Theme : Dreams

Central Administration of a 5-HT2 Receptor Agonist and Antagonist: Lack of Effect on Rapid Eye Movement Sleep and PGO Waves

Larry D. Sanford1,3, Wendy K. Hunt1,3, Richard J. Ross2,3, Allan I. Pack3 and Adrian R. Morrison1,2,3
1Laboratory for the Study of the Brain in Sleep, Department of Animal Biology, The School of Veterinary Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USA; 2Department of Psychiatry, The School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USA; 3Center for Sleep and Respiratory Neurobiology, The University of Pennsylvania, Philadelphia, PA 19104, USA
Abstract
Serotonin (5-HT) has a role in regulating behavioral state and controlling the production of ponto-geniculo-occipital (PGO) waves, though the exact mechanism of action is not known. The most prevailing explanation is that 5-HT exerts its influence on behavioral state and PGO waves by inhibiting and disinhibiting cholinergic cells in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT), which have been implicated in their generation. Recent work in rats has demonstrated 5-HT2 receptors on most cholinergic cells in PPT/LDT. We microinfused the relatively specific 5-HT2 agonist, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), the relatively specific 5-HT2 antagonist, ketanserin, and the nonspecific 5-HT antagonist, methysergide, locally into the peribrachial region of PPT in cats and monitored behavioral state and PGO waves. Neither drug significantly affected behavioral state or PGO wave activity. These results suggest that 5-HT2 receptors associated with cholinergic cells are minimally involved in the control of behavioral state and, together with the recent findings of others, suggest that 5-HT may not modulate PGO wave generation via direct action on cholinergic neurons in PPT/LDT, a departure from the long-held but minimally-tested view.

Current Claim: Behavioral state is not regulated by 5-HT2 receptors in the pedunculopontine tegmentum.

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Absence of serotonergic neuronal activity is considered to permit the occurrence of rapid eye movement sleep (REM). Unit studies have shown that brainstem raphe neurons, particularly those in the rostrally projecting dorsal raphe nucleus (DRN), gradually decrease their firing from wakefulness until they fall silent in REM (Cespuglio et al., 1981; McGinty and Harper, 1976; Trulson and Jacobs, 1979). More recently, Portas et al. (1996) have shown that microdialysis of 8-OH-DPAT, a relatively specific 5-HT1A autoreceptor agonist, into DRN increases REM in cats. Serotonin (5-HT) also has an apparent inhibitory role in the generation of ponto-geniculo-occipital (PGO) waves, though the precise mechanism of action has not been delineated. The most accepted view holds that serotonergic input from DRN into the pedunculopontine and laterodorsal tegmentum (PPT/LDT) inhibits cholinergic cells involved in the generation of PGO waves (Simon et al., 1973). Disinhibition of these cells, such as in REM where DRN is virtually silent, would allow bursting and the generation of PGO waves. The support for this theory is mostly indirect. Global depletion of 5-HT with drugs, such as parachlorophenylalanine (PCPA) and reserpine, releases PGO waves into states other than REM (Delorme et al., 1965; Brooks and Gershon, 1971; Brooks and Gershon, 1972; Brooks et al., 1972; Jacobs et al., 1972), whereas systemically administered 5-HT1 agonists have been found to decrease PGO wave activity and suppress REM (Quattrochi et al., 1992). Lesions of DRN and cuts between DRN and the dorsolateral pons release PGO waves into wakefulness (Simon et al., 1973), and electrical stimulation of the DRN suppresses PGO wave activity during REM (Jacobs et al., 1973).

Interestingly, various studies of the effects of serotonergic agents on unit activity differ across species and are contradictory. Luebke et al. (1992) found that cholinergic "burst" neurons in infant rat LDT were inhibited by 5-HT and by carboxamidotryptamine maleate (5CT), a 5-HT1 agonist, in vitro, in a manner consistent with the hypothesized role of DRN in the control of PGO waves, although neurons with bursting patterns of firing were not found in in vivo recordings of LDT in mature rats (Kayama et al., 1992). In contrast, systemically administered 5-Me-ODMT (5-methoxy-N,N-dimethyl-tryptamine), a 5-HT autoreceptor agonist (Sakai et al., 1990) and iontophoretically applied 5-HT (Koyama and Sakai, 1995) did not alter the firing of PGO "burst" cells in cats. Most recently, local microinjections of 5-Me-ODMT into the PPT pars compacta ("X" area) were found to suppress acetylcholine release in LGB in cats in a manner consistent with the hypothesis of inhibited PGO-related unit activity in PPT though PGO waves were not recorded (Kodama and Honda, 1996).

In cats local microinjections of 8-OH-DPAT into the peribrachial region of PPT (PB) failed to alter PGO wave activity in REM sleep, although 8-OH-DPAT reduced the number of successful entrances into REM (Sanford et al., 1994). Similarly, in rats, local microinjections of 5-HT into LDT suppressed REM but did not affect PGO wave frequency (Horner et al., 1997). Also, local microinjections of 8-OH-DPAT into PPT failed to inhibit elicited PGO waves in rats (Sanford et al., 1995). These findings are complemented by autoradiographic studies that revealed few 5-HT1A receptor sites in rat PPT, and only a moderate amount of labeling in LDT (Sanford et al., 1995).

Most of the work on serotonergic inhibition of PGO waves has suggested the involvement of a 5-HT1 receptor mechanism (Quattrochi et al., 1992; Luebke et al., 1992; Adrien and Hamon, 1989). Recently, however, 5-HT2 receptors have been found in close association with brainstem cholinergic cells in rats (Morilak and Ciaranello, 1993), suggesting that a 5-HT2 receptor mechanism may be involved in the modulation of these cells.

If 5-HT2 receptor sites do participate in inhibiting the activity in PGO generator cells, then 5-HT2 agonists locally applied in PB should reduce PGO wave activity in LGB, whereas antagonists should block serotonergic inhibition and increase PGO waves. In the present study, we tested these predictions. We locally microinjected into PB of cats the 5-HT2 agonist, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), the 5-HT2 antagonist, ketanserin and the broad spectrum 5-HT antagonist, methysergide. In all of the studies, we observed the effects on PGO waves recorded in LGB and also on behavioral state.

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Adult, female cats were implanted with a standard array of electrodes used for sleep recording. Stainless-steel screw electrodes were placed in the frontal sinuses for recording the electrooculogram (EOG) and electroencephalogram (EEG); wire electrodes were inserted into the nuchal muscles for recording the electromyogram (EMG). Tripolar stainless-steel electrodes (tip separation 1 mm) were implanted in LGB bilaterally (coordinates AP: +6.0; ML: +/-10; DV: +2.7; [Berman, 1968]) for recording PGO wave activity (Brooks, 1967). Twenty-two-gauge stainless-steel guide cannulae were implanted bilaterally with the tips aimed 4 mm above PB. For microinjections a thirty-gauge, stainless-steel cannula was lowered into PB (coordinates AP: -2.0; ML: +/-3.0; DV: +0.5; [Berman, 1968]).

All surgical procedures were performed stereotaxically under sterile conditions. The cats were anesthetized with halothane. Subcutaneous injections of butorphanol tartrate (0.4 mg/kg) were used to control potential post-operative pain.

The cats were allowed a minimum of 14 days to recover from surgery prior to being entered in any experimental protocols. The cats were bilaterally infused with DOI (0.00, 1.0, 10.0 and 100.0 ng/0.5 µl saline; n = 5), ketanserin (0.00, 1.0, 10.0 and 100.0 ng/0.5 µl saline; n = 6), methysergide (0.00, 60 ng and 200 ng/0.5 µl saline; n = 4). Some cats served in more than one experiment and all trials with one drug were completed before tests of the next drug were initiated. All drugs were administered in a counterbalanced order. A minimum of 7 days elapsed between drug doses. Six-hour sleep studies were conducted for each dose. A partial data loss occurred for one animal at the high dose of DOI due to a 11/2 hour power outage. These data were estimated using procedures for missing data (Myers and Wells, 1995). Behavioral state was determined by experienced observers from Telefactor videotape records.

Analyses of the number of REM episodes, episode duration and PGO wave frequency (rate/minute) were conducted in all instances where the defining electrophysiological parameters of REM (low-voltage, high-frequency waves on the EEG, rapid eye movements, muscle atonia and PGO waves) were present for one minute or more. We also examined the total sleep time (TST), sleep efficiency (TST/total recording time) and REM percent (time in REM/TST). These data were analyzed with single-factor, within-subjects (Subject X Drug dose) analyses of variance (ANOVAs).

PGO waves were detected using DataWave Experimenter's Workbench software. This program detects waves based on a simple threshold criterion and could miss 25 to 30 percent of the smaller waves in a cluster of PGO waves during REM. To follow the time course of the drugs, four to eight minute episodes of quiet waking and NREM were taken from each of four 90-minute quartiles of the six-hour recording period. This yielded data for within-subjects Quartile X Drug Dose ANOVAs. Because REM was not always observed in each quartile, these data were collapsed across quartiles and analyzed with single factor, within-subjects (Subject X Drug Dose) ANOVAs. PGO waves were not analyzed in the second saline condition because of deteriorated recording quality of LGB electrodes in 2 cats microinjected with DOI and 2 cats microinjected with ketanserin.

After completion of the experiment, the cats were injected with an overdose of pentobarbital (22-23 mg/kg, i.v.) and perfused with saline and 10% formalin. The brains were removed from the skull and postfixed in 10% formalin. For histological localization, brain tissue was cut in 40 µm sections with a freezing microtome, mounted on slides and stained with cresyl violet. All histological sections that contained a lesion made by the microinjector were localized using the atlas of Berman (1968).

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Figure 1

Sleep-wake states after serotonergic drugs

Tables 1-3 present the measurements of sleep architecture after DOI, ketanserin and methysergide. Neither serotonergic drug, in the dosages we administered, significantly altered sleep architecture.

PGO waves after serotonergic drugs

Tables 4-6 present the frequency data for PGO waves after DOI, ketanserin and methysergide. The effects of serotonergic drugs on PGO wave rates were minimal. PGO wave rates in NREM were somewhat increased at the middle dosage of ketanserin (10 ng), and at the high dose of methysergide in two cats, but none of the analyses reached significance.

Histology
The line drawing in Figure 1 shows the localization of the injection sites in the sagittal plane. All effective injection sites were localized in the vicinity of PB, and encompassed regions previously reported to contain PGO burst neurons (Steriade et al., 1990).

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The present study revealed that microinjections into PB of drugs active at the 5-HT2 receptor subtype (DOI, ketanserin, methysergide) had minimal influence on PGO wave generation and behavioral state. These findings complement and extend previous work in which we microinjected into PB the relatively specific 5-HT1A agonist, 8-OH-DPAT, and the less specific 5-HT agonist, mCPP (1(3-chlorophenyl) piperazine) (Sanford et al., 1994). At certain dosages (0.10 ng) 8-OH-DPAT significantly reduced the number of successful entrances into REM, but PGO wave rates and amplitudes were not altered once REM was entered and maintained. In contrast, mCPP did not significantly alter either behavioral state or PGO wave activity. This result parallels the current findings, though mCPP was considered an agonist at 5-HT1B/C receptor sites at the time of the earlier study. Recently, however, the 5-HT1C receptor site has been reclassified as a 5-HT2C receptor subtype because of its homologous nucleotide sequences with other 5-HT2 receptors (Humphrey et al., 1993; Beer et al., 1993).
The relative lack of effect of drugs active at the 5-HT2 receptor site on PGO waves and sleep is somewhat surprising given the recent finding that most cholinergic neurons in PPT/LDT have 5-HT2 receptor sites associated with them, at least in rats (Morilak and Ciaranello, 1993). The authors suggested that 5-HT2 receptors normally may be "masked" by co-localized 5-HT1A receptors except under conditions in which 5-HT1A receptors are down-regulated or 5-HT2 receptors are up-regulated or are pharmacologically activated. Given the range of dosages we administered, masking by 5-HT1A receptors would not seem to be a factor.

One possible explanation is that there may be species differences in the expression of receptor sites; the majority of receptor work in these regions has been done in rats, with comparatively very little in cats. Evidence for such a possibility comes from the finding of Portas et al. (1996) that perfusion of 8-OH-DPAT by microdialysis into DRN in cats increases REM, whereas in rats, a preliminary report using similar techniques, found a decrease in REM (Bjorvatn et al., 1996). Another plausible explanation is that 5-HT2 receptor mechanisms in PPT/LDT may simply not be involved in the regulation of sleep and PGO waves, although they may be effective elsewhere. Our laboratory found an increase in REM percent with systemically administered ketanserin in cats (Ross et al., 1991), whereas the 5-HT2 antagonist, ritanserin, has been reported to decrease both NREM and REM in cats (Sommerfelt and Ursin, 1993). In rats, both systemically administered 5-HT2 agonists and antagonists have generally been found to suppress REM when PGO waves would be most frequent (reviewed in Dugovic, 1992).

That 5-HT, probably originating in DRN, has a role in the generation of PGO waves has been amply demonstrated with systemically administered drugs that deplete 5-HT (e.g., reserpine and PCPA) and release PGO waves, and lesion and stimulation studies of DRN (see Introduction). However, there is sparse evidence of a direct neuroanatomical link between DRN and cholinergic PGO wave generator neurons in PB sufficient to account for the effect of 5-HT on PGO waves. Anatomical studies in rats have found only low to moderate input into PPT/LDT from DRN (Cornwall et al., 1990; Semba and Fibiger, 1992; Steininger et al., 1997), and there may be relatively few serotonergic synapses on cholinergic neurons in PPT/LDT (Honda and Semba, 1994). Approximately 2-4% of the total synaptic input to both ChAT-immunoreactive dendrites and surrounding, noncholinergic neuropil is serotonergic, indicating that serotonergic input is not skewed toward cholinergic neurons in PPT (Steininger et al., 1997). In cats, a preliminary report based on two cats found a weak projection from DRN to LDT (Rodriquez-Veiga et al., 1992). This study did not mention any projections from DRN to PPT, and we are unaware of other such studies in the literature. Also, studies in rats have found only a weak serotonergic projection from DRN to the lateral parabrachial region (Petrov et al., 1992) that has recently been demonstrated in cats to be important in the generation of PGO waves and REM (Datta et al., 1992). Thus, anatomical studies, negative findings in single unit studies (Koyama and Sakai, 1995) and our findings that local applications of several compounds active at 5-HT receptor sites in PPT/LDT do not alter PGO wave activity suggest that DRN probably does not directly inhibit PGO wave generator neurons located in these regions.

The results of the present study and those of other current studies in the literature (Sakai et al., 1990; Koyama and Sakai, 1995) have significant implications for the prevailing notions of how PGO waves are generated. They do not support the general hypothesis that the generation of PGO waves is regulated by the direct inhibition or disinhibition of mesopontine cholinergic cells by 5-HT inputs from DRN. Therefore, we suggest the possibility that 5-HT may regulate PGO wave generation by acting at some other brain region, possibly at the forebrain level. The DRN has a major projection to the central nucleus of the amygdala (CNA), which, in turn, has projections to regions involved in producing PGO waves (Moga and Gray, 1985). Electrical stimulation of CNA during REM in cats increases PGO waves by up to thirty percent (Calvo et al., 1987), and microinjections of carbachol, a cholinergic agonist, into CNA of cats releases PGO waves (Calvo et al., 1996). We have found that mM concentrations of methysergide microinjected into CNA of sleeping rats significantly increases the frequency of PGO waves recorded from the pons, whereas microinjections of 5-HT (1.5 mM) produced short-latency arousal from REM and NREM (Sanford et al., 1996). Thus, DRN may well have an influence on PGO wave mechanisms via an indirect pathway.

1. Adrien J, Hamon M. Involvement of 5-HT3 and 5-HT1A receptors in the control of sleep-wakefulness cycles in the cat. Sleep Research 1989; 18: 29.
2. Beer MS, Middlemiss DK, McAllister G. 5-HT1-like receptors: six down and still counting. Trends In Pharmacological Sciences 1993; 14: 228-31.

3. Berman AL. The Brain Stem of the Cat. A Cytoarchitectonic Atlas with Stereotaxic Co-ordinates. Madison: The University of Wisconsin Press, 1968.

4. Bjorvatn B, Hole K, Ursin R. Sleep and waking after 8-OH-DPAT given systemically as well as perfused into the dorsal raphe nucleus in rats. Society for Neuroscience Abstracts 1996; 22: 1441.

5. Brooks DC. Effect of bilateral optic nerve section on visual monophasic wave activity in the cat. Electroencephalography and clinical Neurophysiology 1967; 23: 134-41.

6. Brooks DC, Gershon MD. Eye movement potentials in the oculomotor and visual systems of the cat: A comparison of reserpine-induced waves with those present during wakefulness and rapid eye movement sleep. Brain Research 1971; 27: 223-39.

7. Brooks DC, Gershon MD. An analysis of the effect of reserpine upon ponto-geniculo-occipital wave activity in the cat. Neuropharmacology 1972; 11: 499-510.

8. Brooks DC, Gershon MD, Simon RP. Brain stem serotonin depletion and ponto-geniculo-occipital wave activity in the cat treated with reserpine. Neuropharmacology 1972; 11: 511-20.

9. Calvo JM, Badillo S, Morales-Ramirez M, Palacios-Salas P. The role of the temporal lobe amygdala in ponto-geniculo-occipital activity and sleep organization in cats. Brain Research 1987; 403: 22-30.

10. Calvo JM, Simón-Arceo K, Fernández-Mas R. Prolonged enhancement of REM sleep produced by carbachol microinjection into the amygdala. NeuroReport 1996; 7: 577-80.

11. Cespuglio R, Faradji H, Gomez ME, Jouvet M. Single unit recordings in the nuclei raphe dorsalis and magnus during the sleep-waking cycle of semi-chronic prepared cats. Neuroscience Letters 1981; 24: 133-8.

12. Cornwall J, Cooper JD, Philipson OT. Afferent and efferent connections of the laterodorsal tegmental nucleus in the rat. Brain Research Bulletin 1990; 25: 271-84.

13. Datta S, Calvo JM, Quattrochi JJ, Hobson JA. Long-term enhancement of REM sleep following cholinergic stimulation. NeuroReport 1992; 2: 619-22.

14. Delorme F, Jeannerod M, Jouvet M. Effets remarquables de la reserpine sur l'activites EEG phasique, ponto-geniculo-occipitale. Compte Rendus Société De Biologie 1965; 159: 900-3.

15. Dugovic C. Functional activity of 5-HT2 receptors in the modulation of the sleep/wakefulness states. Journal of Sleep Research 1992; 1: 163-8.

16. Honda T, Semba K. Serotonergic synaptic input to cholinergic neurons in the rat mesopontine tegmentum. Brain Research 1994; 647: 299-306.

17. Horner RL, Sanford LD, Annis D, Pack AI, Morrison AR. Serotonin at the laterodorsal tegmental nucleus suppresses REM sleep but not phasic REM events. The Journal of Neuroscience 1997; 17: 7451-552.

18. Humphrey P, Hartig PR, Hoyer D. A proposed new nomenclature for 5-HT receptors. Trends In Pharmacological Sciences 1993; 14: 233-6.

19. Jacobs BL, Asher R, Dement WC. Electrophysiological and behavioral effects of electrical stimulation on the raphe nuclei in cats. Physiology & Behavior 1973; 11: 489-95.

20. Jacobs BL, Henriksen SJ, Dement WC. Neurochemical basis of the PGO wave. Brain Research 1972; 48: 406-11.

21. Kayama Y, Ohta M, Jodo E. Firing of "possibly" cholinergic neurons in the rat laterodorsal tegmental nucleus during sleep and wakefulness. Brain Research 1992; 569: 210-20.

22. Kodama T, Honda Y. Acetylcholine releases of mesopontine PGO-on cells in the lateral geniculate nucleus in sleep-waking cycle and serotonergic regulation. Progress In Neuropsychopharmacology & Biological Psychiatry 1996; 20: 1213-27.

23. Koyama Y, Sakai K. Cholinergic inhibition and monoaminergic excitation of presumed cholinergic mesopontine tegmental neurons: A microiontophoretic study in unanesthetized cats. Sleep Research 1995; 24a: 35.

24. Luebke JI, Greene RW, Semba K, Kamondi A, McCarley RW, Reiner PB. Serotonin hyperpolarizes cholinergic low-threshold burst neurons in the rat laterodorsal tegmental nucleus in vitro. Proceedings of the National Academy of Sciences 1992; 89: 743-7.

25. McGinty DJ, Harper RM. Dorsal raphe neurons: depression of firing during sleep in cats. Brain Research 1976; 101: 569-75.

26. Moga MM, Gray TS. Evidence for corticotropin-releasing factor, neurotensin, and somatostatin in the neural pathway from the central nucleus of the amygdala to the parabrachial nucleus. The Journal of Comparative Neurology 1985; 241: 275-84.

27. Morilak DA, Ciaranello RD. 5-HT2 receptor immunoreactivity on cholinergic neurons of the pontomesencephalic tegmentum shown by double immunofluorescence. Brain Research 1993; 627: 49-54.

28. Myers JL, Wells AD. Research Design And Statistical Analysis. New Jersey: Lawrence Erlbaum Associates, 1995.

29. Petrov T, Krukoff TL, Jhamandas JH. The hypothalamic paraventricular and lateral parabrachial nuclei receive collaterals from raphe nucleus neurons: a combined double retrograde and immunocytochemical study. The Journal of Comparative Neurology 1992; 318: 18-26.

30. Portas CM, Thakker M, Rainnie D, McCarley RW. Microdialysis perfusion of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in the dorsal raphe nucleus decreases serotonin release and increases rapid eye movement sleep in the freely moving cat. The Journal of Neuroscience 1996; 16: 2820-8.

31. Quattrochi JJ, Mamelak AN, Binder D, Williams J, Rittenhouse C, Hobson JA. Dynamic suppression of REM sleep by parenteral administration of the serotonin-1 agonist eltoprazine. Sleep 1992; 15: 125-32.

32. Rodriquez-Veiga E, Rodrigo-Angulo ML, deAndres I, Reinoso-Suarez F. Connections of the raphe nuclei with the dorsolateral mesopontine tegmentum. Journal of Sleep Research 1992; 1: 197.

33. Ross RJ, Peymer SI, Sanford LD, Ball WA, Morrison AR. REM sleep suppression induced by serotonin uptake blockage: Evidence for a type 2 receptor mechanism. Society for Neuroscience Abstracts 1991; 17: 879.

34. Sakai K, El Mansari M, Jouvet M. Inhibition by carbachol microinjections of presumptive cholinergic PGO-on neurons in freely moving cats. Brain Research 1990; 527: 213-23.

35. Sanford LD, Ross RJ, Seggos AE, Morrison AR, Ball WA, Mann GL. Central administration of two 5HT receptor agonists: effect on REM sleep initiation and PGO waves. Pharmacology Biochemistry and Behavior 1994; 49: 93-100.

36. Sanford LD, Tejani-Butt SM, Ross RJ, Morrison AR. Amygdaloid control of alerting and behavioral arousal in rats: Involvement of serotonergic mechanisms. Archives Italiennes de Biologie 1995; 134: 81-99.

37. Sanford LD, Tejani-Butt SM, Ross RJ, Morrison AR. Elicited PGO waves in rats: Lack of 5-HT1A inhibition in putative pontine generator region. Pharmacology Biochemistry and Behavior 1996; 53: 323-7.

38. Semba K, Fibiger HC. Afferent connections of the laterodorsal and the pedunculopontine tegmental nuclei in the rat: A retro- and antero-grade transport and immunohistochemical study. The Journal of Comparative Neurology 1992; 323: 387-410.

39. Simon RP, Gershon MD, Brooks DC. The role of raphe nuclei in the regulation of ponto-geniculo-occipital wave activity. Brain Research 1973; 58: 313-30.

40. Sommerfelt L, Ursin R. The 5-HT2 antagonist ritanserin decreases sleep in cats. Sleep 1993; 16: 15-22.

41. Steininger TL, Wainer BH, Blakely RD, Rye DB. Serotonergic dorsal raphe nucleus projections to the cholinergic and noncholinergic neurons of the pedunculopontine tegmental region: A light and electron microscopic anterograde tracing and immunohistochemical study. The Journal of Comparative Neurology 1997; 382: 302-22.

42. Steriade M, Pare D, Datta S, Oakson G, Curro-Dossi R. Different cellular types in mesopontine cholinergic nuclei related to ponto-geniculo-occipital waves. The Journal of Neuroscience 1990; 10: 2546-65.

43. Trulson ME, Jacobs BL. Raphe unit activity in freely moving cats: correlation with level of behavioral arousal. Brain Research 1979; 163: 135-50.

The authors would like to thank Ms. Graziella Mann for her invaluable help in conducting this work. Supported by USPHS grants MH42903 (Adrian Morrison), SCOR HL42236, Project 03 (Allan Pack, Adrian Morrison, Larry Sanford) and the Department of Veterans Affairs (Richard Ross).

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