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Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts
Submitted 15 March 2005; accepted in final form 6 May 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Datta and Siwek 2002). The PPT is situated in the dorsolateral mesopontine tegmentum and contains a prominent group of cholinergic neurons that project widely throughout the brain stem and forebrain (for review, see Datta 1995). Single-cell recordings from the PPT in behaving cats and rats have identified several different classes of cells the firing rates of which correlate with both wakefulness and REM sleep (Datta 1995; Datta and Siwek 2002; Datta et al. 1989; El-Mansari et al. 1989; Steriade et al. 1990).
Neurotransmitter-mediated excitation and inhibition of PPT cells are important processes for the regulation of REM sleep (Datta 1995). Local microinjection studies in the cat and rat have suggested that the excitatory neurotransmitter, glutamate, may be involved in the direct and/or indirect activation of PPT cholinergic cells that trigger and maintain REM sleep (Datta and Siwek 1997; Datta et al. 2001). Subsequent pharmacological and single-cell recording studies have shown that the activation of PPT kainate type glutamate receptors induces REM sleep (Datta 2002; Datta and Siwek 2002; Datta et al. 2002). On the other hand, the inhibitory neurotransmitter GABA activates GABAB receptors that inhibit PPT cholinergic cells and suppresses REM sleep (Datta et al. 2003; Ulloor et al. 2004). Despite tremendous progresses in the identification of specific neurotransmitters and receptors involved in the regulation of the PPT cells neuronal activity and REM sleep, no other attempt has been made to study the intracellular signal transduction mechanisms of PPT cells that may be involved in the regulation of REM sleep.
A number of recent studies in behaving cats and rats have looked at the involvement of signal transduction pathways in the pontine reticular formation (PRF), a site known to be involved in the regulation of REM sleep (Capece and Lydic 1997; Marks and Birabil 2000; Shuman et al. 1995). These studies have indicated that the signal transduction pathway activated by muscarinic cholinergic receptors involves a pertussis-toxin-sensitive G protein, adenylate cyclase (AC), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). In the rat, this signal transduction pathway in the PRF is also shown to be involved in spontaneous REM sleep (Marks and Birabil 2000). One recent study has demonstrated that the activation of GABAB receptors within the PPT suppresses REM sleep in the freely moving rat (Ulloor et al. 2004). It is known that the GABAB receptors couple to Gi/Go G proteins (Couve et al. 2000; Kerr and Ong 1995; Mody et al. 1994; Robbins et al. 2001; Sivilotti and Nistri 1991; Takahashi et al. 1998; Thompson 1994). It is also known that Gi/Go G proteins inhibit AC, and inhibition of AC prevents activation of the cAMP-PKA signal transduction pathway (Gilman 1987; Marinissen and Gutkind 2001). Therefore it is reasonable to suggest that the suppression of REM sleep initiated by active GABAB receptors in the PPT may be due to inhibition of the cAMP-PKA signal transduction pathway. Recent pharmacological and physiological studies have also shown that the activation of PPT kainate-type glutamate receptors induces REM sleep (Datta 2002; Datta and Siwek 2002; Datta et al. 2002). It is well known that the activation of kainate receptors increases the cytoplasmic free calcium concentration (Bernard et al. 1999; Bleakman and Lodge 1998; Haak et al. 1997; Kovacs et al. 2000; Michaelis 1998). In neurons, calcium ions can stimulate the production of cAMP and the activation of PKA by activating AC (Cali et al. 1994; Ginty et al. 1991; Waltereit et al. 2001; Xia et al. 1996). Thus it is possible that the activation of kainate receptors in the PPT could also activate the cAMP-PKA signal transduction pathway to induce REM sleep.
Because the activation of PPT GABAB and kainate receptors is involved in the regulation of REM sleep and activation of these two types of receptors can also directly and/or indirectly modulate the intracellular cAMP signal transduction pathway (which is known to be involved in the PRF), in the present study, we hypothesized that the activation and/or inactivation of PPT intracellular cAMP signaling may also be involved in the regulation of REM sleep. To test the role of the cAMP-signaling pathway in the regulation of spontaneous REM sleep, we examined polygraphic wake-sleep signs after local microinjections of control vehicle or AC-dependent cAMP inhibitor [9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536)] into the PPT of freely moving rats. By comparing the alterations in the patterns of REM sleep after injections of control vehicle or different doses of SQ22536, the contribution made by each dose of SQ22536 in spontaneous REM sleep was evaluated.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Experiments were performed on 52 adult male Sprague-Dawley rats (Charles River, Wilmington, MA) weighing between 250 and 350 g. The rats were housed individually at 24°C with food and water provided ad libitum with lights on from 07:00 to 19:00 (light cycle) and off from 19:00 to 07:00 (dark cycle). The principles for the care and use of laboratory animals in research, as outlined by the National Institutes of Health Publication No. 85–23 (1985), were strictly followed.
Drug and vehicle for microinjections
The drug used in this study was a membrane permeable inhibitor of adenylyl cyclase (AC), 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536; mol. wt. 205.22), purchased from RBI/Sigma Chemicals (St. Louise, MO). The SQ22536 was dissolved in 0.9% saline to make four different doses (0.25, 0.50, 0.75, and 1.0 nmol/100 nl). This 0.9% saline (100 nl) was also used for the vehicle control microinjection. Control saline and drug solutions were freshly prepared under sterile conditions before each use. The selection of this drug was based on the selective inhibitory effect on intracellular AC and cAMP (Fabbri et al. 1991; Johnson et al. 1997; Natsume and Kometani 1999; Shi and Bunney 1992). This commercially available SQ22536 is suitable for our local microinjection studies because it is water soluble and cell-permeable, has reversible effects, and has been used successfully for microinjection studies in behaving animals (Marks and Birabil 2000).
Surgical procedures and implantation of electrodes
Treatment of the animals and surgical procedures were in accordance with an approved institutional animal welfare protocol (AN-14084). Efforts were made to minimize the number of animals used and their suffering. Rats were anesthetized with pentobarbital (40 mg/kg ip), placed in the stereotaxic apparatus, and secured using blunt rodent ear bars (Paxinos and Watson 1997). With the use of sterile procedures, cortical electroencephalogram (EEG), dorsal neck muscle electromyogram (EMG), electrooculogram (EOG), hippocampal EEG (to record theta waves), and pontine EEG (to record P waves), recording electrodes were chronically implanted as described elsewhere (Datta 2000). In addition, stainless steel guide tubes (26 gauge) with an equal length stylett inside were stereotaxically implanted bilaterally 2 mm above the PPT (A: 1.0; L: 1.8; H: 3.0) as described previously (Datta et al. 2001).
Intracerebral microinjections and experimental design
After the adaptation recording sessions, microinjection sessions began. During experimental sessions, animals were connected to the polygraphic recording system 15 min before a microinjection into the PPT. The microinjection system consisted of a 32-gauge stainless steel injector cannula with a 26-gauge collar that extended 2.0 mm beyond the implanted guide tube. The collar was connected to a 1.0-µl motor-driven Hamilton microsyringe with PE 20 tubing. While the animal was connected to the recording system, the stylettes were removed and an injector filled with either control vehicle (100 nl volume of 0.9% saline) or one of the four doses of SQ22536 (0.25, 0.50, 0.75, and 1.0 nmol in 100 nl) was introduced through one of the guide tubes for the injection. This procedure was repeated in the other guide tube. One minute after the insertion of the injector cannulae, 100 nl of control saline or one of the four doses of SQ22536 was bilaterally microinjected over a 60-s period (Pump II Pico Plus, Harvard Apparatus, Holliston, MA). The injector cannulae were gently withdrawn 2 min after the injections, and the stylettes were reinserted into the guide tubes. During the microinjections, animals were free to move around the cage with the cannulae in place. Immediately after completion of the microinjection procedure, polygraphic variables were recorded continuously for a session of 6 h (between 10:00 and 16:00), when rats would normally be sleeping (Datta 2000). Each of these rats received a total of two microinjections (100 nl each, one in the right and one in the left PPT) in a single experimental recording session. None of the rats were used for more than one microinjection recording session. At the end of all experimental sessions and before perfusion, 100 nl of black ink was microinjected 1 mm dorsal to each injection site for localizing the injection sites as described earlier (Datta et al. 2001).
Determination of behavioral states and data analysis
For the purpose of determining possible effects on sleep and wakefulness, three behavioral states were distinguished based on the visual scoring of polygraphic records as described earlier (Datta 2002). In this study, microinjections of SQ22536 or saline into the PPT did not produce any dissociated sleep/wake states. The behavioral states of wakefulness (W), slow-wave sleep (SWS), and REM sleep were scored in successive 10-s epochs. The polygraphic measures provided the following dependent variables, which were quantified for each recording session: percentage of recording time spent in W, SWS, and REM sleep; latency to onset of the first episode of REM sleep after the onset of recordings; total number of REM sleep episodes; and mean duration of REM sleep episodes. The effects of the five different treatments (control saline, 0.25 nmol SQ22536, 0.50 nmol SQ22536, 0.75 nmol SQ22536, and 1.0 nmol SQ22536) on the percentages of W, SWS, and REM sleep were statistically analyzed using a two-way ANOVA with time as a repeated-measure variable (6 levels corresponding to 6 1-h epochs after injections) and treatment as a between-subject variable (5 levels corresponding to the 5 different treatments). After a two-way ANOVA, post hoc Scheffe F tests were done to determine the individual levels of significant difference between the control (saline) and the four different doses of SQ22536 treatment protocols at six individual data points. The latency, number, and duration of REM sleep episodes were analyzed using a one-way ANOVA followed by post hoc Scheffe F tests. Statistical analyses (2-way ANOVA, 1-way ANOVA, and Scheffe F test) were performed with the use of StatView statistical software (Abacus Concepts, Berkeley, CA).
Histological localization of injection site
At the conclusion of the microinjection experiments, rats were killed with pentobarbital (60 mg/kg, ip) and perfused transcardially with heparinized cold phosphate buffer (0.1 M, pH 7.4) followed by 4% paraformaldehyde in 0.1 M phosphate buffer. The brains were removed and processed for NADPH-diaphorase staining and histological localization of injection sites as described earlier (Datta et al. 1997, 2001). This NADPH-diaphorase staining was done to identify the cholinergic cell compartment of the PPT (Bredt and Snyder 1992; Bredt et al. 1991; Hope et al. 1991; Vincent et al. 1983).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Figure 2 illustrates representative sleep-wake architectures for the 6-h postinjection recording sessions (10 AM to 4 PM) starting immediately after each of five different bilateral microinjections. The figure shows that the latency between the end of bilateral microinjections of saline and the first episode of REM sleep was much shorter than after bilateral microinjections of any one of the four different doses of SQ22536. In contrast, the latencies between the end of bilateral microinjections of SQ22536 and the first episode of SWS were shorter compared with after bilateral microinjections of control saline. For 
3 h after microinjections of SQ22536, the numbers of REM sleep episodes were fewer compared with after bilateral microinjections of control saline. During the fifth and sixth hours after bilateral microinjections of SQ22536, the numbers of REM sleep episodes were similar to the number of REM sleep episodes in the fifth and sixth hours after bilateral microinjections of control saline. These results demonstrate that bilateral microinjections of SQ22536, into the cholinergic cell compartment of the PPT change the sleep-wake architecture of the rat.
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The changes in the percentage of time spent in W after bilateral microinjections of saline control and the different SQ22536 doses are summarized in Fig. 3. A two-way ANOVA indicated a significant main effect of treatment [F(4,36) = 3.98, P < 0.01], time [F(5,180) = 47.32, P < 0.001], and a significant treatment x time interaction [F(20,180) = 3.35, P < 0.001] for total percentage of time spent in W. The results of post hoc analysis (Scheffe F test) on the total percentage of time spent in W are presented in Fig. 3. Compared with saline control microinjections, three of the four different doses of SQ22536 (0.50, 0.75, and 1.0 nmol) caused a significant reduction of the total percentage of W. This SQ22536-induced reduction in the total percentage of W was dose dependent. The reduction in W after 0.50 and 0.75 nmol doses lasted for the first hour of recordings. The total percentage of W after the lowest dose of SQ22536 (0.25 nmol) was lower compared with after the saline control, but this reduction did not reach significance. The W reducing effect of SQ22536 microinjection at the higher dose (1.0 nmol) lasted for the first 2 h of recordings. These results show that the application of SQ22536 into the cholinergic cell compartment of the PPT causes a short lasting reduction in the total percentage of W.
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The changes in the percentage of time spent in SWS after microinjection of saline control and different SQ22536 doses are summarized in Fig. 4. A two-way ANOVA indicated a significant main effect of treatment [F(4,36) = 6.44, P < 0.001], time [F(5,180) = 21.0, P < 0.001], and a significant treatment x time interaction [F(20,180) = 3.61, P < 0.001] for total percentage of time spent in SWS. The results of post hoc analysis (Scheffe F test) for the total percentage of time spent in SWS are presented in Fig. 4. After microinjections of SQ22536, there was a dose-dependent increase in the total percentage of time spent in SWS. After the second lowest dose (0.50 nmol) of SQ22536, the rats spent more time in SWS than the saline injected rats during the first hour of recording. As the doses of SQ22536 increased to 0.75 and 1.0 nmol, SWS remained significantly higher for the first 2 h of recording. This SQ22536 microinjection-induced increase in SWS was relatively short-lasting compared with receptor-mediated action in the PPT.
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The changes in the percentage of time spent in REM sleep after microinjection of the saline control and the different SQ22536 doses are summarized in Fig. 5. A two-way ANOVA indicated a significant main effect of treatment [F(4,36) = 7.53, P < 0.001], time [F(5,180) = 94.16, P < 0.001], and a significant treatment x time interaction [F(20,180) = 5.34, P < 0.001] on total percentage of time spent in REM sleep. The results of post hoc analysis (Scheffe F test) on total percentage of time spent in REM sleep are presented in Fig. 5. Compared with postcontrol-injection recordings, after microinjection of SQ22536, there was a dose-dependent decrease in the total percentage of time spent in REM sleep. Post hoc analysis indicated that the total percentage of REM sleep after microinjection of 0.50 nmol dose of SQ22536 was significantly lower in the second and third hours post injection compared with after microinjection of saline. The lowest dose of (0.25 nmol) SQ22536 also reduced the total percentage of REM sleep in the second hour, but this reduction did not reach the level of significance. Microinjections of 0.75 and 1.0 nmol doses of SQ22536 suppressed REM sleep completely for the first two hours post injection. Post hoc analysis indicated that the total percentage of REM sleep after these two higher doses (0.75 and 1.0 nmol) was significantly decreased even in the third and fourth hours post injection compared with after microinjection of saline.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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We chose to study chronically implanted freely moving rats because this preparation provides the most physiological approach to a longitudinal analysis of the behavioral and electrographic events related to the wake-sleep cycle (Datta et al. 2002; Marks and Birabil 2000; Ulloor et al. 2004). After the accommodation period of each experimental condition, the rats demonstrated regular values of wake and sleep stages. Thus the microinjections of a pharmacologically active selective signal transduction-altering inhibitor that affected electrographic signs of wake-sleep patterns could be evaluated accurately (Capece and Lydic 1997; Marks and Birabil 2000). Moreover, understanding the role of the intracellular signal transduction pathway in a behaviorally active living organism is a vital step toward creating ways to converge functional biochemistry and integrative physiology. In this particular study, to identify the involvement of the intracellular signal transduction pathway in the induction of REM sleep, we chose a specific inhibitor, SQ22536, to block AC-dependent cAMP (Fabbri et al. 1991; Froehlich and Wand 1997; Johnson et al. 1997; Marks and Birabil 2000; Natsume and Kometani 1999; Shi and Bunney 1992). The local microinjection of SQ22536 and other signal transduction-altering compounds into the brain of freely moving animals has already been shown to be an important technique when studying the involvement of signal transduction pathways modulating behaviors (Barraco et al. 1988; Capece and Lydic 1997; Cook et al. 1995; De Lima and Davis 1995; Kantak et al. 1981; Marks and Birabil 2000). However, a major limitation of the microinjection method relates to the diversity in the neurochemical nature of the neuronal population affected by the drug application. In this study, a selective inhibitor of AC-dependent cAMP was injected into the part of the PPT (pars compacta) where most cells are known to be cholinergic (Mesulum et al. 1983; Rye et al. 1987). Nonetheless, we acknowledge that if there are noncholinergic cells located within the targeted cholinergic cell groups, they will also be affected by the application of this drug. We also acknowledge that we have no way of knowing whether SQ22536 acted on pre- or postsynaptic elements of the neurons. Another interpretive limitation of this study is that although we suggest that our application of SQ22536 into the PPT revealed an endogenous mechanism of REM sleep regulation, future study is needed to be certain. Additional interpretative limitation comes from the fact that the PPT has also been implicated in the modulation of respiration. Thus it is possible that the observed reduction in REM sleep may partially be due to impaired respiration (Radulovacki et al. 2004). Because in this study, we did not record respiration, it is impossible to rule out that possibility.
In recent years, a number of studies have attempted to identify endogenous neurotransmitters' and their specific receptors' involvement in the cholinergic cell compartment of the PPT in regulating single-cell activity of the PPT and regulating REM sleep (Datta 2002; Datta and Siwek 1997, 2002; Datta et al. 1997, 2001–2003; Garcia-Rill et al. 2003; Kobayashi et al. 2004; Ulloor et al. 2004). However, other than the results of this study, there is no direct evidence to demonstrate that the intracellular signal transduction pathways in the cholinergic cell compartment of the PPT is involved in the regulation of REM sleep. The results of this study, for the first time, provide evidence that the direct inhibition of AC by microinjecting SQ22536 suppresses REM sleep by increasing the latency and decreasing the frequency of REM sleep episodes. Because SQ22536 inhibits the production of the intracellular second-messenger cAMP by inhibiting AC (Gilman 1987; Johnson et al. 1997; Marks and Birabil 2000), these results suggest that the production of intracellular cAMP in the PPT is involved in the generation of REM sleep. This finding is interesting because in another area of the rat's brain stem, the medial pontine reticular formation (mPRF), microinjection of carbachol induces a REM sleep-like state and microinjection of SQ22536 increases REM sleep (Marks and Birabil 1998, 2000). This finding indicates that inhibition of cAMP production in the mPRF is an important step for the induction of REM sleep. This site-specific role of cAMP in the regulation of REM sleep is also supported by the result from the present study as microinjection of SQ22536 into the caudal midbrain in sites adjacent to the PPT was not effective in causing any changes in REM sleep. Other studies in the cat have demonstrated that pretreatment of the mPRF with agents that activate AC, cell-permeable analogues of cAMP, or agonists of protein kinase A (PKA) all antagonize the carbachol or neostigmine microinjection-induced REM sleep-like state (Capece and Lydic 1997; Shuman et al. 1995). These findings also indicate that inhibition of the cAMP signal transduction pathway in the mPRF might be involved in the carbachol and neostigmine microinjection-induced REM sleep-like state in the cat. Yet in another study, microinjection of pituitary adenylyl cyclase-activating polypeptide (PACAP) into the mPRF of rats increased REM sleep (Ahnaou et al. 1999). This result indicates that the activation of the cAMP-dependent signal transduction pathway in the mPRF is involved in the induction of REM sleep. Thus based on the results of these earlier studies and the present study, it is reasonable to suggest that the intracellular cAMP signal transduction pathway in the brain stem is critically involved in the regulation of REM sleep. Because the activation of the cAMP signal transduction pathway causes protein phosphorylation by activating protein kinase A (PKA) that ultimately causes activation of ion channels, receptor up/down regulation, neurotransmitter synthesis/release, and gene expression (Elazar and Fuchs 1991; Gilman 1987; Ginty et al. 1991; Wang et al. 1991, 1993), it is logical to speculate that part of this cAMP activation-mediated REM sleep generating mechanism in the cholinergic cell compartment of the PPT involves activation of the cAMP-dependent PKA signal transduction pathway. However, we acknowledge that future experimental work will be necessary to confirm or refute this pathway's involvement.
In light of the present study, it is interesting to compare the effects of microinjection of the GABA-B receptor-selective agonist, baclofen, into the PPT (Ulloor et al. 2004). The results of that study demonstrated that the activation of GABAB receptors in the cholinergic cell compartment of the PPT suppresses PPT REM-on cells and decreases REM sleep by increasing REM sleep latency and decreasing the number of REM sleep episodes. It has also been demonstrated that the activation of PPT GABAB receptors decreases wakefulness and increases slow-wave sleep (Ulloor et al. 2004). In the present study, we have demonstrated that the microinjections of the selective AC inhibitor into the PPT also caused decreased REM sleep by increasing latency and decreasing number of episodes of REM sleep. This AC inhibitor also caused a reduction in wakefulness and an increase slow-wave sleep. Another interesting common characteristic between activation of GABAB receptors and inhibition of AC in the PPT is neither processes changed the episode durations of REM sleep. The similarity in action on REM sleep by GABAB receptor activation and AC inhibition in the PPT and the fact that the activation of GABAB receptors could inhibit AC suggests that the PPT GABAB receptor-mediated REM sleep regulation mechanism also involves inhibition of AC (Gilman 1987; Marinissen and Gutkind 2001; Takahashi et al. 1998). To explain the mechanism behind the fact that the inhibition of AC in the PPT did not change REM sleep episode duration may require future study.
Because the results of the present study demonstrated that inhibition of AC in the PPT suppresses REM sleep, it is reasonable to suggest the possibility that the activation of AC may increase REM sleep. Earlier studies have demonstrated that the activation of kainate type glutamate receptors in the PPT increases REM sleep (Datta 2002; Datta and Siwek 1997; Datta et al. 2001, 2002). Because it is known that the activation of kainate receptors can activate AC by increasing intracellular calcium ions (Bernard et al. 1999; Bleakman and Lodge 1998; Cali et al. 1994; Ginty et al. 1991; Haak et al. 1997; Kovacs et al. 2000; Michaelis 1998; Waltereit et al. 2001; Wang et al. 1991, 1993; Xia et al. 1996), it is possible that the PPT kainate receptor activation-mediated induction of REM sleep may also have operated through the activation of AC. Because AC-dependent cAMP pathway inhibition in the PPT suppressed REM sleep and other studies have suggested that dysregulation of the normative developmental changes in the PPT could lead to a number of disorders including schizophrenia, panic attacks, bipolar disorder, and obsessive-compulsive disorder (Garcia-Rill et al. 2003; Kobayashi et al. 2004), it would be interesting to design future studies to understand the role of PPT cAMP signal transduction mechanisms in the pathophysiology of these neuropsychiatric disorders. However, at the present time this remains an unexplored area of research.
In conclusion, the present study shows for the first time that the modulation of AC in the cholinergic cell compartment of the PPT may be an important step for the regulation of REM sleep. The data provide a novel perspective on the regulatory aspect of PPT cells' activity in the regulation of REM sleep. The results also suggest that the activation of the cAMP-signaling pathway in the cholinergic cell compartment of the PPT may be an important step in a series of biochemical and molecular events for the induction of REM sleep.
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. Datta, Sleep and Cognitive Neuroscience Laboratory, Dept. of Psychiatry, Boston University School of Medicine, M-902, 715 Albany St., Boston, MA 02118 (E-mail: SUBIMAL{at}BU.EDU)
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REFERENCES |
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