Jaime M. Monti

Serotonin control of sleep-wake behavior

Based on electrophysiological, neurochemical, genetic and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) functions predominantly to promote wakefulness (W) and to inhibit REM (rapid eye movement) sleep (REMS). Yet, under certain circumstances the neurotransmitter contributes to the increase in sleep propensity. Most of the serotonergic innervation of the cerebral cortex, amygdala, basal forebrain (BFB), thalamus, preoptic and hypothalamic areas, raphe nuclei, locus coeruleus and pontine reticular formation comes from the dorsal raphe nucleus (DRN). The 5-HT receptors can be classified into at least seven classes, designated 5-HT(1-7). The 5-HT(1A) and 5-HT(1B) receptor subtypes are linked to the inhibition of adenylate cyclase, and their activation evokes a membrane hyperpolarization. The actions of the 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptor subtypes are mediated by the activation of phospholipase C, with a resulting depolarization of the host cell. The 5-HT(3) receptor directly activates a 5-HT-gated cation channel which leads to the depolarization of monoaminergic, aminoacidergic and cholinergic cells. The primary signal transduction pathway of 5-HT(6) and 5-HT(7) receptors is the stimulation of adenylate cyclase which results in the depolarization of the follower neurons. Mutant mice that do not express 5-HT(1A) or 5-HT(1B) receptor exhibit greater amounts of REMS than their wild-type counterparts, which could be related to the absence of a postsynaptic inhibitory effect on REM-on neurons of the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT). 5-HT(2A) and 5-HT(2C) receptor knock-out mice show a significant increase of W and a reduction of slow wave sleep (SWS) which has been ascribed to the increase of catecholaminergic neurotransmission involving mainly the noradrenergic and dopaminergic systems. Sleep variables have been characterized, in addition, in 5-HT(7) receptor knock-out mice; the mutants spend less time in REMS that their wild-type counterparts. Direct infusion of the 5-HT(1A) receptor agonists 8-OH-DPAT and flesinoxan into the DRN significantly enhances REMS in the rat. In contrast, microinjection of the 5-HT(1B) (CP-94253), 5-HT(2A/2C) (DOI), 5-HT(3) (m-chlorophenylbiguanide) and 5-HT(7) (LP-44) receptor agonists into the DRN induces a significant reduction of REMS. Systemic injection of full agonists at postsynaptic 5-HT(1A) (8-OH-DPAT, flesinoxan), 5-HT(1B) (CGS 12066B, CP-94235), 5-HT(2C) (RO 60-0175), 5-HT(2A/2C) (DOI, DOM), 5-HT(3) (m-chlorophenylbiguanide) and 5-HT(7) (LP-211) receptors increases W and reduces SWS and REMS. Of note, systemic administration of the 5-HT(2A/2C) receptor antagonists ritanserin, ketanserin, ICI-170,809 or sertindole at the beginning of the light period has been shown to induce a significant increase of SWS and a reduction of REMS in the rat. Wakefulness was also diminished in most of these studies. Similar effects have been described following the injection of the selective 5-HT(2A) receptor antagonists volinanserin and pruvanserin and of the 5-HT(2A) receptor inverse agonist nelotanserin in rodents. In addition, the effects of these compounds have been studied on the sleep electroencephalogram of subjects with normal sleep. Their administration was followed by an increase of SWS and, in most instances, a reduction of REMS. The administration of ritanserin to poor sleepers, patients with chronic primary insomnia and psychiatric patients with a generalized anxiety disorder or a mood disorder caused a significant increase in SWS. The 5-HT(2A) receptor inverse agonist APD-125 induced also an increase of SWS in patients with chronic primary insomnia. It is known that during the administration of benzodiazepine (BZD) hypnotics to patients with insomnia there is a further reduction of SWS and REMS, whereas both variables tend to remain decreased during the use of non-BZD derivatives (zolpidem, zopiclone, eszopiclone, zaleplon). Thus, the association of 5-HT(2A) antagonists or 5-HT(2A) inverse agonists with BZD and non-BZD hypnotics could be a valid alternative to normalize SWS in patients with primary or comorbid insomnia.

The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking.

Based on electrophysiological, neurochemical and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) and dopamine (DA) function to promote waking (W) and to inhibit slow wave sleep (SWS) and/or rapid-eye-movement sleep (REMS). Serotonergic neurons of the dorsal raphe nucleus (DRN) fire at a steady rate during W, decrease their firing during SWS and virtually cease activity during REMS. On the other hand, DA cells in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) do not change their mean firing rate across the sleep-wake cycle. It has been proposed that DA cells in the midbrain show a change in temporal pattern rather than firing rate during the sleep-wake cycle. Available evidence tends to indicate that during W and REMS an increase of burst firing activity of DA neurons occurs together with an enhanced release of DA in the VTA, the nucleus accumbens and several forebrain structures. Recently, DA neurons were characterised in the ventral periaqueductal grey matter (VPAG) that express Fos protein during W. Lesioning of these cells resulted in an increase of SWS and REMS, which led to the proposal that VPAG DA neurons may play a role in the promotion of W. Systemic injection of full agonists at postsynaptic 5-HT(1A) (8-OH-DPAT, flesinoxan), 5-HT(1B) (CGS 12066B, CP-94,253), 5-HT(2A/2C) (DOI, DOM) and 5-HT(3) (m-chlorophenylbiguanide) receptors increases W and reduces SWS and REMS. On the other hand, microdialysis perfusion or direct infusion of 8-OH-DPAT or flesinoxan into the DRN, where somatodendritic 5-HT(1A) receptors are located, significantly increases REMS. Systemic administration of the selective DA D(1) receptor agonist SKF 38393 induces behavioural arousal together with an increase of W and a reduction of sleep. On the other hand, injection of a DA D(2) receptor agonist (apomorphine, bromocriptine, quinpirole) gives rise to biphasic effects, such that low doses reduce W and augment SWS and REMS whereas large doses induce the opposite effects. Not much is known about dopamine-serotonin interaction in the regulation of sleep and W. It has been shown that VTA and SNc DA neurons and DRN 5-HT neurons influence each other. Thus, depending on the receptor subtype involved, 5-HT either facilitates or inhibits the functioning of DA cells. On the other hand, activation of DA D(2)-like receptors in the DRN increases the activity of 5-HT neurons. Thus, it can be speculated that local microinjection of DA and 5-HT ligands into the DRN and the VTA/SNc, respectively, would affect the actions of the corresponding neurons on sleep and W.

Sleep in schizophrenia patients and the effects of antipsychotic drugs

Insomnia is a common feature in schizophrenia. However, it seldom is the predominant complaint. Nevertheless, severe insomnia is often seen during exacerbations of schizophrenia, and may actually precede the appearance of other symptoms of relapse. The sleep disturbances of either never-medicated or previously treated schizophrenia patients are characterized by a sleep-onset and maintenance insomnia. In addition, stage 4 sleep, slow wave sleep (stages 3 and 4), non-REM (NREM) sleep in minutes and REM latency are decreased. The atypical antipsychotics olanzapine, risperidone, and clozapine significantly increase total sleep time and stage 2 sleep. Moreover, olanzapine and risperidone enhance slow wave sleep. On the other hand, the typical antipsychotics haloperidol, thiothixene, and flupentixol significantly reduce stage 2 sleep latency and increase sleep efficiency. Future research should address: (1) the sleep patterns in subtypes of schizophrenia patients; (2) the role of neurotransmitters other than dopamine in the disruption of sleep in schizophrenia; (3) the functional alterations in CNS areas related to the pathophysiology of schizophrenia during NREM sleep and REM sleep (brain imaging studies); (4) the short-term, intermediate-term, and long-term effects of atypical antisychotics on sleep variables.

Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat.

The effects of the dopamine (DA) receptor agonists apomorphine, bromocriptine and pergolide were compared with those produced by a DA receptor antagonist, haloperidol, in rats implanted with electrodes for chronic sleep recordings. Apomorphine (0.025–2.0 mg/kg) and bromocriptine (0.25–6.0 mg/kg) induced biphasic effects such that low doses decreased wakefulness (W) and increased slow wave sleep (SWS) and REM sleep (REMS), while large doses induced opposite effects. The effects of pergolide (0.05–0.5 mg/kg) on W and SWS were also biphasic, while REMS was suppressed over the range of dosages given. At 0.040 mg/kg, haloperidol increased W, while at 0.160 mg/kg it produced the opposite effect. Pretreatment with haloperidol (0.020 mg/kg) in a dose which preferentially acts at presynaptic sites reversed the effects of low doses of apomorphine, bromocriptine or pergolide on sleep and W. However, the compound differed substantially in its ability to block agonist effects.The increase in sleep after low doses of apomorphine, bromocriptine or pergolide could be related to activation of presynaptic D-2 receptors located on DA axons of mesolimbic and mesocortical systems. In addition, inhibition of norepinephrine and acetylcholine neurons having inhabitory D-2 receptors could contribute to the increase of sleep after small doses of the DA agonists.

Effects of selective activation or blockade of the histamine H3 receptor on sleep and wakefulness

Abstract The effects of the histamine H 3 receptor agonist, (R)-α-methylhistamine were compared with those of the histamine H 3 antagonist, thioperamide, in rats implanted with electrodes for chronic sleep recordings. (R)-α-Methylhistamine (1.0–4.0 μg) injected bilaterally into the premammillary area where histamine immunoreactive neurons have been detected increased slow wave sleep, whereas wakefulness and REM sleep were decreased. No significant effects were observed when (R)-α-methylhistamine (1.0–8.0 mg/kg) was administered i.p. Thioperamide (1.0–4.0 mg/kg i.p.) increased wakefulness and decreased slow wave sleep and REM sleep. Pretreatment with thioperamide (4.0 mg/kg) prevented the effects of (R)-α-methylhistamine (2.0 μg) on slow wave sleep and wakefulness. Our results further support an active role for histamine in the control of the Waking state.

Sleep disturbance in schizophrenia.

Insomnia is a common symptom in schizophrenia, although it is seldom the predominant complaint. Sleep-onset and maintenance insomnia is a characteristic feature of schizophrenic patients regardless of either their medication status (drug-naive or previously treated) or the phase of the clinical course (acute or chronic). Regarding sleep architecture, the majority of studies indicate that stage 4 sleep and rapid eye movement (REM) latency are reduced in schizophrenia, whereas REM sleep duration tends to remain unchanged. Insomnia in schizophrenic patients could be partly related to the presumed over-activity of the dopaminergic system. However, there is a possibility that the GABAergic system is also involved in sleep disturbance in schizophrenia. Since many signal transmission systems within the CNS can be implicated in the reduction of REM latency in schizophrenia, the characterization of the neurotransmitter systems involved remains a challenging dilemma.

Dose-dependent effects of the 5-HT1A receptor agonist 8-OH-DPAT on sleep and wakefulness in the rat

SUMMARY  Sleep and wakefulness were studied in rats following administration of a selective 5‐HT1A agonist (8‐OH‐DPAT), a non‐selective 5‐HT1A antagonist [(‐) pindolol] and a combination of 8‐OH‐DPAT and (—) pindolol.

Effects on sleep of melanin-concentrating hormone (MCH) microinjections into the dorsal raphe nucleus.

Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are located in the lateral hypothalamus and incerto-hypothalamic area, and project diffusely throughout the central nervous system, including areas that participate in the generation and maintenance of the states of sleep and wakefulness. Recent studies have shown that the hypothalamic MCHergic neurons are active during rapid eye movements (REM) sleep, and that intraventricular microinjections of MCH induce slow wave sleep (SWS) and REM sleep. There are particular dense MCHergic projections to the dorsal raphe nucleus (DR), a neuroanatomical structure involved in several functions during wakefulness, and in the regulation of sleep variables. Because of this fact, we analyzed the effect of microinjections of MCH into this nucleus on sleep and waking states in the rat. Compared to control microinjections, MCH (100 ng) produced a moderate increase in SWS (243.7+/-6.0 vs. 223.2+/-8.8 min, p<0.05) and an important increment in REM sleep (35.5+/-2.5 vs. 20.8+/-3.4 min, p<0.01) due to an increase in the number of REM sleep episodes. The increase of REM sleep was accompanied by a reduction in the time spent in light sleep and wakefulness. We therefore conclude that the hypothalamic MCHergic system, via its action in the DR, plays an important role in the generation and/or maintenance of the states of sleep.

Role of dorsal raphe nucleus serotonin 5-HT1A receptor in the regulation of REM sleep

Cholinergic neurons in the laterodorsal (LDT) and the pedunculopontine (PPT) tegmental nuclei act to promote REM sleep (REMS). The predominantly glutamatergic neurons of the REMS-induction region of the medial pontine reticular formation are in turn activated by cholinergic cells, which results in the occurrence of tonic and phasic components of REMS. All these neurons are inhibited by serotonergic (5-HT), noradrenergic, and presumably histaminergic (H2 receptor) and dopaminergic (D2 and D3 receptor) cells. 5-Hydroxytryptamine-containing neurons in the dorsal raphe nucleus (DRN) virtually cease firing when an animal starts REMS, consequently decreasing the release of 5-HT during this state. The activation of GABA(A) receptors is apparently responsible for this phenomenon. Systemic administration of the selective 5-HT1A receptor agonist 8-OHDPAT induces dose-dependent effects; i.e. low doses increase slow wave sleep and reduce waking, whereas large doses increase waking and reduce slow wave sleep and REM sleep. Direct injection of 8-OHDPAT or flesinoxan, another 5-HT1A agonist into the DRN, or microdialysis perfusion of 8-OHDPAT into the DRN significantly increases REMS. On the other hand, infusion of 8-OHDPAT into the LDT selectively inhibits REMS, as does direct administration into the DRN of the 5-HT1A receptor antagonists pindolol or WAY 100635. Thus, presently available evidence indicates that selective activation of the somatodendritic 5-HT1A receptor in the DRN induces an increase of REMS. On the other hand, activation of the postsynaptic 5-HT1A receptor at the level of the PPT/LDT nuclei decreases REMS occurrence.

Effects of the D3 preferring dopamine agonist pramipexole on sleep and waking, locomotor activity and striatal dopamine release in rats.

Abstract Quantitation of 2 h sessions after administration of the D 3 preferring dopamine (DA) agonist pramipexole (10–500 μg/kg) showed dose-related effects on wakefulness (W), slow wave sleep (SWS) and REM sleep in rats. The 30 μg/kg dose of the DA agonist increased SWS and REM sleep and reduced W during the first recording hour, while the 500 μg/kg dose augmented W. On the other hand, W was increased while SWS and REMS were decreased after the 500 μg/kg dose during the second recording hour. The mixed D 2 - and D 3 receptor antagonist YM-09151-2 (30–500 μg/kg), which per se affected sleep variables prevented the increase of REMS induced by pramipexole. Furthermore, the highest doses (500–1000 μg/kg) of the DA antagonist effectively antagonized the increase of W and reduction of SWS induced by the 500 μg/kg dose of the DA agonist. Pramipexole (30–100 μg/kg) induced a decrease of locomotor activity during the 2 h recording period. In addition, the 500 μg/kg dose gave rise to an initial reduction of motor behavior which was reverted 2 h later. Pramipexole (30 and 500 μg/kg) did not significantly affect striatal DA release during the first two hours following drug administration, as measured by microdialysis. It is tentatively suggested that D 3 receptor could be involved in the pramipexole-induced increase of sleep and reduction of locomotor activity. On the other hand, the increase of W and of motor behavior after relatively high doses could be related to activation of postsynaptic D 2 receptor.