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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