Suppression Of Sleep Research Articles

Effects of eszopiclone and zolpidem on sleep–wake behavior, anxiety-like behavior and contextual memory in rats

At present, eszopiclone and zolpidem are the most commonly prescribed drugs for treating insomnia. Despite the established relationship between sleep disturbance and anxiety, it remains unknown whether targeted treatment for insomnia may affect acute anxiety. Therefore, the objective of this study was to examine the effects of three different doses (1, 3, and 10mg/kg) of eszopiclone and zolpidem on the states of sleep and wakefulness, levels of anxiety-like behavior, and long-term contextual memory in footshock-induced anxious rats. The results of this study demonstrated that the administration of eszopiclone and zolpidem both were equally effective in attenuating footshock stressor-induced suppression of slow-wave sleep (SWS). The administration of eszopiclone at 1mg/kg or zolpidem at 1 and 3mg/kg doses showed a tendency for attenuating stressor-induced suppression of REM sleep. However, the REM sleep attenuating effects of these drugs disappeared when they were administered at higher doses. The administration of eszopiclone at 3 and 10mg/kg doses and zolpidem at all three doses reduced the power of electroencephalographic theta band frequencies during wakefulness. In addition, the administration of eszopiclone at 1 and 3mg/kg doses suppressed stressor-induced anxiety-like behavior. The administration of zolpidem at 1, 3, or 10mg/kg doses was not effective in attenuating stressor-induced anxiety-like behavior. Contextual memory after administration of eszopiclone at 1mg/kg dose had no effects, but was reduced significantly with increased dosage. Contextual memory after administration of zolpidem, at all three doses, was severely disrupted. The results of this study suggest that eszopiclone at a low dose could be used effectively to control anxiety and anxiety-induced insomnia.

Polysomnographic abnormalities in succinic semialdehyde dehydrogenase (SSADH) deficiency.

Patients with SSADH deficiency, a disorder of chronically elevated endogenous GABA and GHB, were studied for sleep symptoms and polysomnography. We hypothesized that patients would have excessive daytime somnolence and decreased REM sleep. Polysomnography and MSLT were performed on patients enrolled for comprehensive clinical studies of SSADH deficiency. Sleep studies were obtained in the sleep laboratories at CNMC and NIH. Sleep recordings were obtained in 10 patients with confirmed SSADH deficiency. Thirteen overnight polysomnograms were obtained in 10 patients (7 male, 3 female, ages 11-27 y). Eleven MSLT studies were completed in 8 patients. Polysomnograms showed prolongation of REM stage latency (mean 272 +/- 89 min) and decreased percent stage REM (mean 8.9%, range 0.3% to 13.8%). Decreased mean sleep latency was present in 6 of 11 MSLTs. SSADH deficiency is associated with prolonged latency to stage REM and decreased percent stage REM. This disorder represents a model of chronic GABA and GHB accumulation associated with suppression of REM sleep.

Alpha-fluoromethylhistidine, a histamine synthesis inhibitor, inhibits orexin-induced wakefulness in rats

Orexins A and B are involved in the regulation of feeding and arousal state. Previously, we reported that third intracerebroventricular (icv) infusion of both orexins A and B induced a significant arousal effect in rats. We determined the effects of intraperitoneal (i.p.) injection of alpha-fluoromethylhistidine (α-FMH), a histamine synthesis inhibitor, on orexin-induced wakefulness in freely behaving rats. Male Sprague–Dawley rats were chronically implanted with cortical electroencephalogram (EEG) and neck electromyogram (EMG) electrodes, and a cannula for icv infusion. EEG and EMG were monitored for three consecutive days during continuous icv saline infusion at a rate of 10 μl/h. For a 5-h diurnal period, orexin-B (10 nmol/50 μl saline) replaced the icv infusion of saline. α-FMH (100 mg/kg, i.p.) was administered 6 h before icv infusion of orexin-B. Orexin-B at a dose of 10 nmol/h markedly increased the amount of wakefulness by 99.4% ( p < 0.05) over the baseline value, whereas α-FMH decreased orexin-B-induced wakefulness by 48.8%. Orexin-B-induced suppression of non-REM sleep was reversed by α-FMH treatment. Pretreatment with α-FMH, significantly inhibited orexin-B-induced wakefulness in rats. The findings of this study therefore suggest that arousal-state regulation by orexin neurons is possibly mediated via the histaminergic system in the tuberomammilary nucleus.

Orexin neurons are necessary for the circadian control of REM sleep.

The orexin-producing neurons are hypothesized to be essential for the circadian control of sleep/wake behavior, but it remains unknown whether these rhythms are mediated by the orexin peptides or by other signaling molecules released by these neurons such as glutamate or dynorphin. To determine the roles of these neurotransmitters, we examined the circadian rhythms of sleep/wake behavior in mice lacking the orexin neurons (ataxin-3 [Atx] mice) and mice lacking just the orexin neuropeptides (orexin knockout [KO] mice). We instrumented mice for recordings of sleep-wake behavior, locomotor activity (LMA), and body temperature (Tb) and recorded behavior after 6 days in constant darkness. The amplitude of the rapid eye movement (REM) sleep rhythm was substantially reduced in Atx mice but preserved in orexin KO mice. This blunted rhythm in Atx mice was caused by an increase in the amount of REM sleep during the subjective night (active period) due to more transitions into REM sleep and longer REM sleep episodes. In contrast, the circadian variations of Tb, LMA, Wake, non-REM sleep, and cataplexy were normal, suggesting that the circadian timekeeping system and other output pathways are intact in both Atx and KO mice. These results indicate that the orexin neurons are necessary for the circadian suppression of REM sleep. Blunting of the REM sleep rhythm in Atx mice but not in orexin KO mice suggests that other signaling molecules such as dynorphin or glutamate may act in concert with orexins to suppress REM sleep during the active period.

Suppression of hippocampal cell proliferation by short‐term stimulant drug administration in adult rats

Sleep loss is known to potently suppress adult hippocampal cell proliferation and neurogenesis. Whether sleep suppression following acute administration of stimulant drugs also decreases hippocampal cell proliferation is not known. The present study examined the effect of three mechanistically distinct stimulants (caffeine, methamphetamine and modafinil) on cell proliferation. To maximize sleep suppression, these drugs were administered to rats (three i.p. injections, once every 4 h) during their sleep period (i.e. 12-h light phase). At the end of the light phase, 5-bromo-2'-deoxyuridine (200 mg/kg, i.p.) was injected and animals were killed 2 h later. Polygraphic recordings and locomotor activity measurements confirmed the wake-promoting and sleep-suppressing actions of each treatment. Results indicate that caffeine (20 mg/kg), methamphetamine (1.5 mg/kg) and modafinil (300 mg/kg) differentially suppressed sleep (45-91%) and selectively reduced cell proliferation in the hilus (12-44%), these results being significant for both caffeine and modafinil. When the same experiment was repeated in the dark (active) phase, the suppressant effect on hippocampal cell proliferation was either absent or greatly attenuated. In a further experiment, the effect of acute modafinil treatment in the light phase was shown to persist for 3 weeks after BrdU administration. We hypothesize that the differential effect of the stimulant drugs in the light vs. dark phase is attributable primarily to sleep suppression in the light. As abuse of stimulant drugs invariably leads to disrupted sleep in humans, our results suggest that they may, at least in part, decrease hippocampal neurogenesis via sleep loss and thereby adversely affect hippocampal-dependent processes.

Modulation of sickness behavior by sleep: The role of neurochemical and neuroinflammatory pathways in mice

Activation of the immune system elicits several behavioral changes that are collectively called sickness behavior and consists in a strategy to overcome infection. Sleep deprivation can increase susceptibility to pathogens and to behavioral alterations. Thus, the present study aimed to determine how paradoxical sleep deprivation (PSD) affects the behavioral and neurochemical responses to lipopolysaccharide (LPS, potent activator of the immune response). Adult inbred mice were paradoxical sleep deprived (72 h), whereas the control group was kept in their home cages. Both groups received either an injection of saline or LPS (5, 10 or 20 µg/animal ip) before behavioral tasks and tissue collection. During the recovery sleep period, LPS provoked a strong inhibition of sleep rebound due to a suppression of paradoxical sleep. PSD increased the susceptibility of mice to LPS-induced immobility in the open field, which was capable of affecting the anxiety-like behavior also. These altered behavioral responses to LPS were accompanied by reduction in dopamine turnover within the striatum and increased expression of cyclooxygenase-2 in the cortex. The study provides some insights into how the sleep–wake cycle affects the expression of sickness behavior induced by LPS.

Effects of nicotine on sleep during consumption, withdrawal and replacement therapy

Smoking constitutes the most important behavioural health risk in the Western world. By acting on various neurotransmitter systems, nicotine consumption also influences sleep and mood. Studies on the relationship between smoking, sleep disturbances, sleep-related disorders and depression led to dissimilar results. The aim of the present work is to provide a descriptive overview of the existing data regarding the relationship of nicotine consumption, withdrawal, replacement therapy and sleep disturbances in both animals and humans. Primarily symptoms of insomnia, such as increased sleep latency, sleep fragmentation and decreased slow wave sleep with reduced sleep efficiency and increased daytime sleepiness, were observed during nicotine consumption. Furthermore, most studies indicated a nicotine induced rapid eye movement (REM) sleep suppression. The effects on sleep due to therapeutic nicotine substitution after smoking cessation were often masked by withdrawal symptoms. Depressive non-smokers experienced a mood improvement under nicotine administration comparable to the effect of anti-depressants. In turn, depressive symptoms and sleep impairment during nicotine withdrawal had a negative impact on abstinence rates. Smoking was also associated with an increased prevalence of sleep-related respiratory disorders, which further worsened sleep quality and daytime sleepiness. The partly inconsistent findings of the analysed 52 studies result mostly from different methodology, necessitating a more unified approach with regard to subjects' assessment of smoking status, control for co-morbidity and use of medication as well as outcome criteria.

Short sleep, poor sleep: novel risk factors for type 2 diabetes

Sleep curtailment has become a very common behavior in industrialized countries. The aging of the population is also associated with an increased prevalence of sleep disturbances. There is rapidly accumulating evidence to indicate that chronic partial sleep loss and decreased sleep quality may increase the risk of obesity and diabetes. Laboratory studies have shown that sleep restriction (4‐6 h bedtimes) is associated with a decrease in Insulin without adequate compensation in beta cell function, resulting in an elevated risk of diabetes. Reduced sleep quality, without change in sleep duration, is also associated with an increased risk of diabetes. Indeed, selective suppression of slow‐wave sleep rapidly results in a marked reduction in insulin sensitivity and disposition index. Prospective epidemiologic studies in both children and adults are consistent with a causative role of sleep disturbances in the increased risk of diabetes. Sleep curtailment is also associated with a dysregulation of the neuroendocrine control of appetite. Under conditions of controlled caloric intake and energy expenditure, there is a robust negative relationship between leptin levels and sleep duration. Ghrelin levels increase with short sleep. Thus, sleep loss may alter the ability of leptin and ghrelin to accurately signal caloric need. The adverse impact of sleep deprivation on appetite regulation is likely to be driven by increased activity orexinergic. Consistent with the laboratory evidence, multiple epidemiologic studies have shown an association between short sleep and higher BMI after controlling for a variety of possible confounders. Taken together, the current evidence suggest that chronic partial sleep curtailment, a novel behavior that appears to have developed with the advent of the 24‐h society, and reduced sleep quality may be involved in the current epidemic of obesity and diabetes.

Microinjection of 70-kDal heat shock protein into the oral reticular nucleus of the pons suppresses rapid eye movement sleep in pigeons

Previous studies have demonstrated that increases in the duration of slow-wave sleep and decreases in somatovisceral measures in response to microinjections of 70-kDal heat shock protein (Hsp70) into the third ventricle in pigeons may be due to activation of GABAA receptors in the preoptic area of the hypothalamus. With the aim of identifying the transmitter mechanisms whose activation is temporally (2-3 h) linked with suppression of rapid eye movement sleep, the present studies were based on injection of Hsp70 into the oral reticular pontine nucleus (nucleus reticularis pontis oralis, NRPO), whose cholinergic neurons are critical for generating rapid eye movement sleep. Hsp70 was found to induce earlier (within the first 2 h) decreases in the number of episodes and the total duration of rapid eye movement sleep, with decreases in electroencephalogram (EEG) spectral power in the range 9-14 Hz, the level of muscle contractile activity, and brain temperature. It is hypothesized that the effects of Hsp70 are mediated by activation of GABAA receptors in the NRPO, evoking suppression of the cholinergic mechanisms initiating rapid eye movement sleep. The increase in the total duration of slow-wave sleep occurring with a long latent period (8-12 h after injection of Hsp70 into the NRPO) may be due to the influence of Hsp70 on the population of neurons responsible for maintaining slow-wave sleep outside the NRPO.

5-HT 7 receptor deletion enhances REM sleep suppression induced by selective serotonin reuptake inhibitors, but not by direct stimulation of 5-HT 1A receptor

5-HT 7 receptors are involved in REM sleep and possibly in mood disorders. REM sleep suppression and antidepressant-like behavior is observed in 5-HT 7 −/− mice and in rats treated with 5-HT 7 receptor antagonists. We recently demonstrated that pharmacological blockade of 5-HT 7 receptors enhances REM sleep suppression and antidepressant-like behavior induced by citalopram in rodents. It has been hypothesized that the effect of citalopram on sleep is essentially mediated by the activation of 5-HT 1A receptors. The present study investigates the impact of 5-HT 7 receptor gene deletion on the effect of various reuptake inhibitors on REM sleep and probes the role of 5-HT 1A receptors in this response. Three SSRIs (citalopram, fluoxetine and paroxetine) but not the tricyclic antidepressant desipramine had a significantly stronger REM sleep suppressive effect in 5-HT 7 −/− mice compared to 5-HT 7 +/+ mice. In contrast, REM sleep was similarly reduced in 5-HT 7 +/+ mice and 5-HT 7 −/− mice after treatment with the 5-HT 1A receptor agonist ipsapirone. Furthermore, both 5-HT 7 +/+ and 5-HT 7 −/− mice displayed the same increase in REM sleep duration produced by the 5-HT 1A receptor antagonist WAY-100635. These findings indicate that 5-HT 7 receptor deletion augments the effect of various SSRIs on REM sleep suppression and that this effect is distinct from those mediated via 5-HT 1A receptors.

Pharmacological REM sleep suppression paradoxically improves rather than impairs skill memory

Rapid eye movement (REM) sleep has been considered important for consolidation of memories, particularly of skills. Contrary to expectations, we found that REM sleep suppression by administration of selective serotonin or norepinephrine re-uptake inhibitors after training did not impair consolidation of skills or word-pairs in healthy men but rather enhanced gains in finger tapping accuracy together with sleep spindles. Our results indicate that REM sleep as a unitary phenomenon is not required for skill-memory consolidation.

Participation of the cholinergic system in the ethanol-induced suppression of paradoxical sleep in rats

Sleep disturbance is among the many consequences of ethanol abuse in both humans and rodents. Ethanol consumption can reduce REM or paradoxical sleep (PS) in humans and rats, respectively. The first aim of this study was to develop an animal model of ethanol-induced PS suppression. This model administered intragastrically (by gavage) to male Wistar rats (3 months old, 200-250 g) 0.5 to 3.5 g/kg ethanol. The 3.5 g/kg dose of ethanol suppressed the PS stage compared with the vehicle group (distilled water) during the first 2-h interval (0-2 h; 1.3 vs 10.2; P < 0.001). The second aim of this study was to investigate the mechanisms by which ethanol suppresses PS. We examined the effects of cholinergic drug pretreatment. The cholinergic system was chosen because of the involvement of cholinergic neurotransmitters in regulating the sleep-wake cycle. A second set of animals was pretreated with 2.5, 5.0, and 10 mg/kg pilocarpine (cholinergic agonist) or atropine (cholinergic antagonist). These drugs were administered 1 h prior to ethanol (3.5 g/kg) or vehicle. Treatment with atropine prior to vehicle or ethanol produced a statistically significant decrease in PS, whereas pilocarpine had no effect on minutes of PS. Although the mechanism by which ethanol induces PS suppression is not fully understood, these data suggest that the cholinergic system is not the only system involved in this interaction.

Abnormal response of melanin-concentrating hormone deficient mice to fasting: Hyperactivity and rapid eye movement sleep suppression

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that has been implicated in energy homeostasis. Pharmacological studies with MCH and its receptor antagonists have suggested additional behavioral roles for the neuropeptide in the control of mood and vigilance states. These suggestions have been supported by a report of modified sleep in the MCH-1 receptor knockout mouse. Here we found that MCH knockout ( MCH − / −) mice slept less during both the light and dark phases under baseline conditions. In response to fasting, MCH − / − mice exhibited marked hyperactivity, accelerated weight loss and an exaggerated decrease in rapid eye movement (REM) sleep. Following a 6-h period of sleep deprivation, however, the sleep rebound in MCH − / − mice was normal. Thus MCH − / − mice adapt poorly to fasting, and their loss of bodyweight under this condition is associated with behavioral hyperactivity and abnormal expression of REM sleep. These results support a role for MCH in vigilance state regulation in response to changes in energy homeostasis and may relate to a recent report of initial clinical trials with a novel MCH-1 receptor antagonist. When combined with caloric restriction, the treatment of healthy, obese subjects with this compound resulted in some subjects experiencing vivid dreams and sleep disturbances.

Sleep‐wakefulness effects after microinjections of hypocretin 1 (orexin A) in cholinoceptive areas of the cat oral pontine tegmentum

Hypocretinergic/orexinergic neurons, which are known to be implicated in narcolepsy, project to the pontine tegmentum areas involved in the control of rapid eye movement (REM) sleep. Here, we report the effects on sleep-wakefulness produced by low-volume microinjections of hypocretin (Hcrt)1 (20-30 nL, 100, 500 and 1000 microm) and carbachol (20-30 nL, 0.1 m) delivered in two areas of the oral pontine tegmentum of free-moving cats with electrodes for chronic sleep recordings: in the dorsal oral pontine tegmentum (DOPT) and in the ventral part of the oral pontine reticular nucleus (vRPO). Carbachol in the DOPT produced dissociate polygraphic states, with some but not all REM sleep signs. In contrast, carbachol in the vRPO produced a shift with short latency from wakefulness (W) to REM sleep with all of its polygraphic and behavioral signs. Hcrt-1 in the DOPT increased W and decreased both slow-wave sleep (SWS) and REM sleep during the first 3 h post-drug. The same doses of Hcr-1 in the vRPO produced a significant suppression of REM sleep without a definitive trend for changes in the other states. Both groups showed significant decreases in the number of transitions from SWS to REM sleep. Thus, Hcrt-1 produced distinct effects in cholinoceptive areas of the oral pontine tegmentum; in the DOPT it promoted W, suppressed SWS and probably defacilitated REM sleep, and in the vRPO it directly inhibited REM sleep. Hypocretinergic/orexinergic signaling is lost in narcoleptics and this absence would mean that pontine defacilitation/inhibition of REM sleep would also be absent, explaining why these patients can fall directly into REM sleep from W.

Effect of 17α-ethinyl estradiol on active phase rapid eye movement sleep microarchitecture

Estrogen treatment decreases active phase rapid eye movement (REM) sleep in ovariectomized rats. Here we explored further the effect of 17α-ethinyl estradiol (17α-EE) on active phase REM sleep in ovariectomized rats by analyzing spectral properties and the number and length of REM sleep bouts. The greatest suppression of REM sleep occurred on day 4 of 17α-EE treatment, was due to decreases in bout length, and was accompanied by decreased EEG theta power. These results further elucidate 17α-EE's effects on REM sleep and provide greater understanding of the mechanisms by which estrogens alter sleep–wakefulness patterns.

SYSTEMIC OXYTOCIN AMELIORATES NATURAL DEFICITS IN SSENORIMOTOR GATING DEFICIENCY IN RATS

The electroneuropharmacological effects of Δ8-tetrahydrocannabinol (Δ8THC) were examined on cats chronically implanted with electrodes. The Δ8THC, when administered either intraperitoneally or intravenously, induced sedation and an enhancement of the 12 Hz burst activity. Alterations in the paradoxical sleep pattern included a trend toward fewer and longer paradoxical sleep episodes following the initial suppression of paradoxical sleep. The Δ8THC did not elicit either hypersynchrony and inappropriate behavior nor desynchrony and stereotyped behavior. This suggests that Δ8THC lacks the psychotomimetic effects of compounds such as the perception distorting psychotomimetics (e.g., LSD) and the central nervous system stimulants (e.g. methamphetamine). It is suggested that Δ8THC might have clinically useful sedative hypnotic properties.

Glutamic acid stimulation of the perifornical-lateral hypothalamic area promotes arousal and inhibits non-REM/REM sleep

The orexinergic neurons, localized in the perifornical hypothalamic area (PeF), are active during waking and quiet during non-rapid eye movement (non-REM) and REM sleep. Orexins promote arousal and suppress non-REM and REM sleep. Although in vitro studies suggest that PeF-orexinergic neurons are under glutamatergic influence, the sleep-wake behavioral consequences of glutamatergic activation of those neurons are not known. We examined the effects of bilateral glutamatergic activation of neurons in and around the PeF on sleep-wake parameters in freely behaving rats. Nine male Wistar rats were surgically prepared for electrophysiological sleep-wake recording and with bilateral guide cannulae targeting the PeF for microinjection. The sleep-wake profiles of each rat were recorded for 8h under baseline (without injection), and after bilateral microinjections of 200nl saline and 200nl saline containing 20 or 40ng of l-glutamic acid (GLUT) using a remote-controlled pump and without disturbing the animals. The injection of 40ng GLUT into the PeF (n=6) significantly increased mean time spent in waking (F=85.11, p<0.001) and concomitantly decreased mean time spent in non-REM (F=19.67, p<0.001) and REM sleep (F=38.72, p<0.001). The increase in waking and decreases in non-REM and REM sleep were due to significantly increased durations of waking episodes (F=24.64; p<0.001) and decreased durations of non-REM (F=12.96; p=0.002) and REM sleep events (F=13.82; p=0.001), respectively. These results suggest that the activation of neurons in and around the PeF including those of orexin neurons contribute to the promotion of arousal and suppression of non-REM and REM sleep.

Let Sleeping Zebrafish Lie: A New Model for Sleep Studies

Let Sleeping Zebrafish Lie: A New Model for Sleep Studies

Pharmacological characterization of JNJ-28583867, a histamine H 3 receptor antagonist and serotonin reuptake inhibitor

Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. The wake-promoting action of histamine H 3 receptor antagonists has been evidenced in numerous animal studies. They may therefore be a viable strategy for use as an antidepressant therapy in conjunction with selective serotonin reuptake inhibitors. JNJ-28583867 (2-Methyl-4-(4-methylsulfanyl-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline) is a selective and potent histamine H 3 receptor antagonist ( K i = 10.6 nM) and inhibitor of the serotonin transporter (SERT) ( K i = 3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters. After subcutaneous administration, JNJ-28583867 occupied both the histamine H 3 receptor and the SERT in rat brain at low doses (< 1 mg/kg). JNJ-28583867 blocked imetit-induced drinking (3–10 mg/kg i.p.), confirming in vivo functional activity at the histamine H 3 receptor and also significantly increased cortical extracellular levels of serotonin at doses of 0.3 mg/kg (s.c.) and higher. Smaller increases in cortical extracellular levels of norepinephrine and dopamine were also observed. JNJ-28583867 (3–30 mg/kg p.o.) showed antidepressant-like activity in the mouse tail suspension test. JNJ-28583867 (1–3 mg/kg s.c.) caused a dose-dependent increase in the time spent awake mirrored by a decrease in NREM. Concomitantly, JNJ-28583867 produced a potent suppression of REM sleep from the dose of 1 mg/kg onwards. JNJ-28583867 has good oral bioavailability in the rat (32%), a half-life of 6.9 h and a C max of 260 ng/ml after 10 mg/kg p.o. In summary, JNJ-28583867 is a combined histamine H 3 receptor antagonist-SERT inhibitor with in vivo efficacy in biochemical and behavioral models of depression and wakefulness.

Activation of Pedunculopontine Tegmental PKA Prevents GABAB Receptor Activation–Mediated Rapid Eye Movement Sleep Suppression in the Freely Moving Rat

The pedunculopontine tegmental (PPT) GABAergic system plays a crucial role in the regulation of rapid eye movement (REM) sleep. I recently reported that the activation of PPT GABA(B) receptors suppressed REM sleep by inhibiting REM-on cells. One of the important mechanisms for GABA(B) receptor activation-mediated physiological action is the inhibition of the intracellular cAMP-dependent protein kinase A (cAMP-PKA) signaling pathway. Accordingly, I hypothesized that the PPT GABA(B) receptor activation-mediated REM sleep suppression effect could be mediated through inhibition of cAMP-PKA activation. To test this hypothesis, a GABA(B) receptor selective agonist, baclofen hydrochloride (baclofen), cAMP-PKA activator, Sp-adenosine 3',5'-cyclic monophosphothioate triethylamine (SpCAMPS), and vehicle control were microinjected into the PPT in selected combinations to determine effects on sleep-waking states of chronically instrumented, freely moving rats. Microinjection of SpCAMPS (1.5 nmol) induced REM sleep within a short latency (12.1 +/- 3.6 min) compared with vehicle control microinjection (60.0 +/- 6.5 min). On the contrary, microinjection of baclofen (1.5 nmol) suppressed REM sleep by delaying its appearance for approximately 183 min; however, the suppression of REM sleep by baclofen was prevented by a subsequent microinjection of SpCAMPS. These results provide evidence that the activation of cAMP-PKA within the PPT can successfully block the GABA(B) receptor activation-mediated REM sleep suppression effect. These findings suggest that the PPT GABA(B) receptor activation-mediated REM sleep regulating mechanism involves inactivation of cAMP-PKA signaling in the freely moving rat.