Lader(rotenberg)

CHAPTER #
REM Sleep Function and Brain Monoamine
Regulation
An Application of the Search Activity Concept
Vadim S. Rotenberg
The present chapter contains the discussion of the very and in the midline raphe. It means that noradrenergic and sero- complicated and controversial topic of brain monoam tonergic activity is present in all main functional states (in active ines activity in REM sleep in relationships with the main and quiet waking and in NREM sleep) except REM sleep and is REM sleep functions. The author is going to present many con- especially high in active wakefulness the latter being similar to tradictory experimental data in this area. He will make an at- REM sleep according to the discharge rate of most brain neurons tempt to overcome at least some of these contradictions by using that are acethylcholinergic in their nature.23 REM-off noradren- the search activity concept that prescribes to REM (paradoxi- ergic and serotoninergic cells do not seem to be responsible for cal– PS) sleep a function of the restoration of search activity that the REM sleep phenomenology because the depletion of norepi- determines subject’s resistance to stress and various noxious fac- nephrine (NE) and serotonin (5-HT), by the electrolytic lesion tors. It is for this reason one of the main features of the behavior of the LC and raphe nuclei does not prevent REM sleep as a physiological phenomenon.14,28,93,33 However, it does not meanthat such lesions and depletion has no effect on the REM sleep Activity of the Monoamines Containing Neurons
functions. For instance, ponto-geniculo-occipital (PGO) spikes in REM Sleep
that are normally tied to REM state, correspond in wakefulnessto orienting activity39 and consequently may relate to REM sleep The sleep-wakefulness cycle is characterized by a very definite psychological functions (see ref. 68) became released into all states dynamic of the discharge of cell groups of the central nervous after lesion of 5-HT containing neurons.93 There are data (see system from wakefulness through nonREM (NREM) sleep to ref. 85) that serotoninergic neurons are related to the regulation REM sleep. Active waking and REM sleep are characterized by very similar (high) discharge rates of most cell groups in neocor- Thus, REM sleep differs from wakefulness according to the tex and different subcortical and brainstem areas in contrast to low activity of noradrenergic and serotoninergic neurons. REM quiet waking and NREM sleep where the same cell groups dis- sleep represents the functioning of the cortex without the influ- play a low activity (see also review of ref. 90).89,97 While this simi- ence of norepinephrine27 and it is reasonable to suggest that such larity between active waking and REM display the main tendency low activity may in some way relate to the peculiarity of REM in brain neuronal activity, some cell groups in the brainstem are sleep functions or to the regulation of REM sleep in different active only during REM sleep (REM-on cells,80,35,89). According functional conditions.90 At the same time, the mesencephalic to the data of lesion studies83,91 it is possible to suggest that dopamine containing neurons discharge on the equal rate in wake- REM-on cells are strongly related to the generation of REM sleep fulness and in all sleep stages.23 According to Siegel and Rogawski90 with all its significant physiological features. However, whether it means that dopamine containing cells have no essential role in these REM-on cells are responsible not only for the phenom- sleep generation or in sleep functions. However, if from all enology of REM sleep but also for REM sleep functions remains monoaminergic neurons only dopaminergic neurons are continu- an open question. There is some evidence that it is the frontal ously active in REM sleep, this activity has probably a special lobe that is related to the production of REM sleep dreams and meaning and relates to the peculiarity of REM sleep functions.23 consequently may relate to the behavioral and psychological REMsleep functions.24,95 Some other cell groups are active during all types of waking Monoamines Containing Neurons in
behavior and, on the relatively lower level, also during NREM Wakefulness: Towards the Functional Meaning
sleep. However they are almost totally inactive during REM sleep Gottesmann,23 has reviewed the role of different neurotrans- (REM-off cells).18,30,42,59 All these REM-off cell groups are ei- mitters in waking activity. According to this review, making the ther noradrenergic or serotonergic,88 and that is especially im- long story short, acetylcholine (Ach) is responsible for the gen- portant for the topic of the present chapter. Moreover, these eral activation of cortical neurons initiated by the reticular acti- REM-off cells are concentrated in the main brain sources of the vating system of the brainstem.37 This general nondifferentiated noradrenergic and serotonergic activity – in locus coeruleus (LC) activation of the cortex is important for maintaining stable tonic Sleep and Sleep Disorders: A Neuropsychopharmacological Approach, edited by Malcolm Lader, Daniel P. Cardinaliand S.R. Pandi-Perumal. 2004 Landes Bioscience/Eurekah.com.
Sleep and Sleep Disorders: A Neurophychopharmacological Approach vigilance and preventing coma. Atropine, an antagonist of acetyl- the efficiency of NE receptor action. In this step, the noradrener- choline, produces EEG slow waves – a state opposite to vigi- gic system is active and does not require REM sleep for its resto- lance.105 However, a general cortical activation promoted by ace- ration. In the second process, the release or potentiation of NE tylcholine is only a nonspecific predisposition to the goal-oriented action is hypothesized to downregulate/desensitize NE receptors, selective activity that requires differentiation (discrimination) this downregulation producing the increased REM sleep pres- between meaningful and meaningless information elicited by the sure. Thus, according to this concept, the cessation of NE cells environment. Such discrimination is based on the partial flexible activity in REM sleep actually contributes to the activity of the inhibition of cortical neuronal activity and as a result – on the noradrenergic system. The evidence confirming this point of view increase of the signal-to-noise ratio that makes neuronal activity can be found in Siegel and Rogawski.90 Much more important task-relevant. NE and 5-HT in wakefulness are responsible for and relevant is to consider and to discuss numerous data that this partial cortical inhibition.27,108 Thus, mental functioning during the waking state depends upon two types of neurotrans- 1. Depression in humans and learned helplessness in animals88 are mitters:23 activators which support the general mobilization of characterized by the stable reduction of monoamine (NE and cortical functions, and inhibitors controlling and modulating this 5-HT) transmission in brain synapses. Thus, according to the activation in order to make mental functions flexible and rel- theory it would be reasonable to expect the decrease of REM sleep requirement in these states as an outcome of the already Dopamine in the normal waking brain plays an important established chronic sensitization of the postsynaptic noradren- role in motivational processes providing “reward” and “reinforce- ergic receptors. However, according to Adrien et al1 there is a ment”, and in novelty seeking that includes exploratory behavior, positive correlation between experimentally induced learned attention, exhilaration and excitement in response to novel helplessness and percentage of paradoxical (REM) sleep. The stimuli.8,10,15,23,36 According to Wise et al107 and Wise and increased REM sleep pressure in depression is shown by the Colle106 dopamine mediates naturally rewarding experiences (like reduction of REM sleep latency, a relative increase of REM sleep pleasure from food, sex, drugs). However it is involved not only in the first cycle, an increased number of the short sleep cycles, in appetitive events and in an approach behavior but also in aver- and by the absence of the first night effect.11,40,61,78,79 Healthy sive ones.81,82 Paradoxically, such aversive behavior in some of its long sleepers are characterized by the relatively increased REM aspects seems to be attractive for the subject and does not contra- sleep27 and at the same time by the inclination toward dict to the general concept of “reinforcement”. In this context it subdepressive reactions.103 A disposition to depressive reactions is possible to ascribe rewarding experiences also to the dopamine is also characteristic of narcoleptic patients who show a con- dependent psychotic symptoms like hallucinations and delusions stantly high REM sleep requirement.9 When the level of de- that are very resistant to any treatment except for the antagonists pression is moderate, an increased REM sleep requirement real- of DA receptors.32 According to some recent investigations96 in izes itself in the increased REM sleep. The relationship between the cortex, and especially in the frontal cortex DA transporters the severity of depression and REM sleep is nonlinear:66 when are under the strong modulating influence of NE nerve terminals the MMPI scale D (depression dominate) and does not exceed while in basal ganglia NE has a little regulatory role for DA. NE 75 T points REM sleep grows longer (compared to the magni- reuptake blocker increases not only NE but even in a more promi- tude of this scale of up to 65 T points). When the scale gets nent way DA concentration in the cortex and only NE in subcor- higher, REM sleep becomes reduced. Thus, before depression starts to destroy sleep structure, it determines a tendency to-wards REM sleep increase. From my point of view, all these Rem Sleep: Resensitization of the Postsynaptic
data do not correspond to the Siegel and Ragowski theory.
Noradrenegic Receptors?
2. Reserpine treatment causes a depletion of NE87 but produces REM sleep state is unique according to the complete cessa- elevation of REM sleep. Siegel and Ragowski90 explain this REM tion of the noradrenergic LC cells activity. It is reasonable to be- sleep elevation as an attempt to upregulate NE receptors in re- lieve that such cessation has a special physiological meaning, and sponse to NE depletion. However, this explanation looks circu- Siegel and Rogawski90 were the first who proposed a coherent lar: REM sleep is characterized by the marked reduction of no- and comprehensive theory of this topic. These authors hypoth- radrenalin cells activity and such reduction has to overcompen- esized that the inhibition of activity of the NE containing cells in REM sleep is required to maintain the sensitivity of NE postsyn-aptic receptors, with consequent benefits for all types of behavior 3. It was shown in many investigations, that antidepressants — in wakefulness that utilize these receptors. During wakefulness monoamine oxidase inhibitors (MAOI) that enhance the nora- all adaptive forms of behavior have to be flexible and require con- drenergic transmission in synapses— suppress REM sleep for stant activity of the noradrenergic system. Such almost nonstop the all period of prescription in animals, in healthy subjects and activity is unavoidably leading to the desensitization of the NE in depressed patients.17,31,41,64 This period of prescription can postsynaptic receptors, and this negative feedback finally causes take a few weeks. According to the theory we are discussing, it the decrease of the NE system efficiency. REM sleep that appears was possible to expect not a decrease but rather an increase of with regular intervals provides this system with an opportunity REM sleep because of a long-lasting and intense stimulation of to restore its functional activity without interference with the the noradrenergic system. Siegel and Ragowski are aware of this ongoing waking behavior. Siegel and Rogawski hypothesized that contradiction. They suggest that the process of NE receptors NE release sets in motion two processes having opposite effect on downregulation caused by enhanced NE transmission can take REM sleep duration. In the first process, NE release or its func- from few minutes to few weeks. However, from our point of tional enhancement suppresses or “substitute” for REM sleep by view such time course is too broad for this micro-physiological increasing the activity of negative feedback circuits monitoring process and instead of making such proposition it is more rea-sonable to search for another explanation.
An Application of the Search Activity Concept 4. In the frame of the discussed theory, it seems difficult to explain The need for a new classification of behavior based on the some data of partial REM deprivation by using awakenings in presence or absence of search activity is determined by its impor- REM sleep. If after momentary awakening, animals were main- tant biological meaning. In research conducted together with V.
tained in a condition of active and emotional wakefulness (i.e., Arshavsky, we found that all forms of behavior which include wakefulness based on the enhanced noradrenergic activity) nei- search activity increase body resistance to the different forms of ther the accumulation of REM need nor the postdeprivation artificial pathology (artificial epilepsy, artificial extrapyramidal REM rebound appear.51,13 It is necessary to take into consider- disturbances caused by neuroleptics, anaphylactoid edema, arti- ation, that REM sleep was already reduced before awakenings ficial arrythmia of cardiac contractions, etc.), while renunciation and nevertheless fragments of active wakefulness were able to of search decreases body resistance, suppresses immune system and predisposes subject to somatic disorders.65,74,77 We concludedthat the process of search activity by itself independently of 5. Siegel and Rogawski predicted that the sensitivity of all LC in- whether it is successful or not (according to the pragmatic results nervated postsynaptic NE receptors should be reduced by pro- of the behavior) protects the subject from somatic disorders.
longed sleep/REM sleep loss. However, Tsai et al98 have shown However, if search activity is so important for survival and if that density and affinity of adrenergic binding sites did not de- renunciation of search is so destructive and harmful, it would be crease after 10 days of total sleep deprivation. Thus sleep depri- reasonable to assume a special brain mechanism able to restore vation made no expected changes in central NE receptor regu- search activity after temporary and occasional renunciation of search. According to the search activity concept, PS fulfils this In spite of all these contradictions, we do not conclude that function. A covert search activity in PS during dreams compen- the theory of Siegel and Rogawski is not relevant at all. The cessa- sates for the lack of search activity in the previous wakefulness tion of the activity of noradrenergic cells in REM is a fundamen- and ensures the resumption of search activity in the subsequent tal fact that needs explanation, and the resensitization of the wakefulness. This claim is based on the following findings: postsynaptic noradrenergic receptors may be a real task of such 1. Renunciation of search evoked by the direct stimulation of cessation. However, the abovementioned contradictions show that ventro-medial hypothalamus causes an increase of PS in the sub- this theory has limitations and is probably relevant only in some sequent sleep, while after search behavior evoked by the brain particular conditions, and, secondly, that it is not an exhaustive one and has to be supplemented by additional suggestions of REM 2. Depression in humans and learned helplessness in animals are sleep functions related to the monoamine activity that may be accompanied by increased PS requirement (decreased PS latency and increase of PS in the first sleep circle). A correlation is de-tected between learned helplessness and PS percentage.1 Search Activity Concept, REM Sleep Functions
and Brain Monoamines
3. Both PS and search activity in wakefulness are characterized by I suggest search activity (SA) concept to represent such a supple- regular and synchronized hippocampal theta-rhythm. Moreover, the more pronounced the theta-rhythm in wakefulness, the less By search activity is understood activity designed to change pronounced it is in the subsequent PS.51 PS in animals regu- the situation or the subject’s attitude to it in the absence of a larly contains ponto-geniculo-occipital (PGO) waves, which in definite forecast of the results of such activity (i.e., in the case of wakefulness correspond to orienting activity.39 The presence of pragmatic indefiniteness), but with constant monitoring of the the PGO spikes in PS means that the subject is predisposed to results at all stages of activity. This definition makes it clear that react to novel stimuli, including spontaneous change of dream certain behavioral categories cannot be classed with search be- havior. This primarily applies to all forms of stereotyped behav- 4. If nucleus coeruleus in the brain stem is artificially destroyed ior having a quite definite forecast of results. Panicky behavior at and as a result muscle tone does not drop during PS, animals first sight may seem to imitate search behavior but differ from it demonstrate complicated behavior that can be generally de- by the disturbance of the feedback between the activity and its scribed as orienting activity48 or search behavior.
regulation. During a panic the results of the activity are not con-sidered at any stage and cannot be used for the correction of be- If behavior in stressful situation contains search activity (ag- havior. No line of activity can be traced to its conclusion and gression or active avoidance), PS decreases without subsequent panicky behavior easily becomes imitative, approaching stereo- rebound because such behavior in wakefulness does not require typed behavior. Finally, the opposite of search behavior is the state the restoration of search activity in PS. This approach can explain of renunciation of search, which in animals may assume the form also data of Oniani and his coworkers.51,13 These investigators of freezing or learned helplessness and in humans corresponds to performed awakenings of animals on every PS onset during sleep.
depression and maladaptive (neurotic) anxiety.76 When they have produced just short fragments (2-3 seconds) of Search activity is a component of many different forms of be- nonemotional wakefulness, a typical effect of PS deprivation ap- havior: self-stimulation in animals, creative behavior in humans, peared: PS onset frequency increased in comparison to the baseline as well as exploratory and active defense (fight/flight) behavior in level and it was also PS rebound in the post-deprivation period.
all species. In all these forms of activity the probability forecast of However, if after momentary awakening animals were maintained the outcome is indefinite, but there is a feedback from the behav- in the condition of active and emotional wakefulness equal in ior and its outcome enabling the subject to correct his behavior length to PS mean duration, neither the accumulation of PS need in accordance with the outcome. One of the best indications of nor the post-deprivation PS rebound appeared. Darchia et al13 search activity in animals is a high-amplitude and well-organized stressed that fragments of active wakefulness are able to satisfy hippocampal theta-rhythm (for details see ref. 68,76).
even the accumulated PS need, and from our point of view thiseffect can be explained by the dominance of search activity in the Sleep and Sleep Disorders: A Neurophychopharmacological Approach evoked wakefulness. Short total sleep deprivation (4-12 hours) reasons to belief that search activity in wakefulness decreases the performed by awakenings decreases sleep latency and increases sensitivity of the inhibitory presynaptic alpha2-adrenoreceptors SWS and delta power in the subsequent sleep.However PS is not thus preventing the inhibition of monoamines neurons. For in- stances, it was suggested that the sensitivity of these receptors is In contrast, immobilization stress makes the manifestation of decreased in REM sleep deprivation3,45 and we have suggested search behavior in wakefulness inavailable, and as a result the (see below) that symptoms of the relatively short REM depriva- need in the subsequent compensatory PS increases.
tion correspond to the notion of search activity. Thus, the more Very similar conditions are created during the sleep depriva- pronounced the search activity, the sooner the turnover and syn- tion on the wooden platform.16,60,73 Of course, it is not a real thesis of monoamines will be, in turn maintaining search behav- immobilization, however animals free behavior in this condition ior (positive feedback system). For search activity to begin, the is restricted and search activity is almost blocked. In addition, brain monoamine concentration must exceed a critical level. If it animals are regularly frustrated in their attempts to satisfy their drops below its level, search activity is canceled.
natural need in sleep, or in PS. Such regular frustration is a con- In a state of renunciation of search, the above-mentioned posi- dition for learned helplessness as a concrete manifestation of re- tive feedback system does not function. Furthermore, in this state, nunciation of search.71 As a result, the need in PS increases, how- which manifests itself particularly in depression, monoamines ever PS is suppressed together with the total sleep. Such a display a tendency to drop. This may be explained by the fact combination of the increased requirement in search activity with that renunciation of search is usually combined with distress, PS deprivation can explain the main outcomes of the total sleep which causes intense monoamine expenditure without subsequent restoration due to the absence of search activity. Thus, according On the one hand, in surviving animals recovery sleep is marked to this hypothesis, monoamine functioning complete a vicious by a dramatic rebound of PS after immobilization stress.16 NREM circle: renunciation of search leads to a drop in the brain monoam- sleep rebound was not observed although most of the lost sleep ines level, which in turn leads to the renunciation of search’s be- was of the NREM sleep type. It means that the requirement in PS caused by the combination of the PS deprivation and the frus- This theoretical approach has some important practical out- tration of behavioral search activity is more important for the comes. For instance, conceptualizing depression as a renuncia- organism than the requirement in NREM sleep which in this tion of search leads to the revised approach to the mechanisms of particular condition is less obligatory. Moreover, after the PS re- bound it is a quick reversal of the somatic outcomes of the pro- To overcome depression characterized by the exhaustive “vi- cious” circle (renunciation—decreased brain monoamine turn- Dreams in REM sleep represent a very specific kind of search over—renunciation), it is necessary not only to restore brain activity, which, however, is compatible with the above-mentioned monoamines level but also to “switch on” the opposite positive notion of search activity : the healthy subject is usually active in feedback (increased brain monoamines – search activity – further his dreams67 and the more active the dream characters and the increase of brain monoamines). Only when renunciation of search dreamer himself the more prominent is the improvement of is replaced by search activity does brain monoamines stabilize on subject’s mood;38 at the same time the dreamer is unable to make an appropriate level. As a result, the number and/or sensitivity of a definite probability forecast according to dream events. Search the postsynaptic receptors in the brain are diminished, which activity in dreams is more flexible, less organized and less probably correlates with the clinical efficacy of antidepressant treat- goal-directed than in wakefulness, and even if dreamer is moder- ment. Thus, the therapeutic tactic has to be directed to the be- ately self-reflective in dream54 it is obvious that he/she is less havioral and intellectual activation of patients in the course of self-reflective than in wakefulness.
drug treatment. This hypothesis can explain paradoxical data of It is worth stressing that dreams provide a good opportunity the reduction of the depressive symptoms in unexpected stressful for the compensatory search activity after giving up in waking behavior.72 First, the subject is separated from the reality while According to the initial hypothesis65 the relationships between sleeping, including those aspects of reality that caused renuncia- monoamines and REM sleep have been presented as following: tion of search. Thus, the subject is free to start from the begin- in the state of renunciation of search the restoration of brain ning. Second, within his dream, the subject is very free in his monoamines requires search activity in REM sleep dreams; its decisions: he can try to solve the his actual problem in a meta- start requires, like in wakefulness, an above critical level of brain phoric manner, or he can start solving another problem, one that monoamines however this level in REM sleep is lower as for the displace the actual problem25 since the search process itself is the start of search activity in wakefulness. On the other hand, a high main restorative factor. Polysemantic image thinking that is ac- monoamines turnover that corresponds to the prominent search tive in dreams is more flexible than logical thinking and is free activity in wakefulness reduces REM sleep without the subse- from the probability forecast.75 Since I assume that the final aim quent REM sleep rebound, it means reduces the REM sleep re- of dream work is not the real solution of the actual problem but quirement. This hypothesis explained REM sleep increase along only the restoration of search activity, all the above features con- with a moderate reduction of norepinephrine system activity and tribute substantially to this restoration.
REM sleep suppression following the pronounced inhibition of Concerning the relationships of the brain monoamine system this system.19,34 However, this initial hypothesis does not fit the to search behavior, the following hypothesis has been developed.65 above data of the total cessation of NE cells activity in REM sleep Search activity can start in the presence of a certain critical level because according to this initial hypothesis this activity had to of the brain monoamines (in particular, norepinephrine) which restore the course of REM sleep in parallel with search activity in are utilized as “oil” in the course of search behavior. Search activ- ity itself, once it starts, further stimulates the synthesis of the By taking into consideration these and many other data from brain monoamines and ensures their availability. There are some recent investigations, in the present chapter I am going to revise An Application of the Search Activity Concept and modify the initial hypothesis. This modification partly in- a very important assumption that even intense and long lasting cludes the hypothesis of Siegel and Ragowski.90 However, the search activity (in chronic stress that is not replaced by distress, corner-stone of the modified hypothesis is the proposition of in short sleepers etc.), in opposite to the routine, stereotyped Gottesmann23 according to the role of different monoamines in activity, does not cause the downregulation (desensitization) of mental activity, particularly in REM sleep.
the postsynaptic noradrenergic receptors. Perhaps it can be ex- According to this modified hypothesis, search activity in wake- plained by the very intense turnover of brain monoamines – fulness is based on the combination of activating (Ach and DA they are released, used for search behavior and immediately re- dependent) and inhibitory (NE and 5-HT dependent) influences on cortical neurons. This combination determines the regulationof search behavior, its goal direction, its relative restriction ac- 2. On the other hand, search activity concept explains the increased cording to the actual tasks and its relevance to the objective real- REM sleep pressure as a response on the depletion of brain ity. Due to this regulative inhibitory influences search activity in monoamines caused by reserpine with its depression-like effect normal wakefulness although relatively flexible, is neither infi- 3. It was found in some investigations49,102,104 that not all antide- In REM sleep, due to the cessation of the inhibitory NE and pressant agents suppress REM sleep and increase REM sleep 5-HT neurons and the absence of its modulating activity, search latency (decrease REM sleep requirement). Nefazodone increased activity being based exclusively on the DA system became free, or at least does not decrease REM sleep and shifted it to earlier unrestricted, labile and almost chaotic. It displays itself in dreams.
in the night. Bupropion reduced REM latency and increased According to Solms,95 dreaming itself occurs only if and when REM sleep percent and REM time. It looks quite opposite to the initial activation stage engages the dopaminergic circuits of the outcome of other antidepressant agents on sleep structure.
the ventromedial forebrain. Dopaminergic agents increase the However, if we accept the proposition that the natural REM frequency, vivacity and duration of dreaming without similarly sleep function is the restoration of search activity and the hy- affecting the frequency, intensity and duration of REM sleep.29 pothesis, partly confirmed in our previous investigations, that It is not an occasion that many prominent authors have under- REM sleep in depression is functionally inefficient65,66,68,73 then lined the similarity between dreams and psychosis (like positive it is possible to speculate that some antidepressant agents may symptoms in schizophrenia) the latter being also related to the help to abolish depression by the restoration of the functional hyperactivity of DA system. This topic was discussed in detail by efficacy of REM sleep. In such cases REM sleep may increase Gottesmann.23 Positive symptoms in schizophrenia have been like in long sleepers who are using sleep for mood restoration already considered as a form of misdirected and maladaptive search activity.70 However, the main difference between them and dreamsis that hallucinations and delusions appear during wakefulness, 4. The revised search activity concept helps to explain the alter- interfere with the reality perception and disturb the adaptive be- ation of sleep structure on different doses of neuroleptic treat- havior while dreams appear in REM sleep when subject is natu- ment: small and moderate doses of neuroleptics increase the rally separated from the reality and predisposed to such extrava- total REM sleep time, whereas large doses suppress it.43 It is gant compensatory search activity in the virtual world. Another possible to suggest that small and moderate doses of neuroleptics difference is that dreams are using the rich potential of the decrease search activity in wakefulness (see ref. 43, 70) thus in- right-hemispheric polysemantic image thinking and are acting creasing the REM sleep requirement, while high doses suppress mostly in the domain of visual system while delusions and hallu- search activity in REM sleep based on DA activity and as a re- cinations are mostly in the domain of the left-hemispheric verbal sult abolish the need in this state.
system, and moreover — they are the outcome of the functional 5. According to Siegel and Ragowski,90 the sensitivity of all LC innervated postsynaptic NE receptors should be downregulated If search activity in REM sleep (in dreams) is based predomi- by prolonged sleep and REM sleep deprivation. Such desensiti- nantly on the nonmodulated activity of DA system, it has a lot of zation was predicted as an outcome of the stable and long last- advantages. First of all, as it was already stressed, it makes search ing NE cells activity in wakefulness. This proposition was not activity in dreams unrestricted and almost omnipotent. Secondly, confirmed after 10 days of total sleep deprivation (TSD) in rats the temporal cessation of NE activity in REM sleep may help to on the rotating platform surrounded by water:98 density and restore the sensitivity of the postsynaptic NE receptors, as Siegel affinity of adrenergic binding sites did not decrease, although it and Ragowski proposed, and the restored sensitivity of the NE was a typical effect of sleep deprivation on body weight and system is very important for the well-regulated and goal-directed energy expenditure and a massive PS rebound after even 5 days search activity (and any mental activity) in the subsequent wake- of sleep deprivation. However, TSD in this condition may not maintain a high NE discharge rate typical for the normal wake- The application of the search activity concept to the REM fulness because this condition gives no place for search behav- sleep-brain monoamines interrelationships provides an opportu- ior, frustrate animal and finally causes renunciation of search73 nity to reconsider some theoretical assumptions avoiding contra- presumably accompanied by brain monoamines depletion.
1. If the main task of REM sleep (PS) is the restoration of search By discussing data of sleep and PS deprivation by the water-tank activity in the subsequent wakefulness and the restoration of technique it is necessary to bear in mind that the behavioral physiological mechanisms that provide search activity then all and physiological reaction on such deprivation has two oppo- conditions that enhance search activity in waking behavior abol- site stages (see review of ref. 65). In the first stage animals ex- ish the demand (requirement) in REM sleep. It is a reason why posed to such deprivation after turning back to normal condi- different antidepressants and amphetamine suppress REM sleep tions exhibit increased activity that may combine search and without rebound effect. At the same time, it allows us to make stereotyped behavior: hypersexuality, hyperphagia, increased Sleep and Sleep Disorders: A Neurophychopharmacological Approach motor activity in the open field, decreased latency for the object energic antagonists reduces REM sleep expression and increases approach, increased object exploration, diminished anxiety, in- the intervals between REM sleep episodes, perhaps reducing tensified self-stimulation.46,50 It is like a rebound effect after the rate of accumulation of REM sleep propensity.7 Another frustration and this rebound effect confirms that the compen- and also very relevant reason for this lack of REM flexibility satory sources of the organism are still not lost. (It is interesting was presented by Gonzales et al.22 They suggested that the de- that a short-lasting REM sleep deprivation increases the explor- generation of NE system prevents the development of stress ative (search) behavior and reduces the latency to the object (distress) and it is the reason why REM sleep does not increase.
approach even in animals with a damaged locus coeruleus and It is very possible: renunciation of search (whether depression damaged NE system.46 This enhanced behavior activity after or helplessness or frustration) that requires REM sleep for its REM deprivation might be at least partly based on the activity compensation is always accompanied by distress and an absence of DA system, activity that cannot be realized in REM sleep of search behavior without distress may not elicit REM sleep.
due to its deprivation. This proposition is in agreement with 7. Mirmiran et al44 Vogel et al101 Vogel and Hagler100 and Feng the assumption of the role of DA system in search activity and and Ma17 have found that if active sleep in postnatal species was experimentally confirmed by Asakura et al3,4 who have that resembles REM sleep of adults is suppressed by mean of shown the involvement of dopamine D2 receptor mechanism antidepressants without a corresponding increase of wakeful- in the REM deprivation induced increase in swimming activity).
ness, it causes subsequently depressive-like disorders in adults.
However, if sleep/PS deprivation in these stressful conditions On the first glance it looks like a paradox, however if an active lasts a sufficiently long time (for PS deprivation – more than 96 sleep in postnatal period is a state that lay a basis for the devel- hours) the brain and body’s reserves deplete and renunciation opment of search activity in adulthood than these results are of search will prevail even after the cessation of the condition of understandable because in this case the suppression of active deprivation. Animals after such prolonged deprivation remained sleep leaves subject without predispositions to an adaptive be- passive and “depressive” for a long time. Mollenhour et al47 as- sumed that the weakening of active (aggressive) behavior in the 8. While discussing the outcome of different psychotropic drugs case of prolonged PS deprivation is connected with the exhaus- on brain monoamines and REM sleep it is necessary to take tion of brain monoamines (NE). We cannot exclude the ex- into consideration that such outcome may differ in patients and haustion of DA also. As it was already mentioned, according to Rechtschaffen et al60 a prolonged sleep/PS deprivation inevita-bly causes death. Thus while discussing the outcome of PS dep- In animals and healthy subjects clonidine, an effective rivation it is necessary to take into consideration these two stages.
alpha2-adrenergic receptor agonist suppress REM sleep and this Brain monoamines sources have to be high enough to allow an effect is blocked by alpha2-adrenoreceptors antagonist yohim- animal to display an active behavior after sleep/PS deprivation.
bine,57 while depressed patients display a blunted effect ofclonidine on REM sleep.86 Depressed patients demonstrated also The investigation of Asakura et al3 seems to confirm this as- a blunted growth hormone response to clonidine.84 According to sumption. Clonidine increases swimming activity in the forced these data, Schittecatte et al86 hypothesized a subsensitivity of swimming test, and a short-lasting REM sleep deprivation in- central alpha2-adrenoreceptors in depression. However, this hy- tensifies this clonidine response while monoamine depletion con- pothesis is in strong contradiction to the hypothesis that endog- tradicts this effect of REM sleep deprivation.
enous depression is characterized by supersensitivity of 6. Another abovementioned contradiction is related to the role of alpha2-adrenoreceptors, in particular inhibitory presynaptic brain NE in REM sleep preservation and functional flexibility.
alpha2-adrenoreceptors53 and that the delayed positive effect of On the one hand, a total destruction of LC with consequent antidepressant medications is related to the desensitization of these depletion of NE in most brain areas does not prevent REM sleep. On the other hand, PS rebound after 10 hours of sleep From our point of view, by discussing these contradictions it deprivation on the small platform was significantly decreased is necessary to take into consideration that clonidine and yohim- after a single injection of a neurotoxic substance which induces bine are only imitating the natural conditions in which presyn- long-term degeneration of NE fibers coming from LC21 and aptic and postsynaptic alpha2-adrenoreceptors are activated or the same substance decreases PS augmentation after the immo- inhibited. In natural conditions, alpha2-adrenoreceptors are ac- bilization stress22 Search activity concept presents a following tivated by the NE transmission as a consequence of the high ac- explanation of these contradictory data. REM-on cells localized tivity of the NE neurons. This high activity of the NE system in medulla and responsible for the generation of REM sleep as provides conditions for active interrelations with the environment a physiological phenomenon are independent of NE system and and the requirement of REM sleep in these conditions became of the whole brain and are continuing their activity even being decreased. Thus, if clonidine stimulates postsynaptic totally separated from the higher parts of the brain. However adrenoreceptors, it is very understandable that in normal sub- after such separation they are working in a very stereotyped au- jects this stimulation causes the suppression of REM sleep and an tomatic way. But being responsible for the restoration of search increase of swimming activity in the forced swimming test in ex- activity REM sleep is flexible and changes in its duration only perimental animals. This explanation is confirmed by data that when this function is required and is available. When monoam- the response on clonidine treatment is dose-dependent, because ines (“oil” of search activity ) became depleted, or monoamines clonidine stimulates postsynaptic adrenoreceptors in doses higher systems are blocked by other reasons, search activity in wakeful- than those required for the stimulation of the presynaptic inhibi- ness in any case cannot be restored by the mean of REM sleep tory alpha2-adrenoreceptors. In animals after a relatively short and the latter has no functional reasons to change in duration.
REM sleep deprivation (48-72 hours) the lower dose of clonidine Actually, a systemic administration of serotonergic or noradr- has a stimulating effect on swimming, and it is in agreement with An Application of the Search Activity Concept our assumption that a short REM sleep deprivation stimulates 8. Benjamin J, Patterson Ch, Greenberg BD et al. Population and search activity and has an activating influence on the brain familial association between the D4 dopamine receptor gene and measures of novelty seeking. Nat Genet 1996; 12:81-84.
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