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REM SLEEP FUNCTION AND BRAIN MONOAMINE REGULATION:
AN APPLICATION OF THE SEARCH ACTIVITY CONCEPT

Vadim S. Rotenberg   vadir@post.tau.ac.il
Abarbanel Mental Health Center, Tel-Aviv University, Israel

SLEEP AND SLEEP DISORDERS: A NEUROPSYCHOPHARMACOLOGICAL APPROACH, EDITED BY MALCOLM LADER, DANIEL P. CARDINALI AND S.R. PANDI-PERUMAL. 2006 LANDES BIOSCIENCE/EUREKAH.COM AND SPRINGER SCIENCE+BUSINESS MEDIA..

The present chapter contains the discussion of the very complicated and controversial topic of brain monoamines activity in REM sleep in relationships with the main REM sleep functions. The author is going to present many contradictory experimental data in this area. He will make an attempt to overcome at least some of these contradictions by using the search activity concept that prescribes to REM (paradoxical PS) sleep a function of the restoration of search activity that determines subject's resistance to stress and various noxious factors. It is for this reason one of the main features of the behavior of highly developed species.

Activity of the Monoamines Containing Neurons in REM Sleep

The sleep-wakefulness cycle is characterized by a very definite dynamic of the discharge of cell groups of the central nervous system from wakefulness through nonREM (NREM) sleep to REM sleep. Active waking and REM sleep are characterized by very similar (high) discharge rates of most cell groups in neocortex and different subcortical and brainstem areas in contrast to quiet waking and NREM sleep where the same cell groups display a low activity (see also review of ref. 90).89,97. While this similarity between active waking and REM display the main tendency in brain neuronal activity, some cell groups in the brainstem are active only during REM sleep (REM-on cells35,80,89). According to the data of lesion stuthes it is possible to suggest that REM-on cells are strongly related to the generation of REM sleep with all its significant physiological features. However, whether these REM-on cells are responsible not only for the phenomenology of REM sleep but also for REM sleep functions remains an open question. There is some evidence that it is the frontal lobe that is related to the production of REM sleep dreams and consequently may relate to the behavioral and psychological REM sleep functions.

Some other cell groups are active during all types of waking behavior and, on the relatively lower level, also during NREM sleep. However they are almost totally inactive during REM sleep (REM-off cells).18,30,42,59. All these REM-off cell groups are either noradrenergic or serotonergic88, and that is especially important for the topic of the present chapter. Moreover, these REM-off cells are concentrated in the main brain sources of the noradrenergic and serotonergic activity in locus coeruleus (LC) and in the midline raphe. It means that noradrenergic and serotonergic activity is present in all main functional states (in active and quiet waking and in NREM sleep) except REM sleep and is especially high in active wakefulness the latter being similar to REM sleep according to the discharge rate of most brain neurons that are acethylcholinergic in their nature 23. REM-off noradrenergic and serotoninergic cells do not seem to be responsible for the REM sleep phenomenology because the depletion of norepi-nephrine (NE) and serotonin (5-HT), by the electrolytic lesion of the LC and raphe nuclei does not prevent REM sleep as a physiological phenomenon. 14, 28,33,93. However, it does not mean that such lesions and depletion has no effect on the REM sleep functions. For instance, ponto-geniculo-occipital (PGO) spikes that are normally tied to REM state, correspond in wakefulness to orienting activity 39 and consequently may relate to REM sleep psychological functions (see ref. 68) became released into all states after lesion of 5-HT containing neurons 93. There are data (see ref. 85) that serotoninergic neurons are related to the regulation of saccadic eye movement.

Thus, REM sleep differs from wakefulness according to the low activity of noradrenergic and serotoninergic neurons. REM sleep represents the functioning of the cortex without the influence of norepinephrine 27 and it is reasonable to suggest that such low activity may in some way relate to the peculiarity of REM sleep functions or to the regulation of REM sleep in different functional conditions. 90 At the same time, the mesencephalic dopamine containing neurons discharge on the equal rate in wake-fulness and in all sleep stages. 23 According to Siegel and Rogawski 90 it means that dopamine containing cells have no essential role in sleep generation or in sleep functions. However, if from all monoaminergic neurons only dopaminergic neurons are continuously active in REM sleep, this activity has probably a special meaning and relates to the peculiarity of REM sleep functions.23

Monoamines Containing Neurons in Wakefulness: Towards the Functional Meaning

Gottesmann 23 has reviewed the role of different neurotransmitters in waking activity. According to this review, making the long story short, acetylcholine (Ach) is responsible for the general activation of cortical neurons initiated by the reticular activating system of the brainstem. 37. This general nondifferentiated activation of the cortex is important for maintaining stable tonic vigilance and preventing coma. Atropine, an antagonist of acetylcholine, produces EEG slow waves a state opposite to vigilance.105. However, a general cortical activation promoted by acetylcholine is only a nonspecific predisposition to the goal-oriented selective activity that requires differentiation (discrimination) between meaningful and meaningless information elicited by the environment. Such discrimination is based on the partial flexible inhibition of cortical neuronal activity and as a result - on the increase of the signal-to-noise ratio that makes neuronal activity task-relevant. NE and 5-HT in wakefulness are responsible for this partial cortical inhibition 27, 108. Thus, mental functioning during the waking state depends upon two types of neurotransmitters 23: activators which support the general mobilization of cortical functions, and inhibitors controlling and modulating this activation in order to make mental functions flexible and relevant to the task.

Dopamine in the normal waking brain plays an important role in motivational processes providing "reward" and "reinforcement", and in novelty seeking that includes exploratory behavior, attention, exhilaration and excitement in response to novel stimuli.8,10,15,23,36. According to Wise et al. 107 and Wise and Colle 106 dopamine mediates naturally rewarding experiences (like pleasure from food, sex, drugs). However it is involved not only in appetitive events and in an approach behavior but also in aversive ones 81,82. Paradoxically, such aversive behavior in some of its aspects seems to be attractive for the subject and does not contradict to the general concept of "reinforcement". In this context it is possible to ascribe rewarding experiences also to the dopamine dependent psychotic symptoms like hallucinations and delusions that are very resistant to any treatment except for the antagonists of DA receptors 32. According to some recent investigations 96 in the cortex, and especially in the frontal cortex DA transporters are under the strong modulating influence of NE nerve terminals while in basal ganglia NE has a little regulatory role for DA. NE reuptake blocker increases not only NE but even in a more prominent way DA concentration in the cortex and only NE in subcortical area.

Rem Sleep: Resensitization of the Postsynaptic Noradrenegic Receptors?

REM sleep state is unique according to the complete cessation of the noradrenergic LC cells activity. It is reasonable to believe that such cessation has a special physiological meaning, and Siegel and Rogawski 90 were the first who proposed a coherent and comprehensive theory of this topic. These authors hypothesized that the inhibition of activity of the NE containing cells in REM sleep is required to maintain the sensitivity of NE postsynaptic receptors, with consequent benefits for all types of behavior in wakefulness that utilize these receptors. During wakefulness all adaptive forms of behavior have to be flexible and require constant activity of the noradrenergic system. Such almost nonstop activity is unavoidably leading to the desensitization of the NE postsynaptic receptors, and this negative feedback finally causes the decrease of the NE system efficiency. REM sleep that appears with regular intervals provides this system with an opportunity to restore its functional activity without interference with the ongoing waking behavior. Siegel and Rogawski hypothesized that NE release sets in motion two processes having opposite effect on REM sleep duration. In the first process, NE release or its functional enhancement suppresses or "substitute" for REM sleep by increasing the activity of negative feedback circuits monitoring the efficiency of NE receptor action. In this step, the noradrenergic system is active and does not require REM sleep for its restoration. In the second process, the release or potentiation of NE action is hypothesized to downregulate/desensitize NE receptors, this downregulation producing the increased REM sleep pressure. Thus, according to this concept, the cessation of NE cells activity in REM sleep actually contributes to the activity of the noradrenergic system. The evidence confirming this point of view can be found in Siegel and Rogawski. Much more important and relevant is to consider and to discuss numerous data that seem to contradict this theory.

    1. Depression in humans and learned helplessness in animals 88 are characterized by the stable reduction of monoamine (NE and 5-HT) transmission in brain synapses. Thus, according to the theory it would be reasonable to expect the decrease of REM sleep requirement in these states as an outcome of the already established chronic sensitization of the postsynaptic noradrenergic receptors. However, according to Adrien et al. 1 there is a positive correlation between experimentally induced learned helplessness and percentage of paradoxical (REM) sleep. The increased REM sleep pressure in depression is shown by the reduction of REM sleep latency, a relative increase of REM sleep in the first cycle, an increased number of the short sleep cycles, and by the absence of the first night effect.11,40,61,78,79. Healthy long sleepers are characterized by the relatively increased REM sleep 27 and at the same time by the inclination toward subdepressive reactions 103. A disposition to depressive reactions is also characteristic of narcoleptic patients who show a constantly high REM sleep requirement 9. When the level of depression is moderate, an increased REM sleep requirement realizes itself in the increased REM sleep. The relationship between the severity of depression and REM sleep is nonlinear 66: when the MMPI scale D (depression dominate) and does not exceed 75 T points REM sleep grows longer (compared to the magnitude of this scale of up to 65 T points). When the scale gets higher, REM sleep becomes reduced. Thus, before depression starts to destroy sleep structure, it determines a tendency towards REM sleep increase. From my point of view, all these data do not correspond to the Siegel and Ragowski theory.

    2. Reserpine treatment causes a depletion of NE 87 but produces elevation of REM sleep. Siegel and Ragowski 90 explain this REM sleep elevation as an attempt to upregulate NE receptors in response to NE depletion. However, this explanation looks circular: REM sleep is characterized by the marked reduction of noradrenalin cells activity and such reduction has to overcompensate NE depletion.

    3. It was shown in many investigations, that antidepressants monoamine oxidase inhibitors (MAOI) that enhance the noradrenergic transmission in synapsessuppress REM sleep for the all period of prescription in animals, in healthy subjects and in depressed patients 17,31,41,64. This period of prescription can take a few weeks. According to the theory we are discussing, it was possible to expect not a decrease but rather an increase of REM sleep because of a long-lasting and intense stimulation of the noradrenergic system. Siegel and Ragowski are aware of this contradiction. They suggest that the process of NE receptors downregulation caused by enhanced NE transmission can take from few minutes to few weeks. However, from our point of view such time course is too broad for this micro-physiological process and instead of making such proposition it is more reasonable to search for another explanation.

    4. In the frame of the discussed theory, it seems difficult to explain some data of partial REM deprivation by using awakenings in REM sleep. If after momentary awakening, animals were maintained in a condition of active and emotional wakefulness (i.e., wakefulness based on the enhanced noradrenergic activity) neither the accumulation of REM need nor the postdeprivation REM rebound appear 13, 51. It is necessary to take into consideration, that REM sleep was already reduced before awakenings and nevertheless fragments of active wakefulness were able to satisfy the accumulated REM need.

    5. Siegel and Rogawski predicted that the sensitivity of all LC innervated postsynaptic NE receptors should be reduced by prolonged sleep/REM sleep loss. However, Tsai et al. 98 have shown diat density and affinity of adrenergic binding sites did not decrease after 10 days of total sleep deprivation. Thus sleep deprivation made no expected changes in central NE receptor regulation.

In spite of all these contradictions, we do not conclude that the theory of Siegel and Rogawski is not relevant at all. The cessa-rion of the activity of noradrenergic cells in REM is a fundamental fact that needs explanation, and the resensitization of the postsynaptic noradrenergic receptors may be a real task of such cessation. However, the abovementioned contradictions show that this theory has limitations and is probably relevant only in some particular conditions, and, secondly, that it is not an exhaustive one and has to be supplemented by additional suggestions of REM sleep functions related to the monoamine activity that may be helpful in solving contradictions.

Search Activity Concept, REM Sleep Functions and Brain Monoamines

I suggest search activity (SA) concept to represent such a supple-mentarytheory.65,68,74.

By search activity is understood activity designed to change the situation or the subject,s attitude to it in the absence of a definite forecast of the results of such activity (i.e., in the case of pragmatic indefiniteness), but with constant monitoring of the results at all stages of activity. This definition makes it clear that certain behavioral categories cannot be classed with search behavior. This primarily applies to all forms of stereotyped behavior having a quite definite forecast of results. Panicky behavior at first sight may seem to imitate search behavior but differ from it by the disturbance of the feedback between the activity and its regulation. During a panic the results of the activity are not considered at any stage and cannot be used for the correction of behavior. No line of activity can be traced to its conclusion and panicky behavior easily becomes imitative, approaching stereotyped behavior. Finally, the opposite of search behavior is the state of renunciation of search, which in animals may assume the form of freezing or learned helplessness and in humans corresponds to depression and maladaptive (neurotic) anxiety 76.

Search activity is a component of many different forms of behavior: self-stimulation in animals, creative behavior in humans, as well as exploratory and active defense (fight/flight) behavior in all species. In all these forms of activity the probability forecast of the outcome is indefinite, but there is a feedback from the behavior and its outcome enabling the subject to correct his behavior in accordance with the outcome. One of the best indications of search activity in animals is a high-amplitude and well-organized hippocampal theta-rhythm (for details see refs. 68, 76).

The need for a new classification of behavior based on the presence or absence of search activity is determined by its important biological meaning. In research conducted together with V. Arshavsky, we found that all forms of behavior which include search activity increase body resistance to the different forms of artificial pathology (artificial epilepsy, artificial extrapyramidal disturbances caused by neuroleptics, anaphylactoid edema, artificial arrythmia of cardiac contractions, etc.), while renunciation of search decreases body resistance, suppresses immune system and predisposes subject to somatic disorders 65; 74, 77. We concluded that the process of search activity by itself independently of whether it is successful or not (according to the pragmatic results of the behavior) protects the subject from somatic disorders.

However, if search activity is so important for survival and if renunciation of search is so destructive and harmful, it would be reasonable to assume a special brain mechanism able to restore search activity after temporary and occasional renunciation of search. According to the search activity concept, PS fulfils this function. A covert search activity in PS during dreams compensates for the lack of search activity in the previous wakefulness and ensures the resumption of search activity in the subsequent wakefulness. This claim is based on the following findings:

    1. Renunciation of search evoked by the direct stimulation of ventro-medial hypothalamus causes an increase of PS in the subsequent sleep, while after search behavior evoked by the brain stimulation PS decreases 74.

    2. Depression in humans and learned helplessness in animals are accompanied by increased PS requirement (decreased PS latency and increase of PS in the first sleep circle). A correlation is detected between learned helplessness and PS percentage 1.

    3. Both PS and search activity in wakefulness are characterized by regular and synchronized hippocampal theta-rhythm. Moreover, the more pronounced the theta-rhythm in wakefulness, the less pronounced it is in the subsequent PS 51. PS in animals regularly contains ponto-geniculo-occipital (PGO) waves, which in wakefulness correspond to orienting activity 39. The presence of the PGO spikes in PS means that the subject is predisposed to react to novel stimuli, including spontaneous change of dream content.

    4. If nucleus coeruleus in the brain stem is artificially destroyed and as a result muscle tone does not drop during PS, animals demonstrate complicated behavior that can be generally described as orienting activity 48 or search behavior.

If behavior in stressful situation contains search activity (aggression or active avoidance), PS decreases without subsequent rebound because such behavior in wakefulness does not require the restoration of search activity in PS. This approach can explain also data of Oniani and his coworkers 13,51. These investigators performed awakenings of animals on every PS onset during sleep. When they have produced just short fragments (2-3 seconds) of nonemotional wakefulness, a typical effect of PS deprivation appeared: PS onset frequency increased in comparison to the baseline level and it was also PS rebound in the post-deprivation period. However, if after momentary awakening animals were maintained in the condition of active and emotional wakefulness equal in length to PS mean duration, neither the accumulation of PS need nor the post-deprivation PS rebound appeared. Darchia et al. 13 stressed that fragments of active wakefulness are able to satisfy even the accumulated PS need, and from our point of view this effect can be explained by the dominance of search activity in the evoked wakefulness. Short total sleep deprivation (4-12 hours) performed by awakenings decreases sleep latency and increases SWS and delta power in the subsequent sleep. However PS is not increased after such deprivation. 26.

In contrast, immobilization stress makes the manifestation of search behavior in wakefulness inavailable, and as a result the need in the subsequent compensatory PS increases.

Very similar conditions are created during the sleep deprivation on the wooden platform 16,60,73. Of course, it is not a real immobilization, however animals free behavior in this condition is restricted and search activity is almost blocked. In addition, animals are regularly frustrated in their attempts to satisfy their natural need in sleep, or in PS. Such regular frustration is a condition for learned helplessness as a concrete manifestation of renunciation of search 71. As a result, the need in PS increases, however PS is suppressed together with the total sleep. Such a combination of the increased requirement in search activity with PS deprivation can explain the main outcomes of the total sleep deprivation.

On the one hand, in surviving animals recovery sleep is marked by a dramatic rebound of PS after immobilization stress 16. NREM sleep rebound was not observed although most of the lost sleep was of the NREM sleep type. It means that the requirement in PS caused by the combination of the PS deprivation and the frustration of behavioral search activity is more important for the organism than the requirement in NREM sleep which in this particular condition is less obligatory. Moreover, after the PS rebound it is a quick reversal of the somatic outcomes of the prolonged sleep deprivation.

Dreams in REM sleep represent a very specific kind of search activity, which, however, is compatible with the above-mentioned notion of search activity: the healthy subject is usually active in his dreams 67 and the more active the dream characters and the dreamer himself the more prominent is the improvement of subjects mood 38; at the same time the dreamer is unable to make a definite probability forecast according to dream events. Search activity in dreams is more flexible, less organized and less goal-directed than in wakefulness, and even if dreamer is moderately self-reflective in dream 54 it is obvious that he/she is less self-reflective than in wakefulness.

It is worth stressing that dreams provide a good opportunity for the compensatory search activity after giving up in waking behavior 72. First, the subject is separated from the reality while sleeping, including those aspects of reality that caused renunciation of search. Thus, the subject is free to start from the beginning. Second, within his dream, the subject is very free in his decisions: he can try to solve the his actual problem in a metaphoric manner, or he can start solving another problem, one that displace the actual problem 25 since the search process itself is the main restorative factor. Polysemantic image thinking that is active in dreams is more flexible than logical thinking and is free from the probability forecast 75. Since I assume that the final aim of dream work is not the real solution of the actual problem but only the restoration of search activity, all the above features contribute substantially to this restoration.

Concerning the relationships of the brain monoamine system to search behavior, the following hypothesis has been developed 65. Search activity can start in the presence of a certain critical level of the brain monoamines (in particular, norepinephrine) which are utilized as "oil" in the course of search behavior. Search activity itself, once it starts, further stimulates the synthesis of the brain monoamines and ensures their availability. There are some reasons to belief that search activity in wakefulness decreases the sensitivity of the inhibitory presynaptic alpha2-adrenoreceptors thus preventing the inhibition of monoamines neurons. For instances, it was suggested that the sensitivity of these receptors is decreased in REM sleep deprivation 3, 45 and we have suggested (see below) that symptoms of the relatively short REM deprivation correspond to the notion of search activity. Thus, the more pronounced the search activity, the sooner the turnover and synthesis of monoamines will be, in turn maintaining search behavior (positive feedback system). For search activity to begin, the brain monoamine concentration must exceed a critical level. If it drops below its level, search activity is canceled.

In a state of renunciation of search, the above-mentioned positive feedback system does not function. Furthermore, in this state, which manifests itself particularly in depression, monoamines display a tendency to drop. This may be explained by the fact that renunciation of search is usually combined with distress, which causes intense monoamine expenditure without subsequent restoration due to the absence of search activity. Thus, according to this hypothesis, monoamine functioning complete a vicious circle: renunciation of search leads to a drop in the brain monoamines level, which in turn leads to the renunciation of searchs becoming more prominent.

This theoretical approach has some important practical outcomes. For instance, conceptualizing depression as a renunciation of search leads to the revised approach to the mechanisms of clinical treatment 69.

To overcome depression characterized by the exhaustive "vicious" circle (renunciationdecreased brain monoamine turnoverrenunciation), it is necessary not only to restore brain monoamines level but also to "switch on" the opposite positive feedback (increased brain monoamines - search activity - further increase of brain monoamines). Only when renunciation of search is replaced by search activity does brain monoamines stabilize on an appropriate level. As a result, the number and/or sensitivity of the postsynaptic receptors in the brain are diminished, which probably correlates with the clinical efficacy of antidepressant treatment. Thus, the therapeutic tactic has to be directed to the behavioral and intellectual activation of patients in the course of drug treatment. This hypothesis can explain paradoxical data of the reduction of the depressive symptoms in unexpected stressful conditions.

According to the initial hypothesis 65 the relationships between monoamines and REM sleep have been presented as following: in the state of renunciation of search the restoration of brain monoamines requires search activity in REM sleep dreams; its start requires, like in wakefulness, an above critical level of brain monoamines however this level in REM sleep is lower as for the start of search activity in wakefulness. On the other hand, a high monoamines turnover that corresponds to the prominent search activity in wakefulness reduces REM sleep without the subsequent REM sleep rebound, it means reduces the REM sleep requirement. This hypothesis explained REM sleep increase along with a moderate reduction of norepinephrine system activity and REM sleep suppression following the pronounced inhibition of this system 19, 34. However, this initial hypothesis does not fit the above data of the total cessation of NE cells activity in REM sleep because according to this initial hypothesis this activity had to restore the course of REM sleep in parallel with search activity in this state.

By taking into consideration these and many other data from recent investigations, in the present chapter I am going to revise and modify the initial hypothesis. This modification partly includes the hypothesis of Siegel and Ragowski.90 However, the corner-stone of the modified hypothesis is the proposition of Gottesmann 23 according to the role of different monoamines in mental activity, particularly in REM sleep.

According to this modified hypothesis, search activity in wakefulness is based on the combination of activating (Ach and DA dependent) and inhibitory (NE and 5-HT dependent) influences on cortical neurons. This combination determines the regulation of search behavior, its goal direction, its relative restriction according to the actual tasks and its relevance to the objective reality. Due to this regulative inhibitory influences search activity in normal wakefulness although relatively flexible, is neither infinite nor omnipotent: it has limits.

In REM sleep, due to the cessation of the inhibitory NE and 5-HT neurons and the absence of its modulating activity, search activity being based exclusively on the DA system became free, unrestricted, labile and almost chaotic. It displays itself in dreams. According to Solms 95, dreaming itself occurs only if and when the initial activation stage engages the dopaminergic circuits of the ventromedial forebrain. Dopaminergic agents increase the frequency, vivacity and duration of dreaming without similarly affecting the frequency, intensity and duration of REM sleep 29. It is not an occasion that many prominent authors have underlined the similarity between dreams and psychosis (like positive symptoms in schizophrenia) the latter being also related to the hyperactivity of DA system. This topic was discussed in details by Gottesmann 23. Positive symptoms in schizophrenia have been already considered as a form of misdirected and maladaptive search activity 70. However, the main difference between them and dreams is that hallucinations and delusions appear during wakefulness, interfere with the reality perception and disturb the adaptive behavior while dreams appear in REM sleep when subject is naturally separated from the reality and predisposed to such extravagant compensatory search activity in the virtual world. Another difference is that dreams are using the rich potential of the right-hemispheric polysemantic image thinking and are acting mostly in the domain of visual system while delusions and hallucinations are mostly in the domain of the left-hemispheric verbal system, and moreoverthey are the outcome of the functional disability of image thinking 70.

If search activity in REM sleep (in dreams) is based predominantly on the nonmodulated activity of DA system, it has a lot of advantages. First of all, as it was already stressed, it makes search activity in dreams unrestricted and almost omnipotent. Secondly, the temporal cessation of NE activity in REM sleep may help to restore the sensitivity of the postsynaptic NE receptors, as Siegel and Ragowski proposed, and the restored sensitivity of the NE system is very important for the well-regulated and goal-directed search activity (and any mental activity) in the subsequent wakefulness.

The application of the search activity concept to the REM sleep-brain monoamines interrelationships provides an opportunity to reconsider some theoretical assumptions avoiding contradictions.

    1. If the main task of REM sleep (PS) is the restoration of search activity in the subsequent wakefulness and the restoration of physiological mechanisms that provide search activity then all conditions that enhance search activity in waking behavior abolish the demand (requirement) in REM sleep. It is a reason why different antidepressants and amphetamine suppress REM sleep without rebound effect. At the same time, it allows us to make a very important assumption that even intense and long lasting search activity (in chronic stress that is not replaced by distress, in short sleepers etc.), in opposite to the routine, stereotyped activity, does not cause the downregulation (desensitization) of the postsynaptic noradrenergic receptors. Perhaps it can be explained by the very intense turnover of brain monoamines they are released, used for search behavior and immediately replaced by the new portion.

    2. On the other hand, search activity concept explains the increased REM sleep pressure as a response on the depletion of brain monoamines caused by reserpine with its depression - like effect on behavior.

    3. It was found in some investigations 49,102,104 that not all antidepressant agents suppress REM sleep and increase REM sleep latency (decrease REM sleep requirement). Nefazodone increased or at least does not decrease REM sleep and shifted it to earlier in the night. Bupropion reduced REM latency and increased REM sleep percent and REM time. It looks quite opposite to the outcome of other antidepressant agents on sleep structure. However, if we accept the proposition that the natural REM sleep function is the restoration of search activity and the hypothesis, partly confirmed in our previous investigations, that REM sleep in depression is functionally inefficient 65,66,68,73 then it is possible to speculate that some antidepressant agents may help to abolish depression by the restoration of the functional efficacy of REM sleep. In such cases REM sleep may increase like in long sleepers who are using sleep for mood restoration without antidepressive treatment.

    4. The revised search activity concept helps to explain the alteration of sleep structure on different doses of neuroleptic treatment: small and moderate doses of neuroleptics increase the total REM sleep time, whereas large doses suppress it 43. It is possible to suggest that small and moderate doses of neuroleptics decrease search activity in wakefulness (see refs. 43, 70) thus increasing the REM sleep requirement, while high doses suppress search activity in REM sleep based on DA activity and as a result abolish the need in this state.

    5. According to Siegel and Ragowski 90, the sensitivity of all LC innervated postsynaptic NE receptors should be downregulated by prolonged sleep and REM sleep deprivation. Such desensitization was predicted as an outcome of the stable and long lasting NE cells activity in wakefulness. This proposition was not confirmed after 10 days of total sleep deprivation (TSD) in rats on the rotating platform surrounded by water 98: density and affinity of adrenergic binding sites did not decrease, although it was a typical effect of sleep deprivation on body weight and energy expenditure and a massive PS rebound after even 5 days of sleep deprivation. However, TSD in this condition may not maintain a high NE discharge rate typical for the normal wake-fulness because this condition gives no place for search behavior, frustrate animal and finally causes renunciation of search 73 presumably accompanied by brain monoamines depletion.

    By discussing data of sleep and PS deprivation by the water-tank technique it is necessary to bear in mind that the behavioral and physiological reaction on such deprivation has two opposite stages (see review of ref. 65). In the first stage animals exposed to such deprivation after turning back to normal conditions exhibit increased activity that may combine search and stereotyped behavior: hypersexualiry, hyperphagia, increased motor activity in the open field, decreased latency for the object approach, increased object exploration, diminished anxiety, intensified self-stimulation 46,50. It is like a rebound effect after frustration and this rebound effect confirms that the compensatory sources of the organism are still not lost. (It is interesting that a short-lasting REM sleep deprivation increases the explorative (search) behavior and reduces the latency to the object approach even in animals with a damaged locus coeruleus and damaged NE system 46. This enhanced behavior activity after REM deprivation might be at least partly based on the activity of DA system, activity that cannot be realized in REM sleep due to its deprivation. This proposition is in agreement with the assumption of the role of DA system in search activity and was experimentally confirmed by Asakura et al. 3-4 who have shown the involvement of dopamine D2 receptor mechanism in the REM deprivation induced increase in swimming activity).

    However, if sleep/PS deprivation in these stressful conditions lasts a sufficiently long time (for PS deprivation more than 96 hours) the brain and bodys reserves deplete and renunciation of search will prevail even after the cessation of the condition of deprivation. Animals after such prolonged deprivation remained passive and "depressive" for a long time. Mollenhour et al. 47 assumed that the weakening of active (aggressive) behavior in the case of prolonged PS deprivation is connected with the exhaustion of brain monoamines (NE). We cannot exclude the exhaustion of DA also. As it was already mentioned, according to Rechtschaffen et al. 60 a prolonged sleep/PS deprivation inevitably causes death. Thus while discussing the outcome of PS deprivation it is necessary to take into consideration these two stages. Brain monoamines sources have to be high enough to allow an animal to display an active behavior after sleep/PS deprivation.

    The investigation of Asakura et al. 3 seems to confirm this assumption. Clonidine increases swimming activity in the forced swimming test, and a short-lasting REM sleep deprivation intensifies this clonidine response while monoamine depletion contradicts this effect of REM sleep deprivation.

    6. Another abovementioned contradiction is related to the role of brain NE in REM sleep preservation and functional flexibility. On the one hand, a total destruction of LC with consequent depletion of NE in most brain areas does not prevent REM sleep. On the other hand, PS rebound after 10 hours of sleep deprivation on the small platform was significantly decreased after a single injection of a neurotoxic substance which induces long-term degeneration of NE fibers coming from LC 21 and the same substance decreases PS augmentation after the immobilization stress 22. Search activity concept presents a following explanation of these contradictory data. REM-on cells localized in medulla and responsible for the generation of REM sleep as a physiological phenomenon are independent of NE system and of the whole brain and are continuing their activity even being totally separated from the higher parts of the brain. However after such separation they are working in a very stereotyped automatic way. But being responsible for the restoration of search activity REM sleep is flexible and changes in its duration only when this function is required and is available. When monoamines ("oil" of search activity) became depleted, or monoamines systems are blocked by other reasons, search activity in wakefulness in any case cannot be restored by the mean of REM sleep and the latter has no functional reasons to change in duration. Actually, a systemic administration of serotonergic or noradrenergic antagonists reduces REM sleep expression and increases the intervals between REM sleep episodes, perhaps reducing the rate of accumulation of REM sleep propensity.7 Another and also very relevant reason for this lack of REM flexibility was presented by Gonzales et al. 22. They suggested that the degeneration of NE system prevents the development of stress (distress) and it is the reason why REM sleep does not increase. It is very possible: renunciation of search (whether depression or helplessness or frustration) that requires REM sleep for its compensation is always accompanied by distress and an absence of search behavior without distress may not elicit REM sleep.

    7. Mirmiran et al. 44, Vogel et al. 101, Vogel and Hagler 100 and Feng and Ma 17 have found that if active sleep in postnatal species that resembles REM sleep of adults is suppressed by mean of antidepressants without a corresponding increase of wakefulness, it causes subsequently depressive-like disorders in adults. On the first glance it looks like a paradox, however if an active sleep in postnatal period is a state that lay a basis for the development of search activity in adulthood than these results are understandable because in this case the suppression of active sleep leaves subject without predispositions to an adaptive behavior.

    8. While discussing the outcome of different psychotropic drugs on brain monoamines and REM sleep it is necessary to take into consideration that such outcome may differ in patients and in normal subjects.

In animals and healthy subjects clonidine, an effective alpha2-adrenergic receptor agonist suppress REM sleep and this effect is blocked by alpha2-adrenoreceptors antagonist yohimbine 57, while depressed patients display a blunted effect of clonidine on REM sleep 86. Depressed patients demonstrated also a blunted growth hormone response to clonidine 84. According to these data, Schittecatte et al. 86 hypothesized a subsensitivity of central alpha2-adrenoreceptors in depression. However, this hypothesis is in strong contradiction to the hypothesis diat endogenous depression is characterized by supersensitivity of alpha2-adrenoreceptors, in particular inhibitory presynaptic alpha2-adrenoreceptors 53 and that the delayed positive effect of antidepressant medications is related to the desensitization of these receptors that takes time 92.

From our point of view, by discussing these contradictions it is necessary to take into consideration that clonidine and yohimbine are only imitating the natural conditions in which presynaptic and postsynaptic alpha2-adrenoreceptors are activated or inhibited. In natural conditions, alpha2-adrenoreceptors are activated by the NE transmission as a consequence of the high activity of the NE neurons. This high activity of the NE system provides conditions for active interrelations with the environment and the requirement of REM sleep in these conditions became decreased. Thus, if clonidine stimulates postsynaptic adrenoreceptors, it is very understandable that in normal subjects this stimulation causes the suppression of REM sleep and an increase of swimming activity in the forced swimming test in experimental animals. This explanation is confirmed by data that the response on clonidine treatment is dose-dependent, because clonidine stimulates postsynaptic adrenoreceptors in doses higher than those required for the stimulation of the presynaptic inhibitory alpha2-adrenoreceptors. In animals after a relatively short REM sleep deprivation (48-72 hours) the lower dose of clonidine has a stimulating effect on swimming, and it is in agreement with our assumption that a short REM sleep deprivation stimulates search activity and has an activating influence on the brain monoamines systems.

This proposition is confirmed also by data diat clonidine is working in the same direction as imipramine (antidepressant that increases the concentration of NE in synapses) and both, directly or indirectly, stimulate alpha2-adrenoreceptors and increase swimming activity in forced swimming test 2,4, and it is very natural that increased activity is accompanied by reduced REM sleep.

In depressed patients, in contrast to healthy subjects, clonidine does not suppress REM sleep, and when it is used after treatment with serotonin reuptake blocker REM sleep even display a tendency to increase 86. Schittecate et al, explained the blunted response of REM sleep on clonidine as a sign of the down-regulation of alpha2-adrenoreceptors in depression. However, from our point of view it is also another possibility: the response on clonidine may be low if adrenoreceptors are already high activated, up-regulated, high sensitive due to the stable low level of monoamines in the synaptic clefts, and its activation by mean of clonidine do not add to much to this initial and unhelpful activation. This approach seems to fit with data that clonidine starts to suppress REM sleep in depressed patients 48 hours after treatment with mirtazapine (alpha2-adrenoreceptor blocker).

Conclusion

Our general conclusion is that the main function of REM sleep is the restoration of search activity in the subsequent wakefulness. In wakefulness search activity in a normal state is relevant to the reality, goal directed and task oriented and sustained by the interrelationships between brain activating and activity modulating brain monoamines. Renunciation of search in wakefulness is accompanied by the decreased activity of most brain monoamine systems, particularly of brain norepinephrine. In the functionally sufficient REM search, activity is based on the nonmodulated brain dopamine activity (that makes search activity in dreams extremely flexible and available for restoration). At the same time REM sleep provides the condition for the resensitization of the norepinephrine postsynaptic receptors that is important for the continuation of search activity in the subsequent wakefulness. The present model helps to explain many controversial data in REM sleep-brain monoamines relationships.

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