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Human melatonin suppression by light: a case for scotopic efficiency
Neuroscience Letters 299 (2001) 45±48
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Human melatonin suppression by light: a case for scotopic ef®ciency Mark S. Rea*, John D. Bullough, Mariana G. Figueiro Lighting Research Center, Rensselaer Polytechnic Institute, 21 Union Street, Troy, NY 12180, USA Received 1 November 2000; received in revised form 7 December 2000; accepted 7 December 2000
Abstract Human adult males were exposed to combinations of two illuminances and two spectral power distributions over the course of four nighttime sessions. A dose-dependent response of acute melatonin suppression to light was found, but photopic (cone-based) illuminance did not adequately predict suppression. When melatonin suppression was plotted against scotopic (rod-based) illuminance, the data formed a nearly monotonic function, implicating rods, or a roddominated mechanism, in the human melatonin regulation system. The results do not, however, rule out mechanisms other than rods, including novel photoreceptors, as candidates for melatonin regulation in humans. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Circadian rhythm; Spectral sensitivity; Photoreceptive system; Pineal response
Much is known about the photoreceptors that convert light into neural signals for vision, but the mechanisms for circadian phototransduction are still largely unknown [7]. Since the ®rst report of acute suppression of melatonin by light in humans [4], efforts have been underway to determine the dose-response characteristics and the spectral sensitivity of the ocular channel that mediates pineal response to light. Based on the wealth of information from the literature on human vision [7], conventional wisdom leads to either a photopic (cone, peaking at 555 nm) [10,11] or a scotopic (rod, peaking at 507 nm) [2] hypothesis for circadian phototransduction. Techniques well established in visual psychophysics [9] but unique to studies of circadian spectral sensitivity were used to experimentally contrast the photopic and scotopic hypotheses. These techniques have the major advantage of ef®ciently testing competing hypotheses, but do not eliminate more complex models based on unusual combinations of known photoreceptors, nor do they eliminate the possibility of novel mechanisms such as cryptochrome [5] or melanopsin [6] in the regulation of melatonin by light. Four adult male subjects (ages 29, 29, 48 and 59 years) participated in this study, which took place on each of ®ve nights (one baseline session and four experimental sessions) * Corresponding author. Tel.: 11-518-687-7100; fax: 11-518687-7120. E-mail address: [email protected] (M.S. Rea).
in the Clinical Pharmacological Studies Unit of Albany Medical College, Albany, NY. Each session lasted 9 h (from 22:00 to 07:00 h) and subjects were seated at a square, 1.25 £ 1.25 m table throughout the study sessions. The table consisted of a white-painted enclosure containing 16 ¯uorescent lamps, eight each of two correlated color temperatures: 3000 K (Philips F40SPEC30, `warm') and 7500 K (Philips F40C75, `cool'). The lamps were mounted in alternating sockets and controlled by electronic dimming ballasts (Lutron) and photocells so that the light output of each set of eight lamps could be independently controlled and mixed together. A clear piece of glass and an acrylic diffuser were mounted over the enclosure and served as the tabletop. When subjects sat around the table, the lamps and diffuser provided uniform illumination at the subjects' eyes. During the study, when the ¯uorescent lamps were switched on, subjects read material printed onto overhead projector transparency sheets so that they received a controlled dose of light exposure while reading. All subjects followed their normal daily routine and refrained from consuming caffeine for 12 h before each session, which always began at 22:00 h. Upon arrival at the study location, a nurse or physician inserted a catheter into a vein of each subject. Starting at 45 min after each hour, blood samples (3 ml) were drawn from each subject in a ®xed order. Samples were spun in a refrigerator centrifuge at 2300 rev./min for 10 min and separated plasma was frozen at 2868C. Frozen samples were sent to an indepen-
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 1) 01 51 2- 9
46
M.S. Rea et al. / Neuroscience Letters 299 (2001) 45±48
Fig. 2. Mean melatonin concentration (and standard error of the mean) for the baseline (dashed curve) and all experimental (solid curve) sessions.
four conditions, when printed reading materials were placed on the table. During the ®rst, third, ®fth, seventh and ninth hours of the experimental sessions, all room lights, including the lamps inside the light table, were extinguished except for the incandescent task lights. During the second, fourth, sixth and eighth hours, the lamps inside the light table were controlled to provide each of the four lighting conditions in Table 1, in a counterbalanced order across all four experimental sessions. Counterbalancing minimized the impact of time on the results, since melatonin suppression could differ at different times of the night. To determine if recovery of melatonin occurred after each hour of darkness during the experimental sessions, the mean hourly melatonin concentrations (pg/ml) of the subjects was plotted for the baseline and experimental sessions in Fig. 2. Fig. 2 shows the recovery of melatonin nearly to the baseline level, as well as the mean impact of all light exposures on melatonin suppression. A paired, one-tailed Student's t-test on the 16 pairs (four for each subject) of melatonin concentrations before and after exposure to light revealed that melatonin concentration after each period of light exposure was signi®cantly lower than before this period (t15 7:6, P , 1026 ). The mean melatonin suppression (in percent) and standard error of the mean for all subjects under each lighting condition is listed in Table 1. Using a two-way, repeatedmeasures analysis of variance on these sets of 16 measurements (four for each subject), both photopic illuminance (F1;15 16:1, P , 0:005) and SPD (F1;15 17:1, P , 0:001) had signi®cant effects on melatonin suppres-
Fig. 1. Spectral power distributions: (a) warm lighting conditions (ratio of scotopic to photopic illuminance 1.1); (b) cool lighting conditions (ratio of scotopic to photopic illuminance 1.7). Distributions are normalized to have peak values of 1.
dent laboratory (DiagnosTech International, Osceola, WI) for melatonin radioimmunoassay. Nine samples were drawn hourly from each subject during each session. During the baseline session, all room lighting was extinguished except for two small incandescent task lights located away from the subjects, which provided less than 0.2 photopic lx at the eye. Four lighting conditions were selected for the experimental study sessions: two photopic illuminances at the eye, and two spectral power distributions (SPDs), warm (yellowish) and cool (bluish) in appearance. Fig. 1 shows the SPDs for the warm and cool conditions. For an equal photopic illuminance, the scotopic illuminance from the cool SPD was higher than from the warm SPD, because the scotopic luminous ef®ciency function gives greater weight to shorterwavelength (`bluer') light than the photopic function. The SPDs were selected by mixing illumination from the sets of lamps so that the scotopic illuminance at the eye under the warm high condition was approximately equal to that under the cool low condition. Table 1 lists the resulting photopic and scotopic illuminances measured at subjects eyes for all
Table 1 Photopic and scotopic illuminances at the eye, and mean melatonin suppression and standard error of the mean (SEM) for the four experimental conditions Lighting condition
Photopic illuminance at eye (lx)
Scotopic illuminance at eye (lx)
Mean melatonin suppression (% ^ SEM)
Warm low Warm high Cool low Cool high
247 454 271 453
274 504 453 766
9.3 ^ 8.9 31.4 ^ 5.6 39.2 ^ 4.2 44.4 ^ 3.6
M.S. Rea et al. / Neuroscience Letters 299 (2001) 45±48
Fig. 3. Mean melatonin suppression (and standard error of the mean). (a) Plotted as a function of the photopic illuminance at the eye; (b) plotted as a function of scotopic illuminance. Also shown are best ®ts to the data using compressive, asymptotic functions giving a response of 0% at 0 lx.
sion; the interaction between them was not statistically signi®cant (F1;15 3:1; P . 0:05). The warm high and the cool low lighting conditions, designed to provide nearly the same scotopic illuminance, resulted in nearly the same melatonin suppression; a paired, two-tailed Student's t-test found that the difference between these two conditions was not statistically signi®cant (t15 1:7, P . 0:05). Fig. 3a shows the mean melatonin suppression (and standard error of the mean) plotted as a function of photopic illuminance at the eye; Fig. 3b shows the same data plotted as a function of scotopic illuminance. Fig. 3 also shows best ®ts to the data using compressive, asymptotic functions of the form y a 2 c= 1 1 x=bd 1 c [10], which have been used to estimate biological responses to light. Zeitzer et al. [10] showed that other curves (e.g. logarithmic and power functions) could be used to predict melatonin suppression; the compressive form used here simply represents a mathematical, rather than biological, model for prediction. For both curves, the parameter a has a ®xed value of 0, an estimate of the response to 0 lx. In Fig. 3a, a 0, b 442, c 0:76 and d 1:51; in Fig. 3b, a 0, b 349, c 0:44 and d 5:01. As Fig. 3 shows, photopic illuminance does not predict melatonin suppression well (r 2 0:35), but when plotted against scotopic illuminance, the data lie along a single, nearly monotonic, function (r 2 0.91). It is clear from these results that cones having a photopic luminous ef®ciency function are not primarily responsible for the suppression of melatonin in humans. The results are more consistent with the suggestion that rods are primarily responsible for melatonin regulation because of the positive
47
slope relating suppression of melatonin to scotopic illuminance at the eye and because the warm high and cool low lighting conditions resulted in nearly the same melatonin suppression. The results do not rule out other interpretations, however. Receptors with spectral sensitivities similar to rods might be responsible for melatonin suppression. Neural mechanisms supporting such a hypothesis remain speculative. In addition, even if a rod hypothesis is largely correct, other receptors, including cones, or novel mechanisms such as cryptochrome or melanopsin, could still play a role in circadian regulation. The pupillary re¯ex, for example, is dominated by the response of the rods, but Alpern and Ohba [1] demonstrated that cones also contribute to pupil size, in proportion to their population in the illuminated area of the retina. Because rods are more numerous than cones (15:1 ratio) throughout the retina (except in the fovea, where rods are absent) [7], these photoreceptors dominate the pupil response. A similar mechanism might exist for circadian regulation whereby inputs from all photoreceptors, perhaps even novel receptors, are combined to regulate melatonin levels. Indeed, both the pupillary re¯ex [3] and the pineal system [8] have been linked to the superior cervical ganglion in mammals, so common photoreceptive elements for these systems might be possible. The same psychophysical techniques employed in the present study can be used to ef®ciently test other hypotheses. In sum, the results presented here support a scotopic rather than a photopic model for circadian phototransduction, but do not rule out more complex or novel mechanisms leading to a spectral sensitivity similar to the scotopic luminous ef®ciency function. This work was supported by Philips Lighting, Niagara Mohawk Power Corporation, Northeast Utilities and the Electric Power Research Institute. Lutron Electronics supplied the dimming ballasts used in this study. The assistance and advice of Peter Boyce, Richard Pysar, Nishantha Maliyagoda, Andrew Bierman, Marylou Nickleson, Daniel Dyer, Robert Lingard, Krzysztof Kryszczuk, Rohini Pendyala, S.H.A. Begemann, Gerrit van der Beld, Peter Morante, John Kesselring, and Benjamin Koyle are also gratefully acknowledged. [1] Alpern, M. and Ohba, N., The effects of bleaching and backgrounds on pupil size, Vision Res., 12 (1972) 943±951. [2] Brainard, G.C., Lewy, A.J., Menaker, M., Fredrickson, R.H., Miller, L.S., Weleber, R.G., Cassone, V. and Hudson, D., Dose-response relationship between light irradiance and the suppression of melatonin in human volunteers, Brain Res., 454 (1988) 212±218. [3] Gabelt, B.T., Robinson, J.C., Gange, S.J. and Kaufman, P.L., Superior cervical ganglionectomy in monkeys: Aqueous humor dynamics and their responses to drugs, Exp. Eye Res., 60 (1995) 575±584. [4] Lewy, A.J., Wehr, T.A., Goodwin, F.K., Newsome, D.A. and Markey, S.P., Light suppresses melatonin secretion in humans, Science, 210 (1980) 1267±1269. [5] Miyamoto, Y. and Sancar, A., Vitamin B2-based blue-light
48
M.S. Rea et al. / Neuroscience Letters 299 (2001) 45±48
photoreceptors in the retinohypothalamic tract as the photoactive pigments for setting the circadian clock in mammals, Proc. Natl. Acad. Sci. USA, 95 (1998) 6097± 6102. [6] Provencio, I., Rodriguez, I.R., Jiang, G., Hayes, W.P., Moreira, E.F. and Rollag, M.D., A novel human opsin in the retina, J. Neurosci., 20 (2000) 600±605. [7] M.S. Rea (Ed.), IESNA Lighting Handbook: Reference and Application, Illuminating Engineering Society of North America, New York, 2000, p. 992. [8] Teclemariam-Mesbah, R., Ter Horst, G.J., Postema, F., Wortel, J. and Buijs, R.M., Anatomical demonstration of
the suprachiasmatic nucleus-pineal pathway, J. Comp. Neurol., 406 (1999) 171±182. [9] Wyszecki, G. and Stiles, W.S., Color Science: Concepts and Methods, Quantitative Data and Formulae, Wiley, New York, 1982, p. 950. [10] Zeitzer, J.M., Dijk, D.-J., Kronauer, R.E., Brown, E.M. and Czeisler, C.A., Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression, J. Physiol., 526.3 (2000) 695±702. [11] Zeitzer, J.M., Kronauer, R.E. and Czeisler, C.A., Photopic transduction implicated in human circadian entrainment, Neurosci. Lett., 232 (1997) 135±138.
www.elsevier.com/locate/neulet
Human melatonin suppression by light: a case for scotopic ef®ciency Mark S. Rea*, John D. Bullough, Mariana G. Figueiro Lighting Research Center, Rensselaer Polytechnic Institute, 21 Union Street, Troy, NY 12180, USA Received 1 November 2000; received in revised form 7 December 2000; accepted 7 December 2000
Abstract Human adult males were exposed to combinations of two illuminances and two spectral power distributions over the course of four nighttime sessions. A dose-dependent response of acute melatonin suppression to light was found, but photopic (cone-based) illuminance did not adequately predict suppression. When melatonin suppression was plotted against scotopic (rod-based) illuminance, the data formed a nearly monotonic function, implicating rods, or a roddominated mechanism, in the human melatonin regulation system. The results do not, however, rule out mechanisms other than rods, including novel photoreceptors, as candidates for melatonin regulation in humans. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Circadian rhythm; Spectral sensitivity; Photoreceptive system; Pineal response
Much is known about the photoreceptors that convert light into neural signals for vision, but the mechanisms for circadian phototransduction are still largely unknown [7]. Since the ®rst report of acute suppression of melatonin by light in humans [4], efforts have been underway to determine the dose-response characteristics and the spectral sensitivity of the ocular channel that mediates pineal response to light. Based on the wealth of information from the literature on human vision [7], conventional wisdom leads to either a photopic (cone, peaking at 555 nm) [10,11] or a scotopic (rod, peaking at 507 nm) [2] hypothesis for circadian phototransduction. Techniques well established in visual psychophysics [9] but unique to studies of circadian spectral sensitivity were used to experimentally contrast the photopic and scotopic hypotheses. These techniques have the major advantage of ef®ciently testing competing hypotheses, but do not eliminate more complex models based on unusual combinations of known photoreceptors, nor do they eliminate the possibility of novel mechanisms such as cryptochrome [5] or melanopsin [6] in the regulation of melatonin by light. Four adult male subjects (ages 29, 29, 48 and 59 years) participated in this study, which took place on each of ®ve nights (one baseline session and four experimental sessions) * Corresponding author. Tel.: 11-518-687-7100; fax: 11-518687-7120. E-mail address: [email protected] (M.S. Rea).
in the Clinical Pharmacological Studies Unit of Albany Medical College, Albany, NY. Each session lasted 9 h (from 22:00 to 07:00 h) and subjects were seated at a square, 1.25 £ 1.25 m table throughout the study sessions. The table consisted of a white-painted enclosure containing 16 ¯uorescent lamps, eight each of two correlated color temperatures: 3000 K (Philips F40SPEC30, `warm') and 7500 K (Philips F40C75, `cool'). The lamps were mounted in alternating sockets and controlled by electronic dimming ballasts (Lutron) and photocells so that the light output of each set of eight lamps could be independently controlled and mixed together. A clear piece of glass and an acrylic diffuser were mounted over the enclosure and served as the tabletop. When subjects sat around the table, the lamps and diffuser provided uniform illumination at the subjects' eyes. During the study, when the ¯uorescent lamps were switched on, subjects read material printed onto overhead projector transparency sheets so that they received a controlled dose of light exposure while reading. All subjects followed their normal daily routine and refrained from consuming caffeine for 12 h before each session, which always began at 22:00 h. Upon arrival at the study location, a nurse or physician inserted a catheter into a vein of each subject. Starting at 45 min after each hour, blood samples (3 ml) were drawn from each subject in a ®xed order. Samples were spun in a refrigerator centrifuge at 2300 rev./min for 10 min and separated plasma was frozen at 2868C. Frozen samples were sent to an indepen-
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 1) 01 51 2- 9
46
M.S. Rea et al. / Neuroscience Letters 299 (2001) 45±48
Fig. 2. Mean melatonin concentration (and standard error of the mean) for the baseline (dashed curve) and all experimental (solid curve) sessions.
four conditions, when printed reading materials were placed on the table. During the ®rst, third, ®fth, seventh and ninth hours of the experimental sessions, all room lights, including the lamps inside the light table, were extinguished except for the incandescent task lights. During the second, fourth, sixth and eighth hours, the lamps inside the light table were controlled to provide each of the four lighting conditions in Table 1, in a counterbalanced order across all four experimental sessions. Counterbalancing minimized the impact of time on the results, since melatonin suppression could differ at different times of the night. To determine if recovery of melatonin occurred after each hour of darkness during the experimental sessions, the mean hourly melatonin concentrations (pg/ml) of the subjects was plotted for the baseline and experimental sessions in Fig. 2. Fig. 2 shows the recovery of melatonin nearly to the baseline level, as well as the mean impact of all light exposures on melatonin suppression. A paired, one-tailed Student's t-test on the 16 pairs (four for each subject) of melatonin concentrations before and after exposure to light revealed that melatonin concentration after each period of light exposure was signi®cantly lower than before this period (t15 7:6, P , 1026 ). The mean melatonin suppression (in percent) and standard error of the mean for all subjects under each lighting condition is listed in Table 1. Using a two-way, repeatedmeasures analysis of variance on these sets of 16 measurements (four for each subject), both photopic illuminance (F1;15 16:1, P , 0:005) and SPD (F1;15 17:1, P , 0:001) had signi®cant effects on melatonin suppres-
Fig. 1. Spectral power distributions: (a) warm lighting conditions (ratio of scotopic to photopic illuminance 1.1); (b) cool lighting conditions (ratio of scotopic to photopic illuminance 1.7). Distributions are normalized to have peak values of 1.
dent laboratory (DiagnosTech International, Osceola, WI) for melatonin radioimmunoassay. Nine samples were drawn hourly from each subject during each session. During the baseline session, all room lighting was extinguished except for two small incandescent task lights located away from the subjects, which provided less than 0.2 photopic lx at the eye. Four lighting conditions were selected for the experimental study sessions: two photopic illuminances at the eye, and two spectral power distributions (SPDs), warm (yellowish) and cool (bluish) in appearance. Fig. 1 shows the SPDs for the warm and cool conditions. For an equal photopic illuminance, the scotopic illuminance from the cool SPD was higher than from the warm SPD, because the scotopic luminous ef®ciency function gives greater weight to shorterwavelength (`bluer') light than the photopic function. The SPDs were selected by mixing illumination from the sets of lamps so that the scotopic illuminance at the eye under the warm high condition was approximately equal to that under the cool low condition. Table 1 lists the resulting photopic and scotopic illuminances measured at subjects eyes for all
Table 1 Photopic and scotopic illuminances at the eye, and mean melatonin suppression and standard error of the mean (SEM) for the four experimental conditions Lighting condition
Photopic illuminance at eye (lx)
Scotopic illuminance at eye (lx)
Mean melatonin suppression (% ^ SEM)
Warm low Warm high Cool low Cool high
247 454 271 453
274 504 453 766
9.3 ^ 8.9 31.4 ^ 5.6 39.2 ^ 4.2 44.4 ^ 3.6
M.S. Rea et al. / Neuroscience Letters 299 (2001) 45±48
Fig. 3. Mean melatonin suppression (and standard error of the mean). (a) Plotted as a function of the photopic illuminance at the eye; (b) plotted as a function of scotopic illuminance. Also shown are best ®ts to the data using compressive, asymptotic functions giving a response of 0% at 0 lx.
sion; the interaction between them was not statistically signi®cant (F1;15 3:1; P . 0:05). The warm high and the cool low lighting conditions, designed to provide nearly the same scotopic illuminance, resulted in nearly the same melatonin suppression; a paired, two-tailed Student's t-test found that the difference between these two conditions was not statistically signi®cant (t15 1:7, P . 0:05). Fig. 3a shows the mean melatonin suppression (and standard error of the mean) plotted as a function of photopic illuminance at the eye; Fig. 3b shows the same data plotted as a function of scotopic illuminance. Fig. 3 also shows best ®ts to the data using compressive, asymptotic functions of the form y a 2 c= 1 1 x=bd 1 c [10], which have been used to estimate biological responses to light. Zeitzer et al. [10] showed that other curves (e.g. logarithmic and power functions) could be used to predict melatonin suppression; the compressive form used here simply represents a mathematical, rather than biological, model for prediction. For both curves, the parameter a has a ®xed value of 0, an estimate of the response to 0 lx. In Fig. 3a, a 0, b 442, c 0:76 and d 1:51; in Fig. 3b, a 0, b 349, c 0:44 and d 5:01. As Fig. 3 shows, photopic illuminance does not predict melatonin suppression well (r 2 0:35), but when plotted against scotopic illuminance, the data lie along a single, nearly monotonic, function (r 2 0.91). It is clear from these results that cones having a photopic luminous ef®ciency function are not primarily responsible for the suppression of melatonin in humans. The results are more consistent with the suggestion that rods are primarily responsible for melatonin regulation because of the positive
47
slope relating suppression of melatonin to scotopic illuminance at the eye and because the warm high and cool low lighting conditions resulted in nearly the same melatonin suppression. The results do not rule out other interpretations, however. Receptors with spectral sensitivities similar to rods might be responsible for melatonin suppression. Neural mechanisms supporting such a hypothesis remain speculative. In addition, even if a rod hypothesis is largely correct, other receptors, including cones, or novel mechanisms such as cryptochrome or melanopsin, could still play a role in circadian regulation. The pupillary re¯ex, for example, is dominated by the response of the rods, but Alpern and Ohba [1] demonstrated that cones also contribute to pupil size, in proportion to their population in the illuminated area of the retina. Because rods are more numerous than cones (15:1 ratio) throughout the retina (except in the fovea, where rods are absent) [7], these photoreceptors dominate the pupil response. A similar mechanism might exist for circadian regulation whereby inputs from all photoreceptors, perhaps even novel receptors, are combined to regulate melatonin levels. Indeed, both the pupillary re¯ex [3] and the pineal system [8] have been linked to the superior cervical ganglion in mammals, so common photoreceptive elements for these systems might be possible. The same psychophysical techniques employed in the present study can be used to ef®ciently test other hypotheses. In sum, the results presented here support a scotopic rather than a photopic model for circadian phototransduction, but do not rule out more complex or novel mechanisms leading to a spectral sensitivity similar to the scotopic luminous ef®ciency function. This work was supported by Philips Lighting, Niagara Mohawk Power Corporation, Northeast Utilities and the Electric Power Research Institute. Lutron Electronics supplied the dimming ballasts used in this study. The assistance and advice of Peter Boyce, Richard Pysar, Nishantha Maliyagoda, Andrew Bierman, Marylou Nickleson, Daniel Dyer, Robert Lingard, Krzysztof Kryszczuk, Rohini Pendyala, S.H.A. Begemann, Gerrit van der Beld, Peter Morante, John Kesselring, and Benjamin Koyle are also gratefully acknowledged. [1] Alpern, M. and Ohba, N., The effects of bleaching and backgrounds on pupil size, Vision Res., 12 (1972) 943±951. [2] Brainard, G.C., Lewy, A.J., Menaker, M., Fredrickson, R.H., Miller, L.S., Weleber, R.G., Cassone, V. and Hudson, D., Dose-response relationship between light irradiance and the suppression of melatonin in human volunteers, Brain Res., 454 (1988) 212±218. [3] Gabelt, B.T., Robinson, J.C., Gange, S.J. and Kaufman, P.L., Superior cervical ganglionectomy in monkeys: Aqueous humor dynamics and their responses to drugs, Exp. Eye Res., 60 (1995) 575±584. [4] Lewy, A.J., Wehr, T.A., Goodwin, F.K., Newsome, D.A. and Markey, S.P., Light suppresses melatonin secretion in humans, Science, 210 (1980) 1267±1269. [5] Miyamoto, Y. and Sancar, A., Vitamin B2-based blue-light
48
M.S. Rea et al. / Neuroscience Letters 299 (2001) 45±48
photoreceptors in the retinohypothalamic tract as the photoactive pigments for setting the circadian clock in mammals, Proc. Natl. Acad. Sci. USA, 95 (1998) 6097± 6102. [6] Provencio, I., Rodriguez, I.R., Jiang, G., Hayes, W.P., Moreira, E.F. and Rollag, M.D., A novel human opsin in the retina, J. Neurosci., 20 (2000) 600±605. [7] M.S. Rea (Ed.), IESNA Lighting Handbook: Reference and Application, Illuminating Engineering Society of North America, New York, 2000, p. 992. [8] Teclemariam-Mesbah, R., Ter Horst, G.J., Postema, F., Wortel, J. and Buijs, R.M., Anatomical demonstration of
the suprachiasmatic nucleus-pineal pathway, J. Comp. Neurol., 406 (1999) 171±182. [9] Wyszecki, G. and Stiles, W.S., Color Science: Concepts and Methods, Quantitative Data and Formulae, Wiley, New York, 1982, p. 950. [10] Zeitzer, J.M., Dijk, D.-J., Kronauer, R.E., Brown, E.M. and Czeisler, C.A., Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression, J. Physiol., 526.3 (2000) 695±702. [11] Zeitzer, J.M., Kronauer, R.E. and Czeisler, C.A., Photopic transduction implicated in human circadian entrainment, Neurosci. Lett., 232 (1997) 135±138.