416 Brief Reports zyxwvut BIOL PSYCHIATRY 1989;26:412-416 atonin- Clinical Perspectives. Oxford: University Press, pp 190-204. Clifford JM, Price M (1984): The reversal of some clonidine-induced effects by single oral doses of idazoxan (RX-781094), an 02-adrenoceptor antagonist. Br J Clin Pharmucol 17:602P. PJ, Fraser S, Sammons R, Green AR (1983): Atenolol reduces plasma melatonin concentrations in man. Br J Clin Pharmacol 15579-581. Cowen Franey C, Aldous M, Burton S, Checkley S, Arendt J (1986): Acute treatment with desipramine stimulates melatonin and 6sulphatoxymelatonin production in man. Br J Clin Pharmacol22:73- 79. Fraser S, Cowen P, Franklin M, Franey C. Arendt J (1983): Direct radioimmunoassay for melatonin in plasma. Clin Chem 29:396- 397. Grasby PM, Cowen PJ (1987): The pineal and psychiatry: Still fumbling in the dark? Psy cho1 M ed 17:817- 820. Grasby PM, Cowen PJ (1988): The effect of clonidine and bright light on plasma melatonin. chopharmucol Hum Psy- 3 ~43- 46. Johansson GEK, Ho AK, Chik CL, Brown GM (1985): Interference in melatonin radioimmunoassay by heparin preparations. In Brown GM, Wainwright SD (ed), The Pineal Gland: Endocrine Aspects, Advances in the Biosciences, vol 53. New York: Pergamon Press, pp 47-52. Lewy AJ, Siever LJ, Uhde TW, Markey SP (1986): Clonidine reduces plasma melatonin levels. J Pharm Pharmacol 38555- 556. Pelayo F, Dubocovich ML, Langer SZ (1977): Regulation of noradrenaline release in the rat pineal through a negative feedback mechanism mediated by presynaptic az-adrenoceptors. Eur J Pharmucol45:317-318. Thompson C, Franey C, Arendt J , Checkley SA (1988): A comparison of melatonin secretion in depressed patients and normal subjects. Br J Psychiatry 152:260-265. Bright Light Blocks Amitriptyline-Induced Cholinoceptor Supersensitivity Steven C. Dilsaver, Mark J. Majchrzak, Introduction and Duane Flemmer thal et al., 1984). This syndrome reportedly responds to daily treatment with 2-6 hr of Seasonal affective disorder (SAD) is a synbright artificial light (Lewy et al. 1982; Rodrome marked by recurrent depressions that senthal et al. 1984, 1986; James et al. 1985; generally occur in the fall or winter (RosenWehr et al. 1986). Neurobiological mechanisms accounting for the efficacy of this treatment remain unknown. Certain forms of afDepartments of Psychiatry (S.C.D., D.F.) and Neuroscifective illness may involve state-independent ence (S.C.D.), Ohio State University, Columbus, OH; and the supersensitivity of central muscarinic mechaDepartment of Psychiatty (M.J.M), University of Michigan, Detrait, Ml. nisms (Janowsky et al. 1972; Dilsaver 1986aAddress reprint requests to: Dr. Steven C. Dilsaver, Departments c). Amitriptyline and other heterocyclic antiof Psychiatry and Neuroscience, Ohio State University, 473 West 12th Avenue. Columbus, OH 432101221. depressants produce supersensitivity of a cenSupported in part by Physician Scientist Career Development Award mechanism involved in the (Muscarinic Receptor Abnormalities in Affective Illness) SRCKl 1 tral muscarinic MHOO553-02, NIH Grant 2507 RR0583-5, the State of Ohio Neuregulation of core temperature (Dilsaver et al. roscience Program, and the Bremer Foundation. 1987; Dilsaver and Davidson 1987; Dilsaver Received June 16, 1988; rewed January 16. 1989 Brief Reports zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA BIOL PSYCHIATRY 417 1989;26:416-423 and Snider 1988). This article presents data indicating that 6 hr of bright artificial light daily blocks amitriptyline-induced supersensitivity of this mechanism. Methods The dependent variable in the experiments below is mean change in core temperature in response to oxotremorine, a muscarinic acetylcholine receptor (mAchR) agonist. Dilsaver and Alessi (1988) outlined the principles governing the use of core temperature in psychopharmacological research. Core temperature was measured using an intraperitoneally (ip) implanted telemetric thermosensor, the Model VM MiniMitter (Mini-Mitter Corp., Sun River, OR). These devices emit radio waves at an AM frequency at a rate directly proportional to core temperature. Temperature was measured every 10 min for 120 min following the injection of saline (1 ml/kg, ip) or oxotremorine (1 mglkg) at 9:00 AM. The response to routine handling and the injection of saline is a mean thermic rise of 0.20.8”C (Dilsaver and Majchrzak 1988b). We routinely challenge animals with saline prior to administering an agonist. It may not be possible to interpret the thermic response of a sample to an agonist in the absence of knowledge of that sample’s response to handling and the injection of placebo. For instance, a sample of 10 rats may exhibit a mean (? SEM) thermic rise of 0.7 + 0.2”C on response to handling and the injection of saline. The sample’s mean change in core temperatures of 0 + 0.2”C when injected with 0.05 mg/kg of oxotremorine would be significant in this instance. The rats used in the experiments reported below were challenged with saline 24 hr prior to the initial challenge with oxotremorine. Information regarding the reliability and validity of measurements using the Mini-Mitter is available elsewhere (Dilsaver and Majchrzak 1989). Full-spectrum bright artificial light, 7400 lux, was emitted from a bank of eight 122-cm long Vita Lite tubes suspended 50 cm above the animals. This light unit (model 5599; Duro Test Corp., Bergen, NJ) is used to treat seasonal depression (Lewy et al. 1982). Temperature under the light unit was 23-23.5”C. Oxotremorine challenges started at baseline and were preceded by the injection of methylscopolamine nitrate (1 mg/kg, ip). Methylscopolamine nitrate blocks the effects of muscarinic agonists on peripheral mAchRs. The quartanary amine group of methylscopolamine renders it lipid-insoluble, and it therefore does not effectively cross the blood-brain barrier. Thus, pretreatment with methylscopolamine allows one to isolate the effects of a treatment on central muscarinic mechanisms. Baseline temperature was examined 30 min after the injection of methylscopolamine. Oxotremorine (base), 1 mg/kg, ip, was then injected, and temperature was measured every 10 min for 120 min. Mean change in core temperature (i.e., the average change at each of the 12 time points) was entered into an analysis using Student’s paired r-test. Mean change at a given time point was calculated by subtracting the core temperature of a given rat at that time point (e.g., 36.O”C) from the temperature of that rat prior to the injection of oxotremorine (e.g., 37.O”C). Measures of variance in the text refer to the standard error of the mean (SEM). Amitriptyline HCl, oxotremorine (base), and methylscopolamine nitrate were purchased from Sigma Chemical Company (St. Louis, MO). All drugs were prepared at a concentration that allowed us to inject 1 ml/kg of the solution. Experimental Design Experiment 1. Mini-Mitters were implanted into 10 adult, male Sprague-Dawley rats weighing 227 .O + 8.4 g . The rats were allowed 5 days to recover from the surgical procedure. The thermic response to saline (1 ml/kg, ip) was measured prior to the first challenge with oxotremotine (1 mg/kg, ip). The rats were then treated with amitriptyline (15 mg/kg, ip) at 9:00 AM and 5:00 PM for 7 days. During this period, the animals were housed under standard conditions in which lights in the vivarium were automatically turned on and off at 6:00 AM and 6:00 PM, respectively. The rats 418 BtOL PSYCHIATRY 1989;26:436 -423 Brief Reports sample was rechallenged with oxotremorine after 1 week of treatment with both amitriptyline and bright artificial light. The oxotremorine chal1. Telemetric (hearing aid powered) thermosensors are calibrated (MiniMiners) lenges occurring in the course of treatment with 2. MiniMitters are implanted amitriptyline started 19 hr after the preceding in3. The rats are zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA given 5 days to recover jection of the tricyclic. Table 1. Sequence I and 2 of Steps for Experiments 4. The mean thermic response to saline (1 mgikg) is measured 5. Twenty-four hours later, the mean thermic response to oxot~mo~ne ( 1 mgikg) is measured 6. Treatment with amitriptyline (15 mglkg ip) begins after the first oxotremorine challenge 7. Treatment with bright (Experiment 1) or dull (Experiment 2) light begins at 5:00 PM (on the day following the first oxotremorine challenge) 8. Seven days later, at 9:00 AM 19 hr after the previous dose (14th) of amitripyline, the second oxotremorine challenge is repeated 9. Treatment with amitriptyline continues for 7 more days 10. A third oxotremorine challenge starts at 9:00 AM. 19 hr after the last dose (28th dose) of oxotremorine. ii. Mean thermic response for each chahenge i$ calculated and data analyzed Experiment 2. The objective of this experiment was to illustrate that a simpIe m~ipulation of the iigh~dark cycle using dull light (300 lux) does not account for effects associated with bright artificial light. Mini-Mitters were implanted into 10 adult, male Sprague-Dawley rats weighing 237.3 rt 3.6 g. The animals were allowed S days to recover from the implantation procedures. The thermic response to saline was then measured. The animals were subsequently challenged with oxotremorine. Treatment with amitriptyline (15 mgikg ip) at 9:00 AM and 5:00 PM followed. The thermic response to oxotremorine was measured 7 days later. The rats were then subjected to 300 lux light emitted from standard Mean themtic response = [core temperature of a rat IO. 20,30. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPO fluorescent light units between 5:OO PM and 11:OO , 120 min after the injection of saline or oxotremorinel - [core temperarure of the same rat prior to the injection of saline or oxoPM and were concurrently treated with amitriptremorine I. tyline ( 15 mg/kg, ip) for 7 days. The sample was otherwise subjected to the standard light/dark cycle. were rechallenged with oxotremorine after a week Table 1 outlines the sequence of steps in both of treatment with amitriptyline. One week of Experiments I and 2. treatment with this tricyclic antidepressant produces dose-dependent supersensitivity to the hyResults pothermic effect of oxotremorine (Dilsaver et al. 1987; Dilsaver and Snider 1988). Enhancement of the hypothetic response to oxotremo~ne Mean core temperature at baseline (prior to the persists for at least 4 weeks after starting treatsaline challenge) was 38.1 & 0.42”C. Table 2 ment with amitriptyline (Dilsaver et al. 1987). summarizes the mean thermic response over the Bright artificial light was administered between 12 points in time. 5:00 PM and 1l:OO PM for 7 days following the The sample exhibited a mean thermic resecond oxotremorine challenge, based on our sponse to saline of + 0.2 -t 0. 10°C. The mean original notion that prolonging the photoperiod thermic response to oxotremorine prior to treatmight contribute to its effects. We have since ment with amitriptyline was - 1.3 C 0.2”C. learned that prolonging the photoperiod is not This differed from the thermic response to saline important to mediating some effects of bright light. at the 0.~3 level Ct = 7.02, df = 9). All For example, bright hght given during part of the IO animals exhibited enhancement of the hyphoto~~od or during the entire photoperiod pothermic response to oxo~mo~ne after 1 week subsensitizes rats to nicotine and oxo~emo~ne of treatment with amitriptyline (p = 0.0001. (Dilsaver 1988; Dilsaver and Flemmer 1988). Treatment with amitriptyline continued during the sign test). The mean thermic response to oxotremorine after 1 week of treatment with amiperiod during which bright light was given. The Brief 419 BIOL PSYCHIATRY 1989;26:416423 Reports Table 2. Experiment I: Mean Thermic Responses Animal number A B C D Saline Oxotremorine challenge I Oxotremorine challenge 2 Oxotremorine challenge 3 -2.5 -1.0 -0.8 -0.3 -0.7 -1.2 -2.3 -1.5 -1.3 - 1.3 0.4 0.3 0.2 0.04 0.2 0.3 0.4 0.2 0.4 0.3 -3.4 -2.3 -2.0 -2.7 -2.9 -1.9 -2.2.t -3.1 -3.4 -2.0 * ? ” 2 2 * 0.4 0.3 0.3 0.3 0.3 0.3 0.4 2 0.4 t 0.5 * 0.3 -0.7 -0.9 -1.7 - 1.8 - 1.0 -0.8 -1.7 -1.7 2 1.5 - 1.0 f 2 * ? k 2 k f * k - 1.3 2 0.20 -2.6 f 0.20 -1.3 2 0.10 3 4 5 6 7 8 9 10 0.2 0.3 0.5 0.1 0.3 0.1 -0.1 0.1 0.4 0.3 + 2 * k 2 2 * 2 * 2 Mean +0.2 f 0.10 L 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 2 + k 2 2 + f * -t 2 0.2 0.1 0.3 0.2 0.2 0.2 0.3 0.2 0.2 0.2 This table presents the thermic response of each animal in Experiment 1 to saline (1 mg/kg, ip) and to oxotremotine (1 mgikg, ip) prior to treatment with amihiptyline (Challenge l), after 1 week of treatment with amitybiptyline (15 mg/kg, ip, at 900 AMand 5:OOPM daily) (Challenge 2). and after 1 week of concurrent treatment with full-spectmm, bright artificial light (between 5:00 and 11:OOPM)and amitriptyline (15 mg/kg, ip, at 900 AMand 5:OOPMdaily) (Challenge 3). Each entry is the mean of 12 measurements of change in core temtwatare relative to the rat’s core temperature immediately prior to the injection of saline or oxotremorine. Please see the Results section for brobability statements. triptyline was -2.6 ? 0.2”C. This differed from the thermic response to oxotremorine prior to treatment with amitriptyline (p < 0.0006, t = 5.2 1, df = 9). The sample exhibited the identical thermic response to oxotremorine ( - 1.3 ? 0. 10°C) after 1 week of treatment with bright artificial light that it displayed prior to the administration of amitriptyline, despite continued treatment with this agent. Figure 1 illustrates the results of this experiment. zyxwvutsrqponml Experiment 2 The mean core temperature of the animals in this experiment at baseline was 37.3 + 0.03”C 3.0 prior to injection with saline. The sample exR hibited a mean thermic response to saline of + zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA f0.36 + 0.6”C. The mean thermic response i I to oxotremorine prior to treatment with ami2.0 J, triptyline was -0.90 + 0.07”C. This differed t from the thermic response to saline (p < 6 0.0001, t = 12.6, df = 9). The mean thermic P lY 1.0 response after 1 week of treatment with ami.v triptyline was - 1.36 ? zyxwvutsrqponmlkjihgfedcbaZYX 0. zyxwvutsrqponmlkjihg 15°C. This differed : 5 from the response to oxotremorine prior to :: ”I” 0.0 _ treatment with amitriptyline @ < 0.0003, t = Baseline AMI AM, 6.10, df = 9). The sample exhibited a mean ($5 m/kg) (15 v/h) thermic response of - 1.42 * 0.12 after an bid - 7 days bid - 14 days + RAL additional week of treatment with amitriptyFigure 1. Six hours of bright light daily blocks the line, during which it was exposed to 300 lux light between 5:00 PM and 11:OO PM. This did capacity of amitriptyline to produce supersensitivity to oxotremorine. not differ from the response to oxotremorine u ‘I 420 BIOL PSYCHIATRY lY89;26:416-423 Brief Reports zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCB subjects. This indicates that at least some forms of affective illness involve stateindependent supersensitivity of a central muscarinic mechanism. Bright artificial light is the first treatment for a depressive disorder discovered to produce subsensitivity of a central muscarinic cholinergic mechanism. / zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Several aspects of this study require comment. The albino rat is useful in conducting preliminary experiments designed to assess the LL effects of bright light on neurotransmitter sysdo se line tems. but it is not the ideal animal for research in this area. A pigmented diurnal species will eventually have to be used in these studies. The Figure 2. Dull light does not produce subsensitivity albino rat may experience irreversible neuroanto oxotremorine. atomic retinal changes when chronically exposed to bright light. We emphasize, however, that although this may occur, albino rats exafter 1 week of treatment with amitriptyline (p posed to bright light at an intensity of 7400 lux > 0.6, t = 0.64, df = 9). Figure 2 illusfor 24 hr a day for 7 consecutive days return to trates the results of Experiment 2. their baseline level of sensitivity to clonidine when returned to standard vivarium conditions (Dilsaver and Majchrzak 1988). This argues Discussion against the possibility that a neuroanatomic effect on the retina accounts for the findings we The data presented indicate that concurrent have reported (Dilsaver 1988: Dilsaver and treatment with bright artificial (7400 lux), but Flemmer 1988). not dull (300 lux), light counteracts the capacity The time fragment of the 24-hr day over which of amitriptyline to produce supersensitivity to the thermic effect of oxotremorine. This sug- one administers bright light to either a diumai or nocturnal species would be physiologically gests that light intensity is a critical variable. All 10 animals in Experiment 1 exhibited an important (Lewy et al. 1983, 1984, 1985; Lewy and Sack 1987). Bright light can either phase increase in the hypothermic response to oxotredelay or phase advance an endogenous pacemorine after 1 week of treatment with amitripmaker (“master clock”), depending on the time tyline. Similarly, all 10 animals in this experiit is administered. During the first half of subment exhibited blunting of the thermic effects jective night (as in the study reported here). of oxotremorine after I week of concurrent treatment with oxotremorine and bright artificial light bright light produces a phase delay. A pulse of bright light of identical intensity and duration (p = 0.0001, sign test). This strongly suggests will produce a phase advance when given during that bright light potently affects the muscarinic the second half of subjective night. We have mechanism supersensitized by amitriptyline. Janowsky et al. (1972) proposed that de- reported that the constant administration of bright light (Dilsaver and Majchrzak 1987) or its pressive disorders are related to a defect in cenadministration during a fragment of the regular tral muscarinic mechanisms. Sitaram et al. (1980) observed that euthymic affective disorder pa- photoperiod (Flemmer and Dilsaver 1988) all of a central muscarinic tients exhibit accelerated onset of rapid eye produce subsensitivity movement (REM) sleep in response to the in- mechanism. Thus, whether the animals are freerunning (as occurs when bright light is given fusion of arecoline (an mAchR agonist) relative f....- I i / to normal BIOL PSYCHIATRY 1989;26:416-423 Brief Reports constantly), circadian phase is supposedly not altered (as occurs when bright light is given during the regular photoperiod) or delayed (in the study reported here) we obtain the same basic result. Finally, with respect to the phasic effects of light, it is important to note that the issue is not whether or not 300 lux light is a physiologically significant stimulus in the albino rat. It unequivocally is! Abruptly removing a stimulus of 300 lux light by turning the lights in a vivarium off leads to a dramatic increase in motor activity in less than 1 min and a rise in body temperature. Turning the lights on during the dark phase leads to a dramatic (but slower occurring) decrease in motor activity. The crucial issue is whether or not 300 lux and 7400 lux light have equivalent phasic effects on an endogenous pacemaker that might affect mAchR sensitivity. This study was not designed to answer this particular question. The possibility that exposure to bright light stresses the rat must be considered. We doubt that it does. First, the animals do not behave as if they are stressed. Second, forced swim stress (Dilsaver et al. 1986; Dilsaver 1988b) and inescapable footshock (Dilsaver and Alessi 1987) enhance the sensitivity of a central muscarinic mechanism involved in the regulation of core temperature. Data from other laboratories also indicate that stressors activate muscarinic mechanisms (for a review of this literature, please see Dilsaver 1988). Thus, the effect of bright light reported here is the opposite of that associated with stressors. Why amitriptyline produces supersensitivity to muscarinic agonists, given that it is an antidepressant, puzzles some thoughtful psychiatrists who have attempted to reconcile this fact with the muscarinic cholinergic system hypothesis of depression. Amitriptyline is an mAchR antagonist (i.e., it blocks the access to acetylcholine to the mAchR) . It produces signs and symptoms of mAchR blockade (Atkinson and Landinsky 1972; Richelson and Dininetz-Romero 1977; Szabadi et al. 1980; Petersen and Richelson, 1982)Drugs blocking the access of acetylcholine to the mAchR compel compensatory changes in cholinoceptive 421 zyxwvutsrqpon neurons. These changes include mAchR up-regulation (for a review of this literature, please see Dilsaver 1986a) and the enhancement of sensitivity to acetylcholine and muscarinic agonists (Jaffe and Sharpless 1968; Friedman et al. 1969; Innes and Nickerson 1975; Jaffe 1980). Amitriptyline, just as classical mAchR antagonists do, produces up-regulation of mAchRs in the rodent brain (Rehavi et al. 1980; Goldman and Erickson 1983) and supersensitivity to a muscarinic agonist (Dilsaver et al. 1987; Dilsaver and Snider 1988). Desipramine similarly produces mAchR up-regulation in the myocardium of rats (Nomura et al. 1982, 1983) and supersensitivity to a muscarinic agonist (D&aver and Davidson 1987). It is important to note that the antimuscarinic effects of the tricyclics are now regarded as being related to their side effect profile, but unrelated to their antidepressant properties. Amitriptyline is not an antidepressant because it is a mAchR antagonist-it is an antidepressant despite this property! As it has this property, it potently produces supersensitivity to a muscarinic agonist. Many outstanding antidepressants either lack or have minimal affinity for the mAchR (Snyder and Yamamura 1977; Blackwell et al. 1978; Tollefson et al. 1982; Richelson and Nelson 1984). Conclusion Data presented in this article indicate that bright artificial, but not dull light blocks the capacity of amitriptyline to produce supersensitivity of a central muscarinic mechanism. These data are consistent with the hypothesis that the depressed state is accompanied by supersensitivity of a central muscarinic mechanism and that a treatment subsensitizing it has antidepressant properties. References Atkinson J, Landinsky H (1972): The quantitative study of the anticholinergic action of several tricyclic antidepressants on the rat isolated fundal strip. Br J Pharmcol45:519- 524. 422 Brief Reports BIOL PSYCHIATRY 1989:26:416-423 Blackwell R, Stefopoulos A, Enders P, Kuzma R, Dilsaver SC, Miller SH, Flemmer D (1988a): Forced Adolphe A (1978): Anticholinergic activity on two swim stress produces dose-dependent supersentricyclic antidepressants. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCB Am J Psychiatry 135:722sitivity to a muscarinic agonist. Presented at the 724. 27th annual meeting of the American College of Nemopsychopharmacology, San Juan, Puerto Rico. Dilsaver SC (1986a): Chohnergic mechanisms in December I I-16, 1988. depression. Br Res Rev I 1:285-3 16. Dilsaver SC, Majchrzak MJ, Alessi NE (1988b): TeDilsaver SC (1986b): Cholinergic mechanisms in aflemetric measurement of core temperature in psyfective disorders: Future directions for investichobiological research: Reliability and validation. gation. Actu Psychiatr Stand 74~312- 324. Prog Neuropsychopharmacol Biol Psychiatry (in Dilsaver SC (1986~): Pathophysiology of “cholinopress). ceptor supersensitivity” in affective disorders. Biol Friedman MJ, Jaffe JH, Sharpless SK (1969): Central Psychiatry 21:813- 829. Dilsaver SC (1988a): Artificial light and nicotine subsensitivity. Biol Psychiatry 24437- 440. Dilsaver SC (1988b): Effects of stress on muscarinic mechanisms. Neurosci Biobehav Rev 12:23- 28. Dilsaver SC, Alessi NE (1987): Chronic inescapable footshock produces cholinergic system supersensitivity. Biol Psychiatry 22:914- 918. nervous system supersensitivity to pilocarpine after withdrawal of chronically administered scopolamine. J Pharmacol Exp Ther I67:45- 55. Goldman ME, Erickson CK (1983): Effects of acute and chronic administration of antidepressant drugs in the central cholinergic nervous system: Comparison with anticholinergic drugs. Neuropharmacology 22: 1285-1322. Dilsaver SC, Alessi NE (1988): Temperature as a dependent variable in the study of cholinergic mechanisms. Prog Neuropsychopharmacol Biol Psychiatry 12: l-32. Innes IR, Nickerson M (1975): Atropine, scopolamine and related antimuscarinic drugs. In Gilman AG. Goodman LS, Gilman A (eds). The Pharmacological Basis of Therapeutics, (ed 5). New York: Macmillan, p 520. Dilsaver SC, Davidson RK (1987): Cholinergic properties of desipramine and amoxapine: Assessment using a thermoregulation paradigm. Prog Neuropsychopharmacol Biol Psychiatry 11581-599. Jaffe JH (1980): Drug addiction and drug abuse. ln Gilman AG, Goodman LS, Gilman A (eds), The Pharmacological Basis of Therapeutics (ed 5). New York: Macmillan, pp 556-557. Dilsaver SC, Flemmer D (1988): Bright light blocks the capacity of a forced stressor to supersensitize a muscarinic mechanism. Presented at the 27th annual meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico, December I l-16, 1988. Jaffe JH, Sharpless SK (1968): Pharmacological denervation supersensitivity in the central nervous system. Res Nerv M ent Dis 461226-241. D&aver SC, Majchrzak MJ (1988): Bright artificial light produces subsensitivity to clonidine. Life Sci 42:597-601. Dilsaver SC, Majchrzak MJ (1989): Effects of placebo (saline) injections on core temperature in the rat. Prog Neuropsychopharmacol Biol Psychiatry (in press). Dilsaver SC, Snider RM (1988): Amitriptyline produces dose-dependent supersensitivity of a central muscarinic mechanism. J Clin Psychopharmacol 8:410- 412. Dilsaver SC, Snider RM, Alessi NE (1986): Stress induces supersensitivity of a cholinergic system in rats. Biol Psychiatry 21: 1093- 1096. Dilsaver SC. Snider RM, Alessi NE (1987): Amitriptyline supersensitizes a central cholinergic mechanism. Biof Psychiatry 22:495- 507. James SP, Wehr TA, Sack DA, Parry BL, Rosenthal NE (1985): 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. Luncet ii:627-635. Lewy AJ, Sack RL ( 1987): Phase typing and bright light therapy of chronobiologic sleep and mood disorders. In Halaris A (ed), Chronobiology and Psy chiatric Disorders. New York: Elsevier. pp 181-206. Lewy AJ, Kern HA, Rosenthal NE, Wehr zyxwvutsrqponmlk TA (1982): Bright artificial light treatment of a manic-depressive patient with seasonal mood cycle. Am J Psychiatry 142:163- 170. Lewy AJ, Sack RL, Fredrickson RH, et al (1983): The use of bright light in the treatment of chronobiologic sleep and mood disorders: The phaseresponse curve. Psychopharmacol Bull 19:523- 525 BIOL PSYCHIATRY Brief Reports zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 423 1989;26:416423 tidepressants of neurotransmitter receptors of norLewy AJ, Sack RL, Singer CM (1984): Assessment mal human brain in vitro. J Pharmacol Exp Ther and treatment of chronobiologic disorders using plasma melatonin levels and bright light exposure: 230:94- 102. The clock-gate model and the phase-response Rosenthal NE, Sack DA, Gillin JC, Levy JA, Goodcurve. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Psychopharrnacol Bull 2056 l- 565. win FK, Davenport Y, Mueller PS , Newsome DS, Lewy AJ, Sack RL, Singer CM (1985): Immediate and delayed effects of bright light on human melatonin production: Shifting “dawn” and “dusk” shifts the dim light melatonin onset (DLMO). Ann NY Acad Sci 453~253- 259. Nomura Y, Kajiyama H, Okai K (1982): Influence of repeated administration of dimethylimipramine on beta-adrenergic and muscarinic cholinergic receptors and 45Ca+ + binding to sacrcoplasmic reticulum in the rat brain. J Pharrnacol Exp Ther 223:834- 840. Nomura Y,Kajiyama H, Segawa T (1983): Possible influence of noradrenalin on beta-adrenergic and muscarinic receptors in rat heart: Effects of 6hydroxydopamine, isoproterenol and dimethylimipramine. In Segawa T (ed), M olecular Pharmacology of Neurotransmitter Receptors. New York: Raven Press, pp 83-90. Petersen RC, Richelson E (1982): Anticholinergic activity of imipramine and some analogs at muscarinic receptors of culture mouse neuroblastoma cells. Psychopharmacology 76:26- 28. Rehavi M, Ramot 0, Yavetz B et al (1980): Amitriptyline: Long-term treatment elevates alpha-adrenergic and muscarinic receptor binding in mouse brain. Brain Res 194:443- 453. Richelson E, Dininetz-Romero S (1977): Blockade by psychotropic drugs of the muscarinic acetylcholine receptor in cultured nerve cells. Biol Psy chiatry 12:771- 785. Richelson E, Nelson A (1984): Antagonism Wehr TA (1984): Seasonal affective disorder: A description of the syndrome and preliminary findings with light therapy. Arch Gen Psy chiatry 4 1:7280. Rosenthal NE, Carpenter CJ, James SP, Parry BL, Rogers SLB, Wehr TA (1986): Seasonal affective disorder in children and adolescents. Am J Psy chiatry 143:356- 358. Sitaram N. Nurnberger JI, Gershon ES, Gillin JC (1980): Faster cholinergic REM sleep induction in euthymic patients with primary affective disorders. Science 208:20&202. Snyder SH, Yamamura HI (1977): Antidepressants and muscarinic acetylcholine receptor. Arch Gen Psy chiatry 34:236- 239. Szabadi P, Baszner P, Bradshaw CM (1980): The peripheral anticholinergic activity of tricyclic antidepressants: Comparison of amitriptyline and desipramine in human volunteers. Br J Psy chiatry 137:433- 439. Tollefson GD, Senogles SE, Frey WH, et al (1982): A comparison of peripheral and central human muscarinic cholinergic receptor affinities for psychotropic drugs. Biol Psy chiatry 17:555-567. Wehr TA, Jacobsen FM, Sack DA, Arendt J, Tamarkin L, Rosenthal NE (1986): Phototherapy of seasonal affective disorder: Time of day and suppression of melatonin are not critical for antidepressant effects. Arch Gen Psy chiatry 43:870875. by an-