10 consecutive days. On the basis of results obtained in these conditions we can conclude that brain muscarinic cholinergic system normal functioning is significant for basic mechanisms of sleep-wakefulness cycle. During wakefulness, at the level of neocortex and hippocampus, MChS supports only EEG activation, while it is one of the main factors in PS triggering and maintaining mechanisms.

Changes of locomotor, exploratory and emotional behavior in animal model of depression induced by deficiency of brain monoamine content.

The character of changes of open field behavior was not studied extensively in animal model of depression with deficiency of brain monoamine/serotonin content and obtained results are controversial. Both, enhancement and invariability of locomotor activity has been obtained. Additional investigation of this question is motivated also by insufficient study of exploratory and emotional behaviors in animal model of depression of this type. Animal model of depression was developed by chronic administration of Clomipramine and/or Melipramine in rat pups from postnatal day 7 (P7) and/or 14 (P14) to P21 and/or P28, respectively. Studies of open field behavior were started in adult age rats i.e. 8-12 weeks after the end of treatment. Control animals were the same age old. Two-week period of postnatal development starting at the P7 and/or P14 appeared equally sensitive to early antidepressant treatment. Modeled animals exhibited significant increase of horizontal locomotor activity. Frequency of center entrance and the time of staying in the center of open field were increased significantly indicating that animal models of depression can not percept really the level of stressfulness of novel surroundings. All of these changes indicate also to the significant level of exploratory behavior in modeled animals. Postnatal exposure of rat pups to Clomipramine or Melipramine produces significant increase of locomotor activity but dos not induces behavioral 'despair' or "refractory loss of interest" at mature age.

Effects of trihexyphenydil, the structural analog of phencyclidine, on neocortical and hippocampal electrical activity in sleep-waking cycle.

Finding about structural and functional relation between NMDA receptors specific binding and phencyclidine sites was very important for a possible modulation of NMDA receptors' function. We have therefore got interested what would happen with EEG and vegetative patterns of PS in the case when NMDA receptors function is modulated by blocking of phencyclidines' site. Consequently, we studied the effects of Trihexyphenydil, the structural analog of phencyclidine, on neocortical and hippocampal electrical activity in SWC. On cats (n=5) metallic electrodes were implanted under Nembutal anesthesia. EEG registration lasting 12 hr daily started after animals' recovery. Trihexyphenydil was administered intraperitoneally (0.5 mg/kg - 1 mg/kg). Statistical processing was made by Students' t-test. Trihexyphenydil resulted in dissociated triggering of PS. Rapid eye movements and PGO waves appeared on the face of active waking state. Therefore on the background of behavioral active waking according to electrical activity of the visual cortex and rapid eye movements, electrographic patterns of paradoxical sleep were recorded. Thus in our experiments it was shown firstly that the mechanism of hallucinogenic action of Trihexyphenydil is closely related to the disturbance of paradoxical sleep integrity. Blocking of NMDA receptors phencyclidines site and therefore functional modulation of these receptors produce the splitting of PS patterns and their intrusion in waking state. Such an effect never takes place in normal conditions since the waking system has the powerful inhibitory influence on the PS triggering system. Suggestion is make that NMDA glutamate receptors must be involved in mechanisms providing structural and functional integrity of PS and that fulfillment of such function is possible in the case when the NMDA receptors phencyclidine site isn't in blocked state. Normal functioning of NMDA receptors phencyclidine site represents the mechanism which inhibits and/or hampers appearance of hallucination. NMDA glutamate receptors, possessing phencyclidine site, are implicated in the mechanisms providing structural and functional integrity of PS.

Influence of diazepam on different behavioral states of sleep-waking cycle.

Diazepam is a widely used benzodiazepine. Their prolonged usage leads to deterioration of cognitive functions and to the reduction of the level of vigilance what is explained by hypnotic effect but not by anxiolytic action of this drug. The novelty of our investigation is the elucidation of whether diazepam produces slow wave sleep reduction likely to the other benzodiazepines and if so what is the bases of positive therapeutic effect of diazepam in insomniac patients. For this aim we decided the study of diazepam effects on the ultradian structure of sleep-waking cycle. On cats (n=5) metallic electrodes were implanted under Nembutal anesthesia. EEG registration lasting 12 hr daily started after animals' recovery. Diazepam was administered intraperitoneally (0.37; 0.75; 1.5; 2 mg/kg). Statistical processing was made by Students' t-test. Diazepam prolonged sleep onset latency and waking overall time. Incidence and overall percentage of deep slow wave sleep decreased significantly but doze dependently. Paradoxical sleep latency was also significantly increased after diazepam action. All dozes of drug used by us significantly decrease the duration of each episode of paradoxical sleep. Diazepam significantly increase incidence of paradoxical sleep episodes with maximal duration till to 5 min. Under the influence of diazepam paradoxical sleep coursed without emotional coloring, without any patterns reflecting the level of emotional tension during this phase. The first episode of paradoxical sleep with partial restoration of patterns of emotional tension developed after 9+/-2 postinjectional hours at the 2 mg/kg doze of diazepam. All parameters reflecting the level of emotional tension during paradoxical sleep wholly recovered after 27+/-2 hour of diazepam administration. Diazepam administration worsens the quality of slow wave sleep. It is suggested that positive therapeutic effect of this drug may be related with the reduction of emotional tension during paradoxical sleep and modulation of behavioral and EEG patterns of this behavioral state.

Septo-hippocampal cholinergic/gabaergic relationship and sleep-waking cycle.

There is controversy in the literature in the results of various septal lesions on the sleep-waking cycle (SWC) ultradian structure. Current investigation was aimed to study the effects of interruption of septo-hippocampal cholinergic/GABAergic afferentation on the ultradian structure of SWC and on PS major indices. Experiments were carried out on 12 adult cats, operated under overall anesthesia (Nembutal, 35-40 mg/kg). Three groups of animals were used: I. Implanted sham lesioned control; II. With isolated lesion of medial septal part; III. With combined lesion of medial and lateral septal parts. Lesion was made by passing of direct current. Continuous EEG registration of SWC was lasted 12 hour. Results were evaluated statistically with Student's t test. Isolated lesion of medial septum doesn't produce significant changes of motivational-emotional behavior, but combined lesion of medial and lateral septal parts lead to enhancement of food and water motivation, development of hyper emotionality and hyperactivity. Interruption of septo-hippocampal cholinergic/GABAergic input, increased sleep onset latency, incidence and percentage of active waking (AW) and passive waking (PW) and PS latency but the last effect was dependent from sleep latency change. In the period from appearance of first PS episode to the end of EEG registration PS incidence and percentage wasn't changed significantly. This surgery completely abolished theta rhythm in waking and PS. Combined lesion of medial and lateral septal parts increased sleep latency still more. Total time of AW and PW increased twice. DSWS was significantly decreased. In this case PS latency was also increased still more. PS incidence and total percentage in whole 12 h registration period were reduced substantially, but for the period calculated after appearance of first PS episode until to the end of EEG registration PS mean value was the same as in sham lesioned animals. It is concluded that: 1.Septo-hippocampal cholinergic/GABAergic relationship doesn't play significant role in the triggering mechanisms of SWC ultradian structure; 2. GABAergic part of this input as well as hippocampo-mesodiecephalic descending pathways through the lateral septum have powerful modulatory influence on basic triggering mechanisms of SWS; 3. Development of hippocampal theta rhythm is the only event of PS affected after medial septal lesion; 4. Septo-hippocampal cholinergic input is not essential in triggering mechanisms of PS.