Ponto-geniculo-occipital Waves Research Articles

Enhancement of tonic and phasic events of rapid eye movement sleep following bilateral ibotenic acid injections into centralis lateralis thalamic nucleus of cats

The excitotoxin ibotenic acid (1.2–2.6 μl of 50 μg/μl) was injected bilaterally into the thalamic centralis lateralis nucleus of chronically implanted cats in order to study the effects of tonic excitation followed by destruction of perikarya on the sleep-waking cycle and its electrographic correlates. Ibotenate injections were performed under mild ketamine anaesthesia. Immediately afterwards, the animals showed behavioural arousal accompanied first by ocular nystagmiform movements and then by pontogeniculooccipital waves. By 6–10 h post-injection, the numbers of rapid eye movement sleep episodes, but not their duration, increased compared to the preinjection control period. The injection sites were histologically confirmed using conventional Thionin stains. Additional control was provided by retrograde transport of wheat-germ agglutinin conjugated with horseradish peroxidase. The present results suggest that a population of neurons important for ocular saccades, pontogeniculooccipital waves, and the state of desynchronized sleep is present in the internal medullary lamina, in particular in the centralis lateralis nuclei.

Dynamic Suppression of REM Sleep by Parenteral Administration of the Serotonin-1 Agonist Eltoprazine

The purpose of this study was to determine the effects of the serotonin-1 agonist eltoprazine on the control of rapid eye movement (REM) sleep. Continuous polygraph recordings were performed for 15-17 days in four adult male cats. During the first 5 control days cats received injections of 0.9% saline intraperitoneally (i.p.) twice per day (b.i.d.). Over the next 5-7 days cats received injections of 0.9% saline intraperitoneally (i.p.) twice per day (b.i.d.). Over the next 5-7 days cats received eltoprazine i.p. (1-2 mg/kg, b.i.d.). For the final 5 recovery days cats received saline alone. During the saline control period, the mean REM sleep percent was 13.8 +/- 0.91%. When eltoprazine was administered for the subsequent 5-7 days, the mean REM percent was reduced to 1.5 +/- 0.59%. During the 5-day recovery period, REM percent increased significantly (p less than 0.0001) above both control and drug injection values to a mean of 24.5 +/- 1.3% with a maximum on recovery day 1 of 28.4 +/- 2.6% (n = 4). In addition to REM suppression, eltoprazine produced other electroencephalographic changes: an increase in slow-wave sleep (S) percent without any change in overall wake (W) percent; an increase in electromyogram (EMG) amplitude; and a decrease in ponto-geniculo-occipital (PGO) wave activity. PGO wave frequency and REM% increased significantly during the recovery period. Thus our findings demonstrate REM and PGO suppression by eltoprazine and document dramatic rebound effects following its withdrawal.

Serotonin hyperpolarizes cholinergic low-threshold burst neurons in the rat laterodorsal tegmental nucleus in vitro.

Serotonergic suppression of cholinergic neuronal activity implicated in the regulation of rapid eye movement sleep and its associated phenomenon, pontogeniculooccipital waves, has long been postulated, but no direct proof has been available. In this study, intracellular and whole-cell patch-clamp recording techniques were combined with enzyme histochemistry to examine the intrinsic electrophysiological properties and response to serotonin (5-HT) of identified cholinergic rat laterodorsal tegmental nucleus neurons in vitro. Sixty-five percent of the recorded neurons demonstrated a prominent low-threshold burst, and of these, 83% were cholinergic. In current-clamp recordings 64% of the bursting cholinergic neurons tested responded to the application of 5-HT with a membrane hyperpolarization and decrease in input resistance. This effect was mimicked by application of the selective 5-HT type 1 receptor agonist carboxamidotryptamine maleate. Whole-cell patch-clamp recordings revealed that the hyperpolarizing response was mediated by an inwardly rectifying K+ current. Application of 5-HT decreased excitability and markedly modulated the discharge pattern of cholinergic bursting neurons: during a 5-HT-induced hyperpolarization these neurons exhibited no rebound burst after hyperpolarizing current input and a burst in response to depolarizing current input. In the absence of 5-HT, the relatively depolarized cholinergic bursting neurons responded to an identical hyperpolarizing current input with a burst and did not produce a burst after depolarizing current input. These data provide a cellular and molecular basis for the hypothesis that 5-HT modulates rapid eye movement sleep phenomenology by altering the firing pattern of bursting cholinergic neurons.

Peripheral and central components of alerting: Habituation of acoustic startle, orienting responses, and elicited waveforms.

Behavioral orienting (OR), the acoustic startle reflex (ASR), pontogeniculooccipital (PGO) waves in the lateral geniculate body, and midlatency auditory evoked responses (MLR) represent components of alerting. The habituation rate for each was examined to test the hypothesis that OR, ASR, and PGO waves have related underlying neural mechanisms and determine the similarity in responsiveness between elicited PGO waves (PGOE) and elicited waves in the thalamic central lateral nucleus (CLE), a site that yields MLR. PGOE and CLE waves did not habituate in amplitude after 120 tones; however, the pattern of responses for each waveform was different. OR and ASR significantly decreased amplitude across trials with OR exhibiting a faster, more pronounced decrement. Some separation exists between the peripheral (OR and ASR) and central (PGOE and CLE) components of alerting. PGO and CL waves may have common underlying neural mechanisms.

Substantia nigra reticulata neurons during sleep-waking states: relation with ponto-geniculo-occipital waves

We have previously hypothesized that the spike bursts of brainstem peribrachial (PB) neurons, leading to ponto-geniculo-occipital (PGO) waves in thalamocortical systems, are triggered by phasic hyperpolarizations of sufficient magnitude or by excitatory inputs reaching a steadily hyperpolarized membrane. We have proposed that the source of these hyperpolarizing actions are substantia nigra pars reticulata (SNr) cells that project to, and exert inhibitory effects upon, PB neurons. Here we tested this hypothesis by recording antidromically identified SNr-PB cells in chronically implanted, naturally sleeping cats. A subpopulation of SNr-PB cells exhibited tonically increased firing preceding by 70–200 ms the thalamic PGO wave. These data support the hypothesis that an enhancement in SNr-cells' discharges may lead to hyperpolarization of PB neurons, with the consequence of spike bursts in one class of PGO-related PB-thalamic neurons.

The effects of changing state on elicited ponto-geniculo-occipital (PGO) waves

Waves similar to ponto-geniculo-occipital (PGO) waves occurring spontaneously in the lateral geniculate body (LGB) pons, and occipital cortex during rapid eye movement (REM) sleep can be elicited in the LGB and the cortex by tones in waking (W), non-rapid eye movement sleep (NREM), and REM. In W, the elicited waves (PGO E) sometimes accompany orienting responses (OR). We have hypothesized that REM is a state resembling exaggerated “orienting” in part because spontaneous PGO waves similar to PGO E accompanying OR are constantly observed in REM. The present experiment tested whether: (1) PGO E and OR were strongly correlated in W across a large number of tone presentations as might be predicted if PGO E were central wave from markers for a state of orienting; and (2) recovery of responsiveness of PGO E to tones would then be greater in REM than NREM, as might be expected if REM but not NREM were a state in which central mechanisms of orienting were highly active. Tones were presented in W and tn REM and NREM to six cats in order to measure the degree of habituation of OR and PGO E simultaneously. PGO E and OR exhibited a degree of independence: the former were readily produced in W despite the rapid decline in OR across trials. Recovery in the amplitude of PGO E occurred in both NREM and REM. The recovery tended to be greater in REM and NREM, although this was not statistically significant. Refinements of the theory that REM represents a state of exaggerated internal orienting are discussed.

Chapter 38 Effects of local pontine injection of noradrenergic agents on desynchronized sleep of the cat

Brain noradrenergic (NA) systems have often been implicated in the regulation of desynchronized sleep (DS). The present experiments investigate the effects on DS of the microinjection, into the cat dorsal pontine tegmentum (DPT), of the alpha 2-agonist clonidine (CLON), the beta-agonist isoproterenol and the beta-antagonist propranolol. The DPT comprises most NA neurons belonging to the locus coeruleus (LC) complex, as well as other cell groups thought to be crucially involved in DS generation. Cats were implanted with standard electrodes (electroencephalogram, electrooculogram and electromyogram, PGO waves, hippocampal activity) and with guide tubes aimed at the DPT. Unilateral or bilateral injections (0.25 microliter) were performed by way of thin cannulae inserted through the guide tubes. Polygraphic activity was then recorded in daily sessions lasting 4 h and scored according to standard criteria. Bilateral injections of CLON into the DPT greatly reduced DS, while unilateral injections were much less effective. Since CLON is known to powerfully inhibit NA LC neurons, its effect was thus opposite to that expected on the basis of the reciprocal interaction model of DS generation, which postulates that NA neurons in the LC inhibit DS-executive cells located in the pontine reticular formation. Bilateral injections of the beta-agonist isoproterenol also reduced DS, while the beta-antagonist propranolol consistently enhanced it, the latter largely due to an increased number of DS episodes. These effects were dose-dependent and strictly site-specific, since injections in immediately neighboring structures were ineffective.(ABSTRACT TRUNCATED AT 250 WORDS)

Anatomical interconnections of the pedunculopontine tegmental nucleus and the nucleus prepositus hypoglossi in the cat

The Pedunculopontine tegmental nucleus (PPT) is a mesopontine structure containing predominantly cholinergic neurons, and physiological data indicate its neurons transfer eye-movement gated ponto-geniculo-occipital (PGO) waves to thalamus during the rapid eye movement phase of sleep. The present study, using anterograde and retrograde tracing of wheat germ agglutinin-conjugated horseradish peroxidase, found that the medullary nucleus Prepositus hypoglossi (PH), whose neurons are known to have eye-movement-related information, projects densely to PPT, and PPT has reciprocal projections to PH. The PH-PPT projection has some topographic organization, with rostral PH to rostral PPT and caudal PH to caudal PPT projections dominating. The PH-PPT projection may furnish the anatomical substrate for input of eye movement-related information into the rostral PGO wave system.

Suppression of the PGO-related lumbar motoneuron IPSP by strychnine

Intracellular recordings from lumbar motoneurons in chronic unanesthetized cats revealed that a distinct inhibitory postsynaptic potential (IPSP) occurs following pontogeniculooccipital;(PGO) waves during active sleep. Strychnine, when applied juxtacellularly by microiontophoresis, was found to block this IPSP. These data suggest that glycine is likely to be the neurotransmitter that is responsible for the inhibition of lumbar motoneurons that occurs in conjunction with the PGO waves of active sleep.

Facilitation of the acoustic startle reflex by ponto-geniculo-occipital waves: effects of PCPA

The relationship between ponto-geniculo-occipital (PGO) waves and motor activity during waking and non-rapid eye movement (non-REM) sleep stages was studied in cats treated with the serotonin synthesis inhibitor p-chlorephenylalanine (PCPA). PGO waves appeared in waking after daily treatment with PCPA. The magnitude of the acoustic startle elicited in the absence of prior PGO waves increased (by a mean of 555%) by the PCPA treatment as compared to that of the pre-drug level. When startle-eliciting stimuli were presented shortly after the occurrence of the PGO wave, the response amplitude was further enhanced as compared to that fo the baseline startle. The effects was maximal 50 ms following the peak of the PGGO wave (average 192% of the baseline level), with return to the baseline startle level within 200 ms. A similar effect could also be seen with waking eye-movement potentials (EMPs) in drug-naive animals. Over half of the spontaneous PGO waves were found to be precedded or followed by discrete head-body movements. After PCPA, the amplitude of auditory-evoked LGN PGO waves increased during quiet waking (QW) while those in non-REM and REM sleep states did not change. It was concluded that serotonergic systems produce a ttonic suppression of startle response and PGO amplitude in waking. PGO spikes in waking are associated with phasic facilitation of the sensorimotor mechanisms involved in startle.

Effects of monoamine reuptake blockade on ponto-geniculo-occipital wave activity

Norepinephrine (NE) and serotonin (5HT) likely inhibit the generation of ponto-geniculo-occipital (PGO) waves. Either desipramine (DMI) or sertraline (SER:1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-cetrahydro-1-naphthylamine) was administered in the cat for 2.5 weeks to probe noradrenergic and serotonergic mechanisms, respectively. Placebo days were compared with the first day of drug and with days that followed 2.5 weeks of drug (chronic). PGO rates during REM sleep and the preceding transition period were significantly decreased by either chronic DMI or SER. Cat PGO waves resemble waves that accompany alerting to intense or novel stimuli in wakefulness. Depressive disorders in humans have features of hyperarousal; PGO wave suppression by antidepressant drugs may relate to clinical antidepressant actions.

Inhibition of carbachol microinjections of presumptive cholinergic PGO-on neurons in freely moving cats

The effects of microinjections of a cholinergic agonist, carbachol (0.2 μg/0.2 μl), were examined on a population of presumptive cholinergic mesopontine PGO-on neurons that presents a tonic pattern of discharge during waking and exhibits short bursts preceding the onset of dorsal lateral geniculate PGO waves during paradoxical sleep and slow wave sleep just prior to it. PGO-on neurons were activated antidromically by the stimulation of the dorsal lateral geniculate, pulvinar and/or medial and intralaminar nuclei. They were all characterized by a long spike duration and a slow conduction velocity. Microinjections of carbachol near unit recording sites in freely moving cats induced a complete suppression of the spontaneous tonic activity during waking, but did not suppress the spontaneous phasic burst activity during sleep. Carbachol microinjections also resulted in a marked reduction in responsiveness of PGO-on neurons to orthodromic stimulation. These spike depressant effects lasted for approximately 90–120 min and were reversed completely by a local or systemic administration of atropine sulfate. These findings point to a direct inhibition of central cholinergic PGO-on neurons via a muscarinic autoreceptor and a difference in the mechanisms underlying the generation of tonic and phasic burst activity of PGO-on neurons occurring during waking and sleep.

Brainstem genesis of reserpine-induced ponto-geniculo-occipital waves: An electrophysiological and morphological investigation

Several experimental results indicate that the peribrachial (PB) cholinergic area of the pedunculopontine nucleus is the final relay for the transfer of brainstem-generated pontogeniculo-occipital (PGO) waves to the thalamus. However, the mechanisms underlying the PGO-related activity of PB neurons remain unknown. In order to study these mechanisms, single unit recordings in the PB area were performed in reserpinized cats. Because PGO waves are closely related to rapid eye movements, our microelectrode explorations were also aimed to some structures of the preoculomotor network, namely, the superior colliculus (SC) and parts of the central tegmental field (FTC). We have found several classes of PGO-on cells in the PB area, most of them descharging 80 ms or less before the peak of PGO waves. These cell-classes comprised high-frequency bursting cells, slow-frequency bursting cells, and neurons discharging single spikes or doublets. Intracellular recordings showed that PGO-on single spikes arise from conventional excitatory postsynaptic potentials. Among PGO-related cells in structures outside the PB limits, it was found that most SC cells discharge during or after the PGO, whereas FTC cells increase their discharge rate several hundreds of ms before PGO waves, thus indicating that PGO waves are elaborated long before the activation of PB neurons. Massive retrograde labeling was found in FTC following horseradish peroxidase injections into the PB area. We suggest that long-lead FTC neurons provide an excitatory input to PGO-on PB neurons.

Different cellular types in mesopontine cholinergic nuclei related to ponto-geniculo-occipital waves

The only mesopontine neurons previously described as involved in the transfer of ponto-geniculo-occipital (PGO) waves from the brain stem to the thalamus were termed PGO-on bursting cells. We have studied, in chronically implanted cats, neuronal activities in brain-stem peribrachial (PB) and laterodorsal tegmental (LDT) cholinergic nuclei in relation to PGO waves recorded from the lateral geniculate (LG) thalamic nucleus during rapid-eye-movement (REM) sleep. We constructed peri-PGO histograms of PB/LDT cells' discharges and analyzed the interspike interval distribution during the period of increased neuronal activity related to PGO waves. Six categories of PGO-related PB/LDT neurons with identified thalamic projections were found: 4 classes of PGO-on cells: PGO-off but REM-on cells: and post-PGO cells. The physiological characteristics of a given cell class were stable even during prolonged recordings. One of these cell classes (1) represents the previously described PGO-on bursting neurons, while the other five (2-6) are newly discovered neuronal types. (1) Some neurons (16% of PGO-related cells) discharged stereotyped low-frequency (120-180 Hz) spike bursts preceding the negative peak of the LG-PGO waves by 20-40 msec. These neurons had low firing rates (0.5-3.5 Hz) during all states. (2) A distinct cell class (22% of PGO-related neurons) fired high-frequency spike bursts (greater than 500 Hz) about 20-40 msec prior to the thalamic PGO wave. These bursts were preceded by a period (150-200 msec) of discharge acceleration on a background of tonically increased activity during REM sleep. (3) PGO-on tonic neurons (20% of PGO-related neurons) discharged trains of repetitive single spikes preceding the thalamic PGO waves by 100-150 msec, but never fired high-frequency spike bursts. (4) Other PGO-on neurons (10% of PGO-related neurons) discharged single spikes preceding thalamic PGO waves by 15-30 msec. On the basis of parallel intracellular recordings in acutely prepared, reserpine-treated animals, we concluded that the PGO-on single spikes arise from conventional excitatory postsynaptic potentials and do not reflect tiny postinhibitory rebounds. (5) A peculiar cellular class, termed PGO-off elements (8% of PGO-related neurons), consisted of neurons with tonic, high discharge rates (greater than 30 Hz) during REM sleep. These neurons stopped firing 100-200 msec before and during the thalamic PGO waves. (6) Finally, other neurons discharged spike bursts or tonic spike trains 100-300 msec after the initially negative peak of the thalamic PGO field potential (post-PGO elements, 23% of PGO-related neurons).(ABSTRACT TRUNCATED AT 400 WORDS)

Evoked potentials during REM sleep reflect dreaming

Polygraphic recordings were collected for 11 normal subjects during sleep and wakefulness in order to investigate characteristics of the rapid eye movement (REM) associated potentials. EEGs were averaged using 5 different triggering points: (1) saccade onset under the normal ambient illumination, (2) saccade onset in the total darkness. (3) onset of REMs during REM sleep, (4) flash during REM sleep, and (5) flash during stage 2 sleep. In the central area, positive potentials appeared with waking saccades under the normal ambient illumination (P240L) and REMs (P185R). The latency of P185R associated with REMs was significantly shorter than that of P240L associated with waking saccades. These findings suggest that P185R is evoked by PGO waves occurring just before the REM. A small positive potential appeared in the occipital area with waking saccade under the normal ambient illumination (P260L) and REMs in the total darkness (250R). Conspicuous absence of these waves for waking saccades in the total darkness suggests that P250R accompanied with REMs reflects activities involved with the cognitive processes occurring when a subject scans a dream image during REM sleep.

Chronic Zimeldine Administration to Cats: Sustained Increase of Serotonergic Effect as Measured with Sleep Parameters

Sleep effects of oral administration of the serotonin uptake inhibitor zimeldine to cats on 15 consecutive days was measured. On administration days 8 and 15 REM sleep and PGO activity were significantly reduced. The amount of SWS-2 was not changed for the whole group, but a subgroup with low baseline values showed an increase during zimeldine administration. A REM sleep rebound was observed on withdrawal day 2, and NREM sleep PGO activity was increased on withdrawal day 5. The results indicate an increased serotonergic inhibition of PGO wave activity and REM sleep during chronic administration of zimeldine.

Phasic activation of lateral geniculate and perigeniculate thalamic neurons during sleep with ponto-geniculo-occipital waves

Ponto-geniculo-occipital (PGO) waves are spiky field potentials generated in cholinergic nuclei of the dorsolateral mesopontine tegmentum just prior to and during rapid-eye-movement (REM) sleep and transferred toward thalamic nuclei. These events are commonly regarded as physiological correlates of oneiric behavior. We have examined the PGO-related discharges of physiologically identified neurons located in the dorsal lateral geniculate (LG) nucleus and perigeniculate (PG) sector of the reticular thalamic complex in chronically implanted, naturally sleeping cats. PGO focal waves and associated unit discharges were simultaneously recorded by the same microelectrode. PGO waves herald the other signs of REM sleep (EEG desynchronization and muscular atonia), appearing 30-90 sec before REM sleep over the EEG-synchronized activity of slow-wave sleep (pre-REM epoch). (1) Most PG neurons discharged bursts of action potentials in relation to PGO waves during both pre-REM and REM sleep. (2) The PGO-related activity of LG neurons was quite different. During the pre-REM stage, PGO waves correlated with a short (7-15 msec), high-frequency (300-500 Hz) spike burst of LG neurons, followed by a long (0.2-0.4 sec) train of single spikes, whereas during REM sleep, the PGO-related activity lacked the initial burst and consisted of a spike train that only slightly exceeded the tonically increased background firing of LG cells. The stereotyped characteristics of the PGO-related spike bursts during the pre-REM epoch suggest that they are the extracellular reflection of a low-threshold spike deinactivated by the tonic membrane hyperpolarization of LG cells associated with the EEG-synchronized sleep state. Such bursts are inactivated during the tonic depolarization of LG cells that occurs in REM sleep. The synchronous spike bursts discharged by LG cells in relation with the PGO waves of the pre-REM epoch probably underlie the much larger amplitude of the PGO waves of the pre-REM epoch as compared with those of the REM-sleep state. Since LG neurons have relatively low spontaneous firing rates during the EEG-synchronized pre-REM epoch, the PGO-related activity of this transitional stage leads to a higher signal-to-noise ratio in the visual thalamocortical channel than during REM sleep. We suggest that the PGO-related activity during the pre-REM epoch is related to vivid imagery during this stage of sleep.

The effects of tones on PGO waves in slow wave sleep and paradoxical sleep

Ponto-geniculo-occipital (PGO) waves are macropotential waveforms occurring spontaneously during paradoxical sleep (PS) in the pons, the lateral geniculate body (LGB), and the occipital cortex of the cat. In our earlier work (6, 20) tones elicited waves in the LGB and the occipital cortex during both slow wave sleep (SWS) and PS that resembled PGO waves in form and amplitude. Using a limited and variable number of trials, we observed that these elicited waveforms, which we term elicited PGO waves (PGO E), seemed to decline rapidly in amplitude and probability during SWS but not during PS. The present two experiments served as a more rigorous test of the hypothesis that the rate of habituation of PGO E would be more rapid in SWS. In a first experiment seven cats were studied in up to four sessions in PS and four in SWS; each session consisted of 32 1000-Hz, 90-dB SPL tones lasting 90 ms. We found that (i) the number of PGO E was significantly greater in PS; (ii) the mean amplitude of the waves was greater in PS; (iii) the probability of eliciting a wave tended to decline faster in SWS, but some decline also occurred in PS; and (iv) on the first trial, PGO E were more easily produced in SWS. Results of a second experiment with five cats suggested that the decline in the probability of PGO E in PS was not accounted for by differences in the ease of eliciting them at different times into a PS episode. The role of the dorsal raphe nucleus (DRN) in modulating state-dependent differences in PGO E is discussed.

Differential enhancement of rapid eye movement sleep signs in the cat: a comparison of microinjection of the cholinergic agonist carbachol and the β-adrenergic antagonist propranolol on pontogeniculo-occipital wave clusters

The cholinergic agonist carbachol and the β-adrenergic antagonist propranolol were microinjected at the same pontine sites and their effects on polygraphic rapid eye movement (REM) sleep, especially pontogeniculo-occipital (PGO) waves, were measured. While both propranolol and carbachol enhanced PGO wave activity and polygraphic REM sleep, the carbachol-correlated enhancement was more impressive. The increases in REM sleep signs elicited by carbachol were 5-fold over baseline and lasted throughout the 4-h recording period. Propranolol elicited 2.5-fold increases that were significant in the first 2 h only. Yet, the increase in PGO wave activity evoked by propranolol was equal to that of carbachol during non-REM sleep and wakefulness. The results indicate that while propranolol is less potent in activating the distributed neuronal network responsible for REM sleep generation, it selectively facilitates that part of the network responsible for PGO waves.

PGO waves and insomnia in PCPA-treated rats

The serotonin-depleting drug, parachlorophenylalanine (PCPA), in a dosage of 300 mg/kg, was administered to rats in an effort to test the hypothesis that altered distribution of PGO waves following drug treatment may be responsible for the sleep disruption and consequent sleep loss that accompany decreased serotonin levels. Consistent with the hypothesis, we found that the greater the proportion of PGO waves that precede spontaneous arousals, the greater the reduction in slow wave sleep. However, inconsistent with the hypothesis, we found that the decrease in sleep did not result from an increase in the number of arousals. Further, though an increase in the proportion of waking waves always accompanied a rise in wake time, the two variables were negatively correlated. These data do not support a PGO wave/arousal hypothesis to account for the decrease in sleep following PCPA treatment in the rat. Rather, the findings tend to implicate an alteration in the mechanisms of arousal linked to serotonin depletion.