Héctor Jantos

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.

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.

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.

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.

Effects of the selective dopamine D-2 receptor agonist, quinpirole on sleep and wakefulness in the rat

The effects of the dopamine D-2 receptor agonist, quinpirole, were compared with those produced by dopamine D-2 antagonist, YM-09151-2, in rats implanted with electrodes for chronic sleep recordings. Quinpirole (0.015-1.0 mg/kg) induced biphasic effects such that low doses decreased wakefulness and increased sleep, while higher doses induced the opposite effects. At 0.015 mg/kg, YM-09151-2 slightly augmented wakefulness, while at 1.0-2.0 mg/kg it significantly increased light sleep but depressed REM sleep. Pretreatment with YM-09151-2 in a dose which preferentially acts at presynaptic sites reversed the suppressant effects of a low dose of quinpirole on wakefulness and slow wave sleep. In contrast, the administration of YM-09151-2 in a dose which blocks postsynaptic D-2 receptors prevented the effect of a high dose of quinpirole on wakefulness and slow wave sleep; the depression of REM sleep was not affected. The opposite effects observed on the waking EEG after activation of either dopamine autoreceptors or postsynaptic D-2 receptors with adequate doses of quinpirole tend to indicate an active role for DA in the control of the waking state.

Sleep and waking during acute histamine H3 agonist BP 2.94 or H3 antagonist carboperamide (MR 16155) administration in rats.

The present study evaluated the effects of histamine H3 receptor agonist BP 2.94 or H3 receptor antagonist carboperamide (MR 16155) given by oral route on sleep and waking in rats surgically prepared for long-term recordings.BP 2.94 produced a significant increase of slow-wave sleep (SWS) that was related to slight decreases of waking, light sleep, and REM sleep. Carboperamide significantly increased waking and decreased SWS and REM sleep. Pretreatment with carboperamide prevented the effect of BP 2.94 on SWS.It is suggested that the effects of BP 2.94 or carboperamide on sleep and waking could depend on changes in the availability of histamine at the postsynaptic H1 receptor. Alternatively, activation or blockade of the H3 heteroreceptors found in the central catecholamine, indolamine, and acetylcholine nerve endings could inhibit or increase the release of noradrenaline, serotonin, dopamine, and acetylcholine. This would secondarily result in changes of sleep variables.

The effects of selective activation of the 5-HT3 receptor with m-chlorophenylbiguanide on sleep and wakefulness in the rat

The effects of the 5-HT3 receptor agonist, m-chlorophenylbiguanide, were compared with those of the 5-HT3 receptor antagonist, MDL 72222, in rats implanted with electrodes for chronic sleep recordings. m-Chlorophenylbiguanide (12.5-50.0 micrograms) injected into the left lateral ventricle increased wakefulness and rapid eye movement (REM) sleep latency, whereas slow wave sleep, REM sleep and the number of REM periods were reduced. MDL 72222 (0.1-1.0 mg/kg, s.c.) induced a delayed and dose-dependent increase of slow wave sleep. Pretreatment with MDL 72222 (0.1-0.5 mg/kg) prevented the effects of m-chlorophenylbiguanide (50 micrograms) on wakefulness and sleep. It is suggested that the increase of wakefulness after 5-HT3 receptor activation could be related to the release of endogenous serotonin and dopamine.

The serotonin 5-HT7 receptor agonist LP-44 microinjected into the dorsal raphe nucleus suppresses REM sleep in the rat

The effects of LP-44, a selective 5-HT7 receptor agonist, and of SB-269970, a selective 5-HT7 receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The 5-HT7 receptor ligands were microinjected directly into the dorsal raphe nucleus (DRN) during the light period of the 12-h light/12-h dark cycle. Infusion of LP-44 (1.25-5.0 mM) into the DRN induced a significant reduction of rapid-eye-movement sleep (REMS) and of the number of REM periods. Similar effects were observed after the direct administration into the DRN of SB-269970 (0.5-1.0 mM). Pretreatment with a dose of SB-269970 (0.5 mM) that significantly affects sleep variables antagonized the LP-44 (2.5 mM)-induced suppression of REMS and of the number of REM periods. It is proposed that the suppression of REMS after microinjection of LP-44 into the DRN is related, at least in part, to the activation of GABAergic neurons in the DRN that contribute to long projections that reach, among others, the laterodorsal and pedunculopontine tegmental nuclei involved in the promotion of REMS.