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Artificial light and nicotine subsensitivity
BIOL PSYCHIATRY 1988;u:437-440
431
BRIEF REPORTS
Artificial Light and Nicotine Subsensitivity Steven C. Dilsaver
Introduction Seasonal affective disorder (SAD) is a syndrome marked by recurrent depressions that generally occurinthefallorwinter(Rosenthaletal. 1984). This syndrome reportedly responds to daily treatment with 2-6 hr of bright artificial light (James et al. 1982; Lewy et al. 1982; Rosenthal et al. 1984, 1986; Wehr et al. 1986). A mechanism accounting for the efficacy for this treatment has not been identified. In order to remedy this gap in the literature we have conducted a series of studies (Dilsaver and Majchrzak 1987, 1988a,b). Twenty-four hours of treatment with bright artificial light for 14 consecutive days obliterates the hypothermic response to nicotine (Dilsaver and Majchtzak 1988a). This is an effect characteristic of several antidepressants (Dilsaver and Davidson 1987; Dilsaver and Hariharan 1988). This article presents data indicating that bright artificial light presented during the regular photoperiod also produces subsensitivity to the hypothermic effects of nicotine.
Methods The dependent variable in this study is change in core temperature in response to the injection of nicotine in 11 adult, male Sprague-Dawley rats Address qrint requests to Dr. S.C. Dilsaver, Neuroscience Program, Department of Psychiatry, Ohio State University, 473 West 12th Avenue, Columbus, OH 4321&1228. Proan the Ne-ience Anagram, Departmnt of Psycbii, Ohio State University, Columbus, OH. Supported by physician Scientist DeveloPmat Award MHOO55302 and NJH Grant 2507 RRO583-5. This work was performed while Dr. Dilsaver was at the Univusity of Michigan. Received August 22, 1987; twined November 16, 1987.
8 1988 Society of Biological Psychiatry
(mean weight k SEM = 303.8 + 5.6g). Principles governing use of this measure are described in detail elsewhere (Dilsaver and Alessi 1988). Nicotine (base) was purchased from Sigma Chemical Co. (St. Louis, MO). Core temperature was measured using an intraperitoneally implanted thermosensor, Model VM Mini-Mitter (Mini Mitter Corp., Sun River, OR). These devices emit radio waves at a rate directly proportional to temperature. The waves are detectable with a standard AM receiver. Temperature was measured every 10 min for 120 min following the injection of nicotine, 4 mgkg SC. The Mini-Mitter can detect a 0. 1°C change in temperature (Tocco-Bradley et al. 1985). Dilsaver and Majchrzak (1988~) established the reliability and validity of measuring core temperature in psychopharmacological research. Full-spectrum bright artificial light (11,500 lux) was emitted between 6:OOAM and 6:00 PM from a bank of eight 122-cm long Vitalight tubes suspended 50 cm above the animals. This light unit (Duo Test Corp., Bergen, NJ; model 5599) is used to treat seasonal depressives (Lewy et al. 1982). All three nicotine challenges started at 7:00 AM. Core temperature was measured immediately prior to each injection of nicotine. Thus, the animals were exposed to bright light for 1 hr prior to each nicotine challenge. Thmughout the study, the animals were housed in a vivarium maintained by the University of Michigan Laboratory Animal Medicine (ULAM). The temperature in the room was 2 1°C. Room
0006-3223/88/$03.50
438
BIOL PSYCHIATRY 1988;24:437--140
lighting automatically went on at 6:00 AM and off at 6:00 PM. Mean change in core temperature in the first and second 60-min periods of each challenge was entered into an analysis using Student’s paired f-test. Measures of variance in the text refer to the standard error of the mean (SEM).
Experimental Design The 11 rats were allowed 5 days to recover from the implantation of Mini-Mitters prior to the first challenge with nicotine. The rats were housed in two containers beneath the light unit. The light unit automatically went on and off at 6:00 AM and 6:00 PM, respectively. The baseline nicotine challenge (the challenge preceeding the 1Cday course of phototherapy) started at 7:00 AM-after the first hour of exposure to bright light. The animals were then treated with bright light between 6:00 AM and 6:OOPM for 14 days. At 7:OO AM on the morning of the 15th day, while still under bright light, the animals were rechallenged with nicotine. Thus, the rats received 14 days of exposure to bright artificial light. The animals were then housed under standard vivarium conditions, and 14 days later, they were rechallenged with nicotine.
Results Mean core temperatures prior to the first (before treatment), second (after 14 days of treatment), and third (14 days after the cessation of treatment) nicotine challenges were 37.4 t O.l4”C, 37.4 it 0.2O”C, and 36.6 + 0.19”C. Core temperature prior to the first and second nicotine challenges did not differ (p = 1, t = 0, df = 10). However, it differed significantly between the first and third (p = O.ooO3,t = 5.46, df = 10) and second and third (p < 0.002, t = 4.24, df = 10) challenges. The mean thermic response to nicotine during the first 60min period was -0.47 + 0.14”C before chronic light treatment compared to - 0.07 + 0.14”C following 2 weeks of phototreatment @ < 0.02, t = 2.86, df = 10). Themean hypothermic response during the second 60-min period before
Brief Reports
chronic light treatment was - 0.85 +- 0.18”C compared to - 0.13 + 0.17”C following 2 weeks of light treatment @ < 0.003, t = 3.99, df = 10). Following 2 weeks of housing under standard vivarium conditions, the mean thermic responses to nicotine during the first and second 60-min periods were -1.31 + 0.2O”C and - 3.43 t O.l4”C, respectively. These differed from the response prior to light therapy at the 0.002 (t = 4.14, df = IO) and O.OOOOO7 (t = 8.57, df = 10) levels, respectively. Figure 1 summarizes the change in thermic responsiveness to nicotine after 14 days of phototherapy compared to responsiveness prior to chronic treatment with bright artificial light.
Discussion These data indicate that bright artificial light administered during the regular photoperiod produces subsensitivity of a nicotinic mechanism involved in the regulation of core temperature. The potential importance of this finding is highlighted by the finding that fluoxetine (Dilsaver and Davidson 1987), desipramine, and phenelzine (Dilsaver and Hariharan 1988) also produce subsensitivity to nicotine. Dilsaver and Majchrzak (1988) reported that bright artificial light, 24 hr a day for 14 days, obliterated the hypothermic response to nicotine. The former study also indicated that constant exposure to light at an intensity of 300 lux does not alter sensitivity to nicotine. This suggests that light intensity is a critical variable. The results of the third nicotine challenge are provocative. The dramatic difference in mean core temperature at the time of this challenge relative to the first and second challenges is noteworthy. Bright light can have dramatic effects on the amplitude of circadian rhythms. This is certainly true of the circadian temperature rhythm. The simplest way to assess whether bright light might have shifted the amplitude of the diurnal temperature rhythm is to determine whether or not mean core temperature, measured at the same time of day, differed depending on whether the animals were subjected to bright light or standard lighting conditions. Core
BIOL PSYCHIATRY 1988;24:437-440
Brief Reports
439
Hypothermic Response to Nicotine Before and After Chronic Treatment With Bright Artificial Light
0.9
0.8 0.7 P !
0.6
* cr” .o
0.5
% a 2
0.4
0.3 0.2
0.1
Boseline After 2 wk 1st 60 min period
Baseline
After 2 wk
2nd 60 min period
Figure 1. This illustrates the mean change (k SEM) in hypothermic responsiveness during the first and second 60-min periods following the injection of nicotine before and after chronic exposure to full-spectrum bright artificial light.
temperature was identical on the two occasions it was measured while the animals were subjected to bright light. However, mean baseline core temperaturz was significantly lower (0.8”C) when measured under standard vivarium conditions (i.e., 2 weeks after treatment with bright artificial light ended). It appears that treatment with bright artificial light may have shifted the amplitude of the circadian temperature rhythm. Second, the animals were more sensitive to nicotine after 2 weeks of exposure to standard vivarium conditions. Perhaps a circadian shift explains this fmding. This contmsts with the results of our previous study in which rats were subjected to bright light (11,500 lux) for 2 weeks
(Dilsaver and Majchrzak 1988a). In that study, the animals were challenged with nicotine, 1 mg/kg ip. The mean hypothermic response prior to light treatment was 1.69 + 0.25”C (n = 11). One week after the discontinuation of phototreatment, the sample exhibited a mean hypothermic response to nicotine of 0.26 + 0. 11°C (p < 0.00006, t = 6, df = 11). The results of the present study suggest that the effect of treatment with bright light during the regular photoperiod; at an intensity of 11,500 lux, for 14 days is not sufficient to cause a blunting of the hypothermic response 14 days after its discontinuation. Indeed, the animals may have shifted from a state of marked subsensitivity to nicotine
440
BIOL PSYCHIATRY 1988;24:437-440
to a state of supersensitivity. Alternatively, subjecting the rats to bright lightfor only 1 hr prior to measuring the core temperature before each nicotine challenge may have blunted the response to nicotine. Whether or not there is an acute e@ect of bright artificial light on the thermic response to nicotine must be addressed in a separate experiment. Janowsky et al. (1972) proposed that depressive disorders are related to a hyperactive cholinergic mechanism. Data supporting the cholinergic hypotheses of depression were recently summarized (Dilsaver et al. 1986a,b). It is essential to emphasize that the relative roles of nicotinic and muscarinic cholinergic mechanisms in the pathophysiology of depression have not been addressed.
References Dilsaver SC (1986a): Cholinergic mechanisms in depression. Bruin Res Rev 11:285-316. Dilsvaer SC (1986b): Cholinergic mechanisms in affective disorders: Future directions for investigation. Acta Psych& Scund 74:312-332. Dilsaver SC, Alessi NE (1988): Temperature as a dependent variable in the study of cholinergic mechanisms. Prog Neuro-psychopharmacol Biol Psychiatry
12: l-32.
Dilsaver SC, Davidson RK (1987): Fluoxetine subsensitizes a nicotinic mechanism involved in the regulation of core temperature. Life Sci 41: 11655 1169. Dilsaver SC, Hariharan M (1988): Nicotinic effects of antidepressants. In: Gershon S, Lerer B (eds), New Directions in Affective Disorders. New York: Springer-Verlag (in press). Dilsaver SC, Majchrzak MJ (1987): Bright artificial light produces subsensitivity to oxotremorine. Life Sci 4:2607-2614.
Brief Reports
Dilsaver SC, Majchrzak MJ (1988a): Bright artificial light produces subsensitivity to nicotine. Life Sci 421225-230.
Dilsaver SC, Majchrzak MJ (1988b): Bright artificial light produces subsensitivity to clonidine. Life Sci 42597-601. Dilsaver SC, Majchrzak MJ (1988~): Telemetric measurement of core temperature in psychobiological research: Reliability and validity. Prog Neurpsychopharmacol Biol Psychiatry (in press). James SP, Wehr TA, Sack DA, Parry BL, Rosenthal NE (1982): Treatment of seasonal affective disorder with light in the evening. Br J Psychiatry 147~424-485.
Janowsky DS, Davis JM, El-Yousef MK, Sekerke HJ (1972): A cholinergic adrenergic hypothesis of depression and mania. Lancet ii:672-635. Lewy AJ, Kern HA, Rosenthal NE, Wehr TA (1982): Bright artificial light treatment of a manic-depressive patient with seasonal mood cycle. Am ./ Psychiatry 142:163-170. Rosenthal NE, Sack DA, Gillin JC, Levy JA, Goodwin FK, Davenport Y, Meuller PS, Newsome DS, Wehr TA (1984): Seasonal affective disorder: A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 41:7280.
Rosenthal NE, Carpenter CJ, James SP, Parry BL, Rogers SLB, Wehr TA (1986): Seasonal affective disorder in children and adolescents. Am J Psychiatry 143:356-358. Tocco-Bradley R, Kluger MJ, Kauffman LA (1985): Effect of age on fever and acute-phase response of rats to endotoxin and Salmonella typhimurium. Infect Immun 47: 106-l 11. Wehr ‘IA, Jacobsen FM, Sack DA, Arendt J, Tamarkin L., Rosenthal NE (1986): Phototherapy of seasonal affective disorder: Time of day and suppression of metatonin are not critical for antidepressant effects. Arch Gen Psychiatry 43:870875.
431
BRIEF REPORTS
Artificial Light and Nicotine Subsensitivity Steven C. Dilsaver
Introduction Seasonal affective disorder (SAD) is a syndrome marked by recurrent depressions that generally occurinthefallorwinter(Rosenthaletal. 1984). This syndrome reportedly responds to daily treatment with 2-6 hr of bright artificial light (James et al. 1982; Lewy et al. 1982; Rosenthal et al. 1984, 1986; Wehr et al. 1986). A mechanism accounting for the efficacy for this treatment has not been identified. In order to remedy this gap in the literature we have conducted a series of studies (Dilsaver and Majchrzak 1987, 1988a,b). Twenty-four hours of treatment with bright artificial light for 14 consecutive days obliterates the hypothermic response to nicotine (Dilsaver and Majchtzak 1988a). This is an effect characteristic of several antidepressants (Dilsaver and Davidson 1987; Dilsaver and Hariharan 1988). This article presents data indicating that bright artificial light presented during the regular photoperiod also produces subsensitivity to the hypothermic effects of nicotine.
Methods The dependent variable in this study is change in core temperature in response to the injection of nicotine in 11 adult, male Sprague-Dawley rats Address qrint requests to Dr. S.C. Dilsaver, Neuroscience Program, Department of Psychiatry, Ohio State University, 473 West 12th Avenue, Columbus, OH 4321&1228. Proan the Ne-ience Anagram, Departmnt of Psycbii, Ohio State University, Columbus, OH. Supported by physician Scientist DeveloPmat Award MHOO55302 and NJH Grant 2507 RRO583-5. This work was performed while Dr. Dilsaver was at the Univusity of Michigan. Received August 22, 1987; twined November 16, 1987.
8 1988 Society of Biological Psychiatry
(mean weight k SEM = 303.8 + 5.6g). Principles governing use of this measure are described in detail elsewhere (Dilsaver and Alessi 1988). Nicotine (base) was purchased from Sigma Chemical Co. (St. Louis, MO). Core temperature was measured using an intraperitoneally implanted thermosensor, Model VM Mini-Mitter (Mini Mitter Corp., Sun River, OR). These devices emit radio waves at a rate directly proportional to temperature. The waves are detectable with a standard AM receiver. Temperature was measured every 10 min for 120 min following the injection of nicotine, 4 mgkg SC. The Mini-Mitter can detect a 0. 1°C change in temperature (Tocco-Bradley et al. 1985). Dilsaver and Majchrzak (1988~) established the reliability and validity of measuring core temperature in psychopharmacological research. Full-spectrum bright artificial light (11,500 lux) was emitted between 6:OOAM and 6:00 PM from a bank of eight 122-cm long Vitalight tubes suspended 50 cm above the animals. This light unit (Duo Test Corp., Bergen, NJ; model 5599) is used to treat seasonal depressives (Lewy et al. 1982). All three nicotine challenges started at 7:00 AM. Core temperature was measured immediately prior to each injection of nicotine. Thus, the animals were exposed to bright light for 1 hr prior to each nicotine challenge. Thmughout the study, the animals were housed in a vivarium maintained by the University of Michigan Laboratory Animal Medicine (ULAM). The temperature in the room was 2 1°C. Room
0006-3223/88/$03.50
438
BIOL PSYCHIATRY 1988;24:437--140
lighting automatically went on at 6:00 AM and off at 6:00 PM. Mean change in core temperature in the first and second 60-min periods of each challenge was entered into an analysis using Student’s paired f-test. Measures of variance in the text refer to the standard error of the mean (SEM).
Experimental Design The 11 rats were allowed 5 days to recover from the implantation of Mini-Mitters prior to the first challenge with nicotine. The rats were housed in two containers beneath the light unit. The light unit automatically went on and off at 6:00 AM and 6:00 PM, respectively. The baseline nicotine challenge (the challenge preceeding the 1Cday course of phototherapy) started at 7:00 AM-after the first hour of exposure to bright light. The animals were then treated with bright light between 6:00 AM and 6:OOPM for 14 days. At 7:OO AM on the morning of the 15th day, while still under bright light, the animals were rechallenged with nicotine. Thus, the rats received 14 days of exposure to bright artificial light. The animals were then housed under standard vivarium conditions, and 14 days later, they were rechallenged with nicotine.
Results Mean core temperatures prior to the first (before treatment), second (after 14 days of treatment), and third (14 days after the cessation of treatment) nicotine challenges were 37.4 t O.l4”C, 37.4 it 0.2O”C, and 36.6 + 0.19”C. Core temperature prior to the first and second nicotine challenges did not differ (p = 1, t = 0, df = 10). However, it differed significantly between the first and third (p = O.ooO3,t = 5.46, df = 10) and second and third (p < 0.002, t = 4.24, df = 10) challenges. The mean thermic response to nicotine during the first 60min period was -0.47 + 0.14”C before chronic light treatment compared to - 0.07 + 0.14”C following 2 weeks of phototreatment @ < 0.02, t = 2.86, df = 10). Themean hypothermic response during the second 60-min period before
Brief Reports
chronic light treatment was - 0.85 +- 0.18”C compared to - 0.13 + 0.17”C following 2 weeks of light treatment @ < 0.003, t = 3.99, df = 10). Following 2 weeks of housing under standard vivarium conditions, the mean thermic responses to nicotine during the first and second 60-min periods were -1.31 + 0.2O”C and - 3.43 t O.l4”C, respectively. These differed from the response prior to light therapy at the 0.002 (t = 4.14, df = IO) and O.OOOOO7 (t = 8.57, df = 10) levels, respectively. Figure 1 summarizes the change in thermic responsiveness to nicotine after 14 days of phototherapy compared to responsiveness prior to chronic treatment with bright artificial light.
Discussion These data indicate that bright artificial light administered during the regular photoperiod produces subsensitivity of a nicotinic mechanism involved in the regulation of core temperature. The potential importance of this finding is highlighted by the finding that fluoxetine (Dilsaver and Davidson 1987), desipramine, and phenelzine (Dilsaver and Hariharan 1988) also produce subsensitivity to nicotine. Dilsaver and Majchrzak (1988) reported that bright artificial light, 24 hr a day for 14 days, obliterated the hypothermic response to nicotine. The former study also indicated that constant exposure to light at an intensity of 300 lux does not alter sensitivity to nicotine. This suggests that light intensity is a critical variable. The results of the third nicotine challenge are provocative. The dramatic difference in mean core temperature at the time of this challenge relative to the first and second challenges is noteworthy. Bright light can have dramatic effects on the amplitude of circadian rhythms. This is certainly true of the circadian temperature rhythm. The simplest way to assess whether bright light might have shifted the amplitude of the diurnal temperature rhythm is to determine whether or not mean core temperature, measured at the same time of day, differed depending on whether the animals were subjected to bright light or standard lighting conditions. Core
BIOL PSYCHIATRY 1988;24:437-440
Brief Reports
439
Hypothermic Response to Nicotine Before and After Chronic Treatment With Bright Artificial Light
0.9
0.8 0.7 P !
0.6
* cr” .o
0.5
% a 2
0.4
0.3 0.2
0.1
Boseline After 2 wk 1st 60 min period
Baseline
After 2 wk
2nd 60 min period
Figure 1. This illustrates the mean change (k SEM) in hypothermic responsiveness during the first and second 60-min periods following the injection of nicotine before and after chronic exposure to full-spectrum bright artificial light.
temperature was identical on the two occasions it was measured while the animals were subjected to bright light. However, mean baseline core temperaturz was significantly lower (0.8”C) when measured under standard vivarium conditions (i.e., 2 weeks after treatment with bright artificial light ended). It appears that treatment with bright artificial light may have shifted the amplitude of the circadian temperature rhythm. Second, the animals were more sensitive to nicotine after 2 weeks of exposure to standard vivarium conditions. Perhaps a circadian shift explains this fmding. This contmsts with the results of our previous study in which rats were subjected to bright light (11,500 lux) for 2 weeks
(Dilsaver and Majchrzak 1988a). In that study, the animals were challenged with nicotine, 1 mg/kg ip. The mean hypothermic response prior to light treatment was 1.69 + 0.25”C (n = 11). One week after the discontinuation of phototreatment, the sample exhibited a mean hypothermic response to nicotine of 0.26 + 0. 11°C (p < 0.00006, t = 6, df = 11). The results of the present study suggest that the effect of treatment with bright light during the regular photoperiod; at an intensity of 11,500 lux, for 14 days is not sufficient to cause a blunting of the hypothermic response 14 days after its discontinuation. Indeed, the animals may have shifted from a state of marked subsensitivity to nicotine
440
BIOL PSYCHIATRY 1988;24:437-440
to a state of supersensitivity. Alternatively, subjecting the rats to bright lightfor only 1 hr prior to measuring the core temperature before each nicotine challenge may have blunted the response to nicotine. Whether or not there is an acute e@ect of bright artificial light on the thermic response to nicotine must be addressed in a separate experiment. Janowsky et al. (1972) proposed that depressive disorders are related to a hyperactive cholinergic mechanism. Data supporting the cholinergic hypotheses of depression were recently summarized (Dilsaver et al. 1986a,b). It is essential to emphasize that the relative roles of nicotinic and muscarinic cholinergic mechanisms in the pathophysiology of depression have not been addressed.
References Dilsaver SC (1986a): Cholinergic mechanisms in depression. Bruin Res Rev 11:285-316. Dilsvaer SC (1986b): Cholinergic mechanisms in affective disorders: Future directions for investigation. Acta Psych& Scund 74:312-332. Dilsaver SC, Alessi NE (1988): Temperature as a dependent variable in the study of cholinergic mechanisms. Prog Neuro-psychopharmacol Biol Psychiatry
12: l-32.
Dilsaver SC, Davidson RK (1987): Fluoxetine subsensitizes a nicotinic mechanism involved in the regulation of core temperature. Life Sci 41: 11655 1169. Dilsaver SC, Hariharan M (1988): Nicotinic effects of antidepressants. In: Gershon S, Lerer B (eds), New Directions in Affective Disorders. New York: Springer-Verlag (in press). Dilsaver SC, Majchrzak MJ (1987): Bright artificial light produces subsensitivity to oxotremorine. Life Sci 4:2607-2614.
Brief Reports
Dilsaver SC, Majchrzak MJ (1988a): Bright artificial light produces subsensitivity to nicotine. Life Sci 421225-230.
Dilsaver SC, Majchrzak MJ (1988b): Bright artificial light produces subsensitivity to clonidine. Life Sci 42597-601. Dilsaver SC, Majchrzak MJ (1988~): Telemetric measurement of core temperature in psychobiological research: Reliability and validity. Prog Neurpsychopharmacol Biol Psychiatry (in press). James SP, Wehr TA, Sack DA, Parry BL, Rosenthal NE (1982): Treatment of seasonal affective disorder with light in the evening. Br J Psychiatry 147~424-485.
Janowsky DS, Davis JM, El-Yousef MK, Sekerke HJ (1972): A cholinergic adrenergic hypothesis of depression and mania. Lancet ii:672-635. Lewy AJ, Kern HA, Rosenthal NE, Wehr TA (1982): Bright artificial light treatment of a manic-depressive patient with seasonal mood cycle. Am ./ Psychiatry 142:163-170. Rosenthal NE, Sack DA, Gillin JC, Levy JA, Goodwin FK, Davenport Y, Meuller PS, Newsome DS, Wehr TA (1984): Seasonal affective disorder: A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 41:7280.
Rosenthal NE, Carpenter CJ, James SP, Parry BL, Rogers SLB, Wehr TA (1986): Seasonal affective disorder in children and adolescents. Am J Psychiatry 143:356-358. Tocco-Bradley R, Kluger MJ, Kauffman LA (1985): Effect of age on fever and acute-phase response of rats to endotoxin and Salmonella typhimurium. Infect Immun 47: 106-l 11. Wehr ‘IA, Jacobsen FM, Sack DA, Arendt J, Tamarkin L., Rosenthal NE (1986): Phototherapy of seasonal affective disorder: Time of day and suppression of metatonin are not critical for antidepressant effects. Arch Gen Psychiatry 43:870875.