Adenosine: A mediator of the sleep-inducing effects of prolonged wakefulness

Science

Volumn 276, Issue 5316, 1997, Pages 1265-1267

  Porkka Heiskanen, Tarja ^a,b   Strecker, Robert E ^a   Thakkar, Mahesh ^a   Bjørkum, Alvhild A ^a   Greene, Robert W ^a   McCarley, Robert W ^a  

^a VETERANS AFFAIRS MEDICAL CENTER   (United States)

^b UNIVERSITY OF HELSINKI   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE;

AMINO ACID SYNTHESIS; AROUSAL; ARTICLE; BRAIN METABOLISM; CHOLINERGIC NERVE; FOREBRAIN; HUMAN; PRIORITY JOURNAL; SLEEP WAKING CYCLE; WAKEFULNESS;

ADENOSINE; ANIMALS; CATS; ELECTROPHYSIOLOGY; MICRODIALYSIS; PROSENCEPHALON; SLEEP; SLEEP DEPRIVATION; THIOINOSINE; TIME FACTORS; WAKEFULNESS;

EID: 0030995841     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.276.5316.1265     Document Type: Article

References (48)

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9. I. Pull and H. McIlwain, Biochem. J. 126, 965 (1972); H. R. Winn, J. E. Welsh, R. Rubio, R. M. Berne, Circ. Res. 47, 568 (1980); J. Schrader, M. Wahl, W. Kuschinsky, G. W. Kreutzberg, Pfluegers Arch. Eur. J. Physiol. 387, 245 (1980); R. M. Berne, in Cerebral Hypoxia in the Pathogenesis of Migraine, F. C. Rose and W. K. Amery, Eds. (Pitman, London, 1982), pp. 82-91; D. G. Van Wylen, T. S. Park, R. Rubio, R. M. Berne, J. Cereb. Blood Flow Metab. 6, 522 (1986); H. McIlwain and J. D. Poll, Neurochem. Int. 7, 103 (1985).
10. I. Pull and H. McIlwain, Biochem. J. 126, 965 (1972); H. R. Winn, J. E. Welsh, R. Rubio, R. M. Berne, Circ. Res. 47, 568 (1980); J. Schrader, M. Wahl, W. Kuschinsky, G. W. Kreutzberg, Pfluegers Arch. Eur. J. Physiol. 387, 245 (1980); R. M. Berne, in Cerebral Hypoxia in the Pathogenesis of Migraine, F. C. Rose and W. K. Amery, Eds. (Pitman, London, 1982), pp. 82-91; D. G. Van Wylen, T. S. Park, R. Rubio, R. M. Berne, J. Cereb. Blood Flow Metab. 6, 522 (1986); H. McIlwain and J. D. Poll, Neurochem. Int. 7, 103 (1985).
11. I. Pull and H. McIlwain, Biochem. J. 126, 965 (1972); H. R. Winn, J. E. Welsh, R. Rubio, R. M. Berne, Circ. Res. 47, 568 (1980); J. Schrader, M. Wahl, W. Kuschinsky, G. W. Kreutzberg, Pfluegers Arch. Eur. J. Physiol. 387, 245 (1980); R. M. Berne, in Cerebral Hypoxia in the Pathogenesis of Migraine, F. C. Rose and W. K. Amery, Eds. (Pitman, London, 1982), pp. 82-91; D. G. Van Wylen, T. S. Park, R. Rubio, R. M. Berne, J. Cereb. Blood Flow Metab. 6, 522 (1986); H. McIlwain and J. D. Poll, Neurochem. Int. 7, 103 (1985).
12. I. Pull and H. McIlwain, Biochem. J. 126, 965 (1972); H. R. Winn, J. E. Welsh, R. Rubio, R. M. Berne, Circ. Res. 47, 568 (1980); J. Schrader, M. Wahl, W. Kuschinsky, G. W. Kreutzberg, Pfluegers Arch. Eur. J. Physiol. 387, 245 (1980); R. M. Berne, in Cerebral Hypoxia in the Pathogenesis of Migraine, F. C. Rose and W. K. Amery, Eds. (Pitman, London, 1982), pp. 82-91; D. G. Van Wylen, T. S. Park, R. Rubio, R. M. Berne, J. Cereb. Blood Flow Metab. 6, 522 (1986); H. McIlwain and J. D. Poll, Neurochem. Int. 7, 103 (1985).
13. I. Pull and H. McIlwain, Biochem. J. 126, 965 (1972); H. R. Winn, J. E. Welsh, R. Rubio, R. M. Berne, Circ. Res. 47, 568 (1980); J. Schrader, M. Wahl, W. Kuschinsky, G. W. Kreutzberg, Pfluegers Arch. Eur. J. Physiol. 387, 245 (1980); R. M. Berne, in Cerebral Hypoxia in the Pathogenesis of Migraine, F. C. Rose and W. K. Amery, Eds. (Pitman, London, 1982), pp. 82-91; D. G. Van Wylen, T. S. Park, R. Rubio, R. M. Berne, J. Cereb. Blood Flow Metab. 6, 522 (1986); H. McIlwain and J. D. Poll, Neurochem. Int. 7, 103 (1985).
14. 2 was determined by P. L. Madsen et al. [J. Appl. Physiol. 70, 2597 (1991)].
15. 2 was determined by P. L. Madsen et al. [J. Appl. Physiol. 70, 2597 (1991)].
16. T. V. Dunwiddie, B. J. Hoffer, B. B. Fredholm, Naunyn-Schmiedeberg's Arch. Pharmacol. 316, 326 (1981); R. W. Greene, H. L. Haas, A. Hermann, Br. J. Pharmacol. 85, 163 (1985); A. Zwyghuisen-Doorenbos, T. A. Roehrs, L. Lipschutz, V. Timms, T. Roth, Psychopharmacology 100, 36 (1990); D. Penetar et al., ibid. 112, 359 (1993). B. Schwierin, A. A. Borbély, and I. Tobler [Eur. J. Pharmacol. 300, 163 (1996)] showed that caffeine given at the beginning of 6-hour sleep deprivation decreased delta power during rebound sleep.
17. T. V. Dunwiddie, B. J. Hoffer, B. B. Fredholm, Naunyn-Schmiedeberg's Arch. Pharmacol. 316, 326 (1981); R. W. Greene, H. L. Haas, A. Hermann, Br. J. Pharmacol. 85, 163 (1985); A. Zwyghuisen-Doorenbos, T. A. Roehrs, L. Lipschutz, V. Timms, T. Roth, Psychopharmacology 100, 36 (1990); D. Penetar et al., ibid. 112, 359 (1993). B. Schwierin, A. A. Borbély, and I. Tobler [Eur. J. Pharmacol. 300, 163 (1996)] showed that caffeine given at the beginning of 6-hour sleep deprivation decreased delta power during rebound sleep.
18. T. V. Dunwiddie, B. J. Hoffer, B. B. Fredholm, Naunyn-Schmiedeberg's Arch. Pharmacol. 316, 326 (1981); R. W. Greene, H. L. Haas, A. Hermann, Br. J. Pharmacol. 85, 163 (1985); A. Zwyghuisen-Doorenbos, T. A. Roehrs, L. Lipschutz, V. Timms, T. Roth, Psychopharmacology 100, 36 (1990); D. Penetar et al., ibid. 112, 359 (1993). B. Schwierin, A. A. Borbély, and I. Tobler [Eur. J. Pharmacol. 300, 163 (1996)] showed that caffeine given at the beginning of 6-hour sleep deprivation decreased delta power during rebound sleep.
19. T. V. Dunwiddie, B. J. Hoffer, B. B. Fredholm, Naunyn-Schmiedeberg's Arch. Pharmacol. 316, 326 (1981); R. W. Greene, H. L. Haas, A. Hermann, Br. J. Pharmacol. 85, 163 (1985); A. Zwyghuisen-Doorenbos, T. A. Roehrs, L. Lipschutz, V. Timms, T. Roth, Psychopharmacology 100, 36 (1990); D. Penetar et al., ibid. 112, 359 (1993). B. Schwierin, A. A. Borbély, and I. Tobler [Eur. J. Pharmacol. 300, 163 (1996)] showed that caffeine given at the beginning of 6-hour sleep deprivation decreased delta power during rebound sleep.
20. T. V. Dunwiddie, B. J. Hoffer, B. B. Fredholm, Naunyn-Schmiedeberg's Arch. Pharmacol. 316, 326 (1981); R. W. Greene, H. L. Haas, A. Hermann, Br. J. Pharmacol. 85, 163 (1985); A. Zwyghuisen-Doorenbos, T. A. Roehrs, L. Lipschutz, V. Timms, T. Roth, Psychopharmacology 100, 36 (1990); D. Penetar et al., ibid. 112, 359 (1993). B. Schwierin, A. A. Borbély, and I. Tobler [Eur. J. Pharmacol. 300, 163 (1996)] showed that caffeine given at the beginning of 6-hour sleep deprivation decreased delta power during rebound sleep.
21. C. M. Portas, M. Thakkar, D. G. Rainnie, R. W. Greene, R. W. McCarley, Neuroscience, in press. This study also demonstrated a concentration-response relation over a four-log-unit concentration range between adenosine perfused into the cholinergic basal forebrain and the extent of reduction of wakefulness.
22. R. Ursin and M. B. Sterman, A Manual for Standardized Scoring of Sleep and Waking States in the Adult Cat (Brain Information Service, Brain Research Institute, University of California, Los Angeles, 1981). EEG activation was scored in 20-s epochs.
23. Intracerebral guide cannulae (CMA 10 guide; CMA/Microdialysis, Stockholm, Sweden) were implanted 12 mm above the target. The coordinates for the basal forebrain (substantia innominata) were AP 15.5, ML 5, and DV -1.5, for the thalamus they were (VA/VL) AP 11, ML 5, and DV 2.5 [A. L. Berman and E. G. Jones, The Thalamus and Basal Telencephalon of the Cat (Univ. of Wisconsin Press, Madison, WI, 1982)]. After surgery, the animals were allowed to recover for 2 weeks. Histological processing was on 40-μm sections of formaldehyde-fixed brain tissue processed for immunohistochemistry with an antibody for choline acetyltransferase [P. J. Shiromani, S. Winston, R. W. McCarley, Mol. Brain Res. 38, 77 (1996)].
24. Intracerebral guide cannulae (CMA 10 guide; CMA/Microdialysis, Stockholm, Sweden) were implanted 12 mm above the target. The coordinates for the basal forebrain (substantia innominata) were AP 15.5, ML 5, and DV -1.5, for the thalamus they were (VA/VL) AP 11, ML 5, and DV 2.5 [A. L. Berman and E. G. Jones, The Thalamus and Basal Telencephalon of the Cat (Univ. of Wisconsin Press, Madison, WI, 1982)]. After surgery, the animals were allowed to recover for 2 weeks. Histological processing was on 40-μm sections of formaldehyde-fixed brain tissue processed for immunohistochemistry with an antibody for choline acetyltransferase [P. J. Shiromani, S. Winston, R. W. McCarley, Mol. Brain Res. 38, 77 (1996)].
25. We wished to test the hypothesis that adenosine exerts a selectively stronger influence on neurons that are intimately related to sleep-wakefulness control; we chose cholinergic neurons for study because our in vitro data indicate that adenosine exerts powerful inhibitory effects on them.
26. 2, at a pH of 6.6) was pumped through the probe at a flow rate of 1.5 μl/min, the same flow rate used for drug perfusion. Consecutive 10-min dialysis samples were collected throughout the day via tubing with a low dead space volume (1.2 μl per 10 cm, FEP tubing; CMA/Microdialysis) and correlated with electrographically defined sleep-wakefulness states. Adenosine from a microdialysis sample produced a sharp chromatogram peak with a high signal-to-noise ratio and the same 8-min retention time as the adenosine standard (Fig. 1A).
27. For the analysis of the group data, a sleep cycle was defined as a continuous period that contained all of the behavioral states (W, SWS, and REM sleep), and began and ended with waking periods; the validity of comparisons over time was ensured by rejection of any cycles where there were suggestions of nonstationarity (adenosine values with >25% change between the first and last waking epochs). Of the samples in this comparison of W and SWS, 65% were 100% in a single state, and the remaining 35% had less than 20% of another state. The mean cycle duration was not different in the basal forebrain and thalamus samples.
28. NBTI actions are discussed in G. Sanderson and C. N. Scholfield [Pfluegers Arch. Eur. J. Physiol. 406, 25 (1996)] and H. L. Haas and R. W. Greene [Naunyn-Schmiedeberg's Arch. Pharmacol. 337, 561 (1988)]. These references and our preliminary data confirmed 1 μM as the lowest dose producing maximal effect. To ensure the presence of normal sleep, the 3-hour baseline period was not started until 30 min after the first REM episode (typically 1 to 2 hours after the animal was connected to the polygraph and microdialysis lines). Basal extracellular concentrations of adenosine were determined during the 3-hour baseline period that preceded the drug administration.
29. NBTI actions are discussed in G. Sanderson and C. N. Scholfield [Pfluegers Arch. Eur. J. Physiol. 406, 25 (1996)] and H. L. Haas and R. W. Greene [Naunyn-Schmiedeberg's Arch. Pharmacol. 337, 561 (1988)]. These references and our preliminary data confirmed 1 μM as the lowest dose producing maximal effect. To ensure the presence of normal sleep, the 3-hour baseline period was not started until 30 min after the first REM episode (typically 1 to 2 hours after the animal was connected to the polygraph and microdialysis lines). Basal extracellular concentrations of adenosine were determined during the 3-hour baseline period that preceded the drug administration.
30. EEG power spectral analysis was performed during ACSF perfusion, during perfusion with 1 μM NBTI in the basal forebrain and thalamus, and during recovery sleep after 6 hours of wakefulness. Parietal EEG screw electrodes were used for EEG acquisition. The data were filtered at 70 Hz (low-pass filter) and 0.3 Hz (high-pass filter) with a Grass electroencephalograph and were continuously sampled at 128 Hz by a Pentium microprocessor computer with a Data-Wave (Data-Wave Technology, Longmont, CO) system. Absolute total power was calculated for the frequency range between 0.3 and 55 Hz. Five different frequency bands were used to calculate the relative power: delta, 0.3 to 4 Hz; theta, 4.1 to 9 Hz; alpha, 9.1 to 15Hz; beta, 15.1 to 25 Hz; and gamma, 25.1 to 55 Hz. After basal forebrain NBTI perfusion, the relative power was significantly increased in the delta and decreased in the theta, alpha, beta, and gamma bands (P < 0.04; nonparametric Wilcoxon matched pairs signed-ranks test, used because of nonnormality of data). There was no change in power in any frequency band after NBTI infusion in the thalamus.
31. In evaluating the physiological relevance of adenosine at various concentrations, it is important to note that in vitro data from our laboratory (3) demonstrated that endogenous adenosine had a consistent inhibitory effect on cholinergic neurons. These data imply that adenosine's physiological effects in vivo are to be expected at baseline that is, without sleep deprivation or NBTI. Rainnie et al. (3) did not measure endogenous adenosine concentrations, and thus the precise in vitro effects of doubling adenosine concentrations have not yet been specified, although it is known that there are progressive increases in inhibition of cholinergic neurons (beyond that seen from the endogenous inhibitory effect) with increasing concentrations of exogenously applied adenosine. Furthermore, we believe that the actions of adenosine that we have found in animal studies apply also to humans. First, the increase in EEG sleepiness with increasing duration of wakefulness has been documented in humans (1). Second, the adenosine physiology and pharmacology of experimental animals and of humans appear to be comparable (see reviews in (4-7) and also L. J. Findley, M. Boykin, T. Fallon, L. Belardinelli, J. Appl. Physiol. 65, 556 (1988); and H. L. Haas, R. G. Greene, M. G. Yasargil, V. Chan-Palay, Neurosci. Abstr. 13, 155 (1987)].
32. In evaluating the physiological relevance of adenosine at various concentrations, it is important to note that in vitro data from our laboratory (3) demonstrated that endogenous adenosine had a consistent inhibitory effect on cholinergic neurons. These data imply that adenosine's physiological effects in vivo are to be expected at baseline that is, without sleep deprivation or NBTI. Rainnie et al. (3) did not measure endogenous adenosine concentrations, and thus the precise in vitro effects of doubling adenosine concentrations have not yet been specified, although it is known that there are progressive increases in inhibition of cholinergic neurons (beyond that seen from the endogenous inhibitory effect) with increasing concentrations of exogenously applied adenosine. Furthermore, we believe that the actions of adenosine that we have found in animal studies apply also to humans. First, the increase in EEG sleepiness with increasing duration of wakefulness has been documented in humans (1). Second, the adenosine physiology and pharmacology of experimental animals and of humans appear to be comparable (see reviews in (4-7) and also L. J. Findley, M. Boykin, T. Fallon, L. Belardinelli, J. Appl. Physiol. 65, 556 (1988); and H. L. Haas, R. G. Greene, M. G. Yasargil, V. Chan-Palay, Neurosci. Abstr. 13, 155 (1987)].
33. Finally, the adenosine antagonist caffeine increases wakefulness in formal experimental studies [see (7) and H. P. Landolt, D. J. Dijk, S. E. Gaus, A. A. Borbely, Neuropsychopharmacology 12, 229 (1995)] and, as with the adenosine antagonist theophylline, constitutes the sleep-delaying ingredient in coffee and tea.
34. Changes in the entire relative power spectrum with NBTI infusion and in recovery sleep after prolonged wakefulness were, for each band, in the same direction (n = four animals).
35. P. H. Wu, R. A. Barraco, J. W. Phillis, Gen. Pharmacol. 15, 251 (1984); R. Padua, J. D. Geiger, S. Dambock, J. I. Nagy, J. Neurochem 54, 1169 (1990); J. G. Gu and J. D. Geiger, ibid. 58, 1699 (1992). Both N-methyl-D-aspartate receptor agonists [C. G. Craig and T. D. White, J. Pharmacol. Exp. Ther. 260, 1278 (1992); J. Neurochem. 60, 1073 (1993)] and agonists that increase adenosine 3′,5′-monophosphate [R. W. Gereau and P. J. Conn, Neuron 12, 1121 (1994); P. A. Rosenberg, R. Knowles, Y. Li, J. Neurosci. 14, 2953 (1994)] might also increase extracellular adeonosine concentrations by increasing extracellular adenine nucleotides that are catabolized to adenosine by 5′-ectonucleotidase (also a potential modulatory target).
36. P. H. Wu, R. A. Barraco, J. W. Phillis, Gen. Pharmacol. 15, 251 (1984); R. Padua, J. D. Geiger, S. Dambock, J. I. Nagy, J. Neurochem 54, 1169 (1990); J. G. Gu and J. D. Geiger, ibid. 58, 1699 (1992). Both N-methyl-D-aspartate receptor agonists [C. G. Craig and T. D. White, J. Pharmacol. Exp. Ther. 260, 1278 (1992); J. Neurochem. 60, 1073 (1993)] and agonists that increase adenosine 3′,5′-monophosphate [R. W. Gereau and P. J. Conn, Neuron 12, 1121 (1994); P. A. Rosenberg, R. Knowles, Y. Li, J. Neurosci. 14, 2953 (1994)] might also increase extracellular adeonosine concentrations by increasing extracellular adenine nucleotides that are catabolized to adenosine by 5′-ectonucleotidase (also a potential modulatory target).
37. P. H. Wu, R. A. Barraco, J. W. Phillis, Gen. Pharmacol. 15, 251 (1984); R. Padua, J. D. Geiger, S. Dambock, J. I. Nagy, J. Neurochem 54, 1169 (1990); J. G. Gu and J. D. Geiger, ibid. 58, 1699 (1992). Both N-methyl-D-aspartate receptor agonists [C. G. Craig and T. D. White, J. Pharmacol. Exp. Ther. 260, 1278 (1992); J. Neurochem. 60, 1073 (1993)] and agonists that increase adenosine 3′,5′-monophosphate [R. W. Gereau and P. J. Conn, Neuron 12, 1121 (1994); P. A. Rosenberg, R. Knowles, Y. Li, J. Neurosci. 14, 2953 (1994)] might also increase extracellular adeonosine concentrations by increasing extracellular adenine nucleotides that are catabolized to adenosine by 5′-ectonucleotidase (also a potential modulatory target).
38. P. H. Wu, R. A. Barraco, J. W. Phillis, Gen. Pharmacol. 15, 251 (1984); R. Padua, J. D. Geiger, S. Dambock, J. I. Nagy, J. Neurochem 54, 1169 (1990); J. G. Gu and J. D. Geiger, ibid. 58, 1699 (1992). Both N-methyl-D-aspartate receptor agonists [C. G. Craig and T. D. White, J. Pharmacol. Exp. Ther. 260, 1278 (1992); J. Neurochem. 60, 1073 (1993)] and agonists that increase adenosine 3′,5′-monophosphate [R. W. Gereau and P. J. Conn, Neuron 12, 1121 (1994); P. A. Rosenberg, R. Knowles, Y. Li, J. Neurosci. 14, 2953 (1994)] might also increase extracellular adeonosine concentrations by increasing extracellular adenine nucleotides that are catabolized to adenosine by 5′-ectonucleotidase (also a potential modulatory target).
39. P. H. Wu, R. A. Barraco, J. W. Phillis, Gen. Pharmacol. 15, 251 (1984); R. Padua, J. D. Geiger, S. Dambock, J. I. Nagy, J. Neurochem 54, 1169 (1990); J. G. Gu and J. D. Geiger, ibid. 58, 1699 (1992). Both N-methyl-D-aspartate receptor agonists [C. G. Craig and T. D. White, J. Pharmacol. Exp. Ther. 260, 1278 (1992); J. Neurochem. 60, 1073 (1993)] and agonists that increase adenosine 3′,5′-monophosphate [R. W. Gereau and P. J. Conn, Neuron 12, 1121 (1994); P. A. Rosenberg, R. Knowles, Y. Li, J. Neurosci. 14, 2953 (1994)] might also increase extracellular adeonosine concentrations by increasing extracellular adenine nucleotides that are catabolized to adenosine by 5′-ectonucleotidase (also a potential modulatory target).
40. P. H. Wu, R. A. Barraco, J. W. Phillis, Gen. Pharmacol. 15, 251 (1984); R. Padua, J. D. Geiger, S. Dambock, J. I. Nagy, J. Neurochem 54, 1169 (1990); J. G. Gu and J. D. Geiger, ibid. 58, 1699 (1992). Both N-methyl-D-aspartate receptor agonists [C. G. Craig and T. D. White, J. Pharmacol. Exp. Ther. 260, 1278 (1992); J. Neurochem. 60, 1073 (1993)] and agonists that increase adenosine 3′,5′-monophosphate [R. W. Gereau and P. J. Conn, Neuron 12, 1121 (1994); P. A. Rosenberg, R. Knowles, Y. Li, J. Neurosci. 14, 2953 (1994)] might also increase extracellular adeonosine concentrations by increasing extracellular adenine nucleotides that are catabolized to adenosine by 5′-ectonucleotidase (also a potential modulatory target).
41. P. H. Wu, R. A. Barraco, J. W. Phillis, Gen. Pharmacol. 15, 251 (1984); R. Padua, J. D. Geiger, S. Dambock, J. I. Nagy, J. Neurochem 54, 1169 (1990); J. G. Gu and J. D. Geiger, ibid. 58, 1699 (1992). Both N-methyl-D-aspartate receptor agonists [C. G. Craig and T. D. White, J. Pharmacol. Exp. Ther. 260, 1278 (1992); J. Neurochem. 60, 1073 (1993)] and agonists that increase adenosine 3′,5′-monophosphate [R. W. Gereau and P. J. Conn, Neuron 12, 1121 (1994); P. A. Rosenberg, R. Knowles, Y. Li, J. Neurosci. 14, 2953 (1994)] might also increase extracellular adeonosine concentrations by increasing extracellular adenine nucleotides that are catabolized to adenosine by 5′-ectonucleotidase (also a potential modulatory target).
42. This possibility has recently been reviewed by J. M. Brundege and T. V. Dunwiddie [J. Neurosci. 16, 5603 (1996)], who also provided direct evidence for the possibility that an increase in intracellular adenosine (either by exogenous adenosine or inhibiting metabolism of endogenous adenosine) could lead to an increase in extracellular adenosine and its actions on receptors.
43. V. C. de Sánchez et al., Brain Res. 612, 115 (1993); J. P. Huston ef al., Neuroscience 73, 99 (1996). Adenosine appears to have a tighter linkage to sleep after wakefulness than do other putative SWS factors [see review by J. M. Krueger and J. Fang, in Sleep and Sleep Disorders: From Molecule to Behavior, O. Hayaishi and S. Inoue, Eds. (Academic Press and Harcourt Brace, Tokyo, Japan, in press)].
44. V. C. de Sánchez et al., Brain Res. 612, 115 (1993); J. P. Huston ef al., Neuroscience 73, 99 (1996). Adenosine appears to have a tighter linkage to sleep after wakefulness than do other putative SWS factors [see review by J. M. Krueger and J. Fang, in Sleep and Sleep Disorders: From Molecule to Behavior, O. Hayaishi and S. Inoue, Eds. (Academic Press and Harcourt Brace, Tokyo, Japan, in press)].
45. V. C. de Sánchez et al., Brain Res. 612, 115 (1993); J. P. Huston ef al., Neuroscience 73, 99 (1996). Adenosine appears to have a tighter linkage to sleep after wakefulness than do other putative SWS factors [see review by J. M. Krueger and J. Fang, in Sleep and Sleep Disorders: From Molecule to Behavior, O. Hayaishi and S. Inoue, Eds. (Academic Press and Harcourt Brace, Tokyo, Japan, in press)].
46. It is also possible that adenosine's effects in the neocortex may be directly attenuated by cholinergic receptor activation, as has been shown in the hippocampus [P. F. Worley, J. M. Baraban, M. McCarren, S. H. Snyder, B. E. Alger, Proc. Natl. Acad. Sci. U.S.A. 84, 3467 (1987)]. Thus, adenosine's direct inhibitory effects on cholinergic somata might be enhanced by a consequent disinhibition of adenosine's effects on neocortical neurons. The specificity of sleep-wakefulness effects of NBTI does not support the idea that adenosine's effects result from a global action on brain neurons, as suggested by J. H. Benington and H. C. Heller [Prog. Neurobiol. 45, 347 (1995)].
47. It is also possible that adenosine's effects in the neocortex may be directly attenuated by cholinergic receptor activation, as has been shown in the hippocampus [P. F. Worley, J. M. Baraban, M. McCarren, S. H. Snyder, B. E. Alger, Proc. Natl. Acad. Sci. U.S.A. 84, 3467 (1987)]. Thus, adenosine's direct inhibitory effects on cholinergic somata might be enhanced by a consequent disinhibition of adenosine's effects on neocortical neurons. The specificity of sleep-wakefulness effects of NBTI does not support the idea that adenosine's effects result from a global action on brain neurons, as suggested by J. H. Benington and H. C. Heller [Prog. Neurobiol. 45, 347 (1995)].
48. We thank P. Shiromani, D. Rainnie, and D. Stenberg for their advice during this work; L. Camara and M. Gray for technical assistance; and C. Portas for her preliminary work on this project. Supported by National Institute of Mental Health, grant R37 MH39, 683 and awards from the Department of Veterans Affairs to R.W.M.