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The Effects of Nicotine and Smoking on the Central Nervous System

Date: 15 Mar 1967
Length: 170 pages
TIMN0436953-TIMN0437122
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236 Annals New York Academy of Sciences felt "dizzy," "light-headed," and nauseated. This feeling seldom lasted more than 5 minutes. Usually, the subjects fell asleep about the same time as after the saline injection and showed no striking alteration in their sleep behavior. Immediately after the injections of nicotine, the heart rates increased slightly. Lysine vasopressin and, especially PLV-2, in doses of 50 mPu/kg, occa- sionally caused a decrease in heart rate which lasted less than one hour. During this time, some subjects complained of a slight uneasiness and the feeling of having to move their bowels. These were not prominent symptoms, and the subjects usually fell asleep promptly. In comparison to no medication, lysine vasopressin increased significantly the percentage of Stage I, from a mean t SE of 20.9 f 2.2 to 28.6 f 3.0. PLV-2 also increased significantly the amount of Stage III. Lysine vasopressin was more effective than PLV-2 in shortening the time between the injection and the onset of Stage I. In this very preliminary study, six of the eight subjects were nonsmokers and the other two were light smokers, averaging less than 1 pack of cigarettes per day. No differences between light smokers and nonsmokers were observed in onset, duration, pattern of sleep, or responses to nicotine. One can conclude that under the conditions of this study, in which nicotine was given at bedtime, no evidence of a wake-up effect or facilitation of Stage I sleep was obtained. The reason may be that the action of nicotine is relatively short, so that the compound could hardly be expected to alter a sleep cycle 7-8 hours long. The vasopressins also had no significant effects upon the sleep cycle under these circumstances. However, this needs to be studied further. BEHAVIORAL ACTIONS OF NICOTINE IN THE RAT Differential Effects upon Latency of Avoidance in "Slow"vs. "Fast"Rats There have been many studies of the behavioral effects of nicotine in animals and man (see Silvette et al., 1962). One can summarize the litera- ture by saying that nicotine has little to no effect, and that when it does act, it is either a stimulant or a depressant according to dose, duration of treatment, behavioral task, and species. Our interest in the behavioral effects of nicotine developed from a desire to understand the significance of the EEG activation it induces. As already noted, the EEG actions are rather transient. Nevertheless, in cats, they are associated with behavioral arousal and are followed by an increase in fast-wave sleep. It can be predicted that this brief wake-up effect observed in the EEG can be shown to have behavior- al correlates under the proper experimental circumstances. It has been previously reported (Domino, 1965a) that nicotine in large doses has marked effects upon conditioned avoidance behavior in the rat. The action of large doses of nicotine upon established conditioned pole-jumping behavior is reminiscent of the effects of chlorpromazine. These actions are produced by relatively large doses of nicotine and therefore are probably Domino: Nicotine-Induced Arousal 237 unrelated to the effects of the small doses absorbed during tobacco smoking. In our experiments, nicotine has shown no consistent effect upon the acquisi- tion of conditioned avoidance behavior. It has been possible upon occasions to show that nicotine, in small doses, facilitates acquisition and delays extinc- tion, but that large doses have reproducibile depressant actions. We reported these findings at the Tobacco Symposium in Stockholm (Domino, 1965a). At that time, Bovet (1965) and Bovet-Nitti (1965) pointed out that small doses of nicotine have facilitating effects upon behavior, especially in the naive rat. These effects were considered to be similar to those of amphetamine, and different from those of chlorpromazine and other related drugs. The Bovets emphasized some very important facts: It was necessary to use split-litter techniques to reduce variability. Furthermore, by using separate "bright" and "dull" groups of rats, they were able to demonstrate the facilitating effects of nicotine, especially in slow learners. Our own data have indicated that the EEG-activating actions of nicotine, or its behavioral wake- up effect in chronic cats, appeared only when the dose was administered during a state of mild central nervous system depression or sleep. This suggests that nicotine should have an alerting effect upon behavior only in fatigue states or other states of slight central nervous system depression. The degree of depression must be slight, however; because barbiturates, even in small doses, easily block nicotine's EEG activating effects. We have previously reported that small doses of nicotine have no consis- tent effect upon the response latency for conditioned avoidance behavior in monkeys (Domino, 1965a). On the other hand, Bovet-Nitti (1965) has been able to show a reduction in reaction times following nicotine. We have re- examined this problem from the point of view of the effect of nicotine in animals with "fast" vs. "slow" latency times for conditioned avoidance pole jumping. In a modification of the original Cook and Weidley (1957) technique, rats were trained to react to a buzzer stimulus to avoid an electric shock applied to the grid floor. A 5-second buzzer tone was the conditioned stimulus (CS), and a 5-second, 1 milliampere, 60 cps electroshock was the uncondi- tioned stimulus (US); these were used under overlap conditions. Male Holtz- man rats of 200-500 gm were employed. The rats were trained in blocks of 20 trials to a total of 200 trials for a 90%r avoidance criterion. Animals not reaching this criterion were discarded. On the day of testing, the trained rats were given 20 control trials and 60 postdrug trials. Within each block of 20 trials, there were random intertrial intervals with a mean duration of 45 seconds; the interval between blocks was three minutes. Latency of avoidance and escape were measured auto- matically. Nicotine was given in doses of 40, 80, and 160 µg/kg as base, subcutaneously. Physiological saline was given in comparable volumes, which did not exceed 0.5 ml. After the 20 control trials, the drug was injected; then, after a one-minute wait, the postdrug trials began. The mean avoidance latency t SE for saline and for increasing doses of nicotine, for groups of six
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238 Annals New York Academy of Sciences or more rats selected at random, are shown in FIGURE 17. It can be seen that after saline and 40 µg/kg of nicotine, there was a tendency for the mean avoidance latency to increase with the number of trial blocks. This trend was reversed after the administration of 80 and 160 µg/kg of nicotine, especially for postnicotine trials 1-20 and 21-40. A dose of 40 µg/kg of nicotine was not significantly different from saline in altering the percentage of avoidance behavior in postinjection trials 1-20. However, 80 µg/kg caused a 1.3% reduction of avoidance behavior, and 160 µg/kg caused a 4% reduction. Therefore, another experiment was run in which 12 trained rats were given 20 control trials, followed by saline injection and one US. Then the normal CS-US sequence was run in blocks of 20 trials. This experiment mimicked the actions of nicotine by causing an automatic 5°lc increase in the number of escape responses. Under these circumstances the mean avoidance latency tSE was 1.59 t 0.12 before injection, and 1.41 t 0.16 for post-injection trials 1-20, 1.65 t0.19 for trials 21-40, and 1.79 f 0.16 for trials 41-60. These effects with saline plus electroshock are almost identical with those obtained after nicotine (see FIGURE 18). The slight increase in the number of escape 0 0 U ~ 2.5 2.0 1.5 I.0 0.5 0 2.5 2.0 1.5 I.0 0.5 0 2.5 2.0 1.5 1.0 0.5 0 2.5 2.0 1.5 1.0 0.5 0 E 0 I CONTROL 1-20 21-40 mm~ 41-60 Trials Post Injection Trials PHYSIOLOGICAL SALINE NICOTINE 40 Ag / kg NICOTINE 80 µg /kg NICOTINE 160Ag/kg FIGURE 17. Effects of Increasing Doses of Nicotine upon Mean Avoidance Latency for Pole Jumping in Trained Rats. The mean latencies t SE, in seconds, of groups of 6 or more rats given either saline or various doses of nicotine subcutaneously are shown. The mean latencies of 20 control trials before injection are followed by the mean latencies of postinjection blocks of 20 trials each. Note that latencies for saline and for 40µg/kg of nicotine increased with each block of trials. On the other hand, 80 and 160 µg/kg of nicotine temporarily reverse this trend for the first and second postinjection blocks. z w Domino: Nicotine-Induced Arousal 239 2.5 0 CONTROL Trials ® SALINE ® NICOTINE ® SALINE+EST 1-20 21-40 Post Injection Trials 41-60 FIGURE 18. Similarity of Effect of Saline plus Electroshock to that of Nicotine upon Mean Avoidance Latencies for Conditioned Pole Jumping in Rats. After saline injection and one unconditioned stimulus, the subsequent mean avoidance latencies were decreased to the same extent as after nicotine. responses due to exposure to electroshock after nicotine might account for the decrease in latency, since one postsaline US speeds up subsequent avoid- ance responses. A dose of 80 µg/kg of nicotine produced much less depression of avoidance behavior and an even greater decrease in mean avoidance latency than 160 µg/kg of nicotine. It seemed that the speed-up effect of nicotine was not associated only with its ability to decrease conditioned avoidance behavior and thus increase the motivation of the rats due to exposure to electroshock during the US interval. A large number (30) of trained rats were given 80 µg/kg of nicotine each and tested for the latency of pole jump avoidance as described above. The animals were divided into two groups, one "fast" and the other "slow," on the basis of their control avoidance latencies. The differential effects of saline and nicotine are graphed in FIGURE 19. Saline and nicotine caused the same prolongation of mean avoidance latency in the "fast" rats. The nicotine-treated rats tended to be slightly faster, but the standard errors overlapped with those for saline except for postinjection trials 41-60. On the other hand, the "slow" rats given nicotine showed a definite decrease in mean latency compared to those given saline, especially in postinjection trials 1-20 and 21-40. This decrease was statistically signifi- cant (P < 0.05). Nicotine reduced avoidance behavior in both groups during postinjection trials 1-20 (see FIGURE 20), by 3.7(ii for the "fast" group and 5.7o/r for the "slow" group. Is it possible that this 2t1'i difference in exposure to electroshock can account for such dramatic differences? Since electroshock is an effective motivator, one would be inclined to answer yes, although further work must obviously be done to prove this. It should be noted that during postinjection trials 21-40 there was no reduction of avoidance behavior
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240 Annals New York Academy of Sciences 2.50 ® SALINE M NICOTINE 2.00 i 100 1.50 i N FAST N 80 ~ 2 O 0 1.00 Z RATS 0 0 W N z 0.50 L) 60 (n z 40 uwi 0 w N 20 +1 +1 u 2.50 0 0 z w I— z a 0 a 2.00 J z a 1.50 p 100 Q H 80 w ~ SLOW z W RATS 0 1.00 a: 60 0.50 nw. z 40 Q W 2 0 20 CONTROL 1-20 21-40 41-60 0 Trials Post Injection Trials FIGURE 19. Differential Effects of Nicotine upon the Mean Avoidance Latencies for Pole Jumping in "Fast" vs. "Slow" Rats. The mean latencies f SE in seconds of groups of 15 or more rats given saline or nicotine in a subcutaneous dose of 80 µg/kg are shown. "Fast" rats, whether treated with saline or with nicotine show similar trends for slower mean avoidance latencies after injection. The "slow" rats treated with saline show a similar trend. However, "slow" rats treated with 80 µg/kg of nicotine show a temporary speed-up for the first and second postinjection trial blocks. in either group, yet the mean avoidance latency of the slow rats was still less than that of the saline-treated "slow," or saline- or nicotine-treated "fast" rats. However, similar effects were noted with saline plus electroshock. SUMMARY There are two different reasons for interest in the actions of nicotine on the central nervous system. One is related to the presence of nicotine in tobacco, possibly serving as a reinforcer of the habit of smoking tobacco. The other is the use of nicotine to increase the understanding of cerebral cholinergic mechanisms. These two interests are quite compatible, particularly if small doses of nicotine are used. For the past six years, research in our laboratory has been directed toward elaborating the central actions of nicotine. To date, we can say something about the actions of small doses of nicotine upon the central nervous system and central cholinergic mechanisms. Their relationship to tobacco smoking is still unknown, but the fact that very small doses of nicotine cause rather clear-cut central actions suggests that any theory of the Domino: Nicotine-Induced Arousal 241 0 SALINE i 1-20 SLOW RATS CONTROL Trials ® NICOTINE RIC,; N FAST rr, RATS 41-60 Post Injection Trials FIGURE 20. Differential Effects of Nicotine upon Mean Percentage of Avoidance Response in "Fast" and "Slow" Rats. The mean t SE percentage of avoidance responses for pole jumping are plotted. Note that nicotine at 80 µg/kg depressed avoidance behavior in the "slow" rats slightly more than in the "fast" ones. Thus, the findings given in FIGURE 19 may be related to the number of electroshocks obtained from failure to avoid when under the influence of nicotine. cause or maintenance of tobacco smoking must take into account these phar- macological facts. If one were arbitrarily choosing a drug for studying its possible actions on the central nervous system, perhaps no poorer choice could be made than nicotine. This agent has so many pharmacological actions that they easily confound, reinforce, and obscure its direct central actions. As an n cholinergic agonist, nicotine acts at a variety of sites in the peripheral nervous system. These multiple actions must be considered in any study of nicotine's effects upon the central nervous system. We have used a neuro- and psychopharmacologic approach to determine the central actions of nicotine. Since nicotine releases acetylcholine, catechol- amines, serotonin, and vasopressin, these compounds were studied as well. The effects of nicotine and related drugs upon the EEGs of acute and chronic animals were determined. In addition, the effects of nicotine upon gross and conditioned avoidance behavior were studied to provide behavioral correlates of the EEG changes.
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242 Annals New York Academy of Sciences Nicotine, in doses of 5-20 µg/kg i.v., causes EEG activation in acute experiments which is related to a behavioral wake-up effect. This action, which lasts only a few minutes, involves both central and peripheral com- ponents. Nicotine also causes an increase in fast-wave sleep, which may be related to vasopressin release. The initial behavioral consequences of small doses of nicotine are consistent with a brief wake-up effect. In rats trained to pole jump, nicotine in subcutaneous doses of 80 and 160 µg/kg produced a transient decrease in mean avoidance latency within one or two minutes. In contrast, saline or 40 µg/kg of nicotine, produced a slight increase in avoidance latency. Mean avoidance latency decreased more in "slow" rats than in "fast" ones. The effects of nicotine were highly significant; the role of slightly increased percentages of unconditioned stimuli (electroshock) in increasing motivation in the nicotine-treated animals needs to be studied further. In conclusion, the research reported here indicates that nicotine, in doses comparable to those absorbed by a man smoking tobacco, has pharmacological actions consistent with a brief wake-up effect as well as a transient period of mild central nervous system depression. The behavior depressant effects of nicotine are more evident with larger doses. Acknowledgments The author would like to acknowledge the collaboration of his former students and associates Drs. Dren, Knapp, Varma, Villarreal, and Yamamoto, as well as Mary Corcoran, Diana Fitzgerald, Myron Newton, and Jack Stawiski in completing various portions of this research. Re ferences BARLOW, R. B. 1965. Chemical structure and biological activity of nicotine and related compounds. In Tobacco Alkaloids and Related Compounds. U. S. von Euler, Ed. : 277-301. Pergamon Press. Oxford. BARLOW, R. B. & J. T. HAMILTON. 1962. Effects of pH on the activity of nicotine and nicotine monomethiodide on the rat diaphragm preparation. Brit. J. Pharmacol. 18: 543-549. BONVALLET, M., P. DELL & G. HIEBEL. 1954. Tonus sympathique et activite electrique corticale. Electroenceph. Clin. Neurophysiol. 6: 119-144. BOVET, D. 1965. Action of nicotine on conditioned behaviour in naive and pretrained rats. In Tobacco Alkaloids and Related Compounds. U. S. von Euler, Ed. : 126- 136. Pergamon Press. Oxford. BOVET-NITTI, F. 1965. Action of nicotine on conditioned behaviour in naive and pretrained rats. II: Complex forms of acquired behaviour-discussion. In Tobacco Alkaloids and Related Compounds. U. S. von Euler, Ed. : 137-143. Pergamon Press. Oxford. BREMER, F. 1953. Some Problems in Neurophysiology. : 31. Athlone Press. London. COOK, L. & E. WEIDLEY. 1957. Behavioral effects of some psychopharmacological agents. Ann. N. Y. Acad. Sci. 66: 740-752. Domino: Nicotine-Induced Arousal 243 DEMENT, W. 1958. The occurrence of low voltage, fast electroencephalogram patterns during behavioral sleep in the cat. Electroenceph. Clin. Neurophysiol. 10: 291-296. DEMENT, W. & N. KLEITMAN. 1957. Cyclic variations of EEG during sleep and their relation to eye movements, body motility and dreaming. Electroenceph. Clin. Neurophysiol. 9: 673-690. DENISENKO, P. O. 1962. Influence of pharmacological agents upon cholinoreactive and adrenoreactive systems of the reticular formation and other regions of the brain. First Internat. Pharmacol. Meeting, Pharmacological Analysis of Central Nervous Action. W. D. M. Paton, Ed. 8: 199-209. Macmillan. New York. DOMINO, E. F. 1965a. Some behavioral actions of nicotine. In Tobacco Alkaloids and Related Compounds. U. S. von Euler, Ed. : 145-166. Pergamon Press. Oxford. DOMINO, E. F. 1965b. Some comparative pharmacological actions of (-) nicotine, its optical isomer, and related compounds. In Tobacco Alkaloids and Related Com- pounds. U. S. von Euler, Ed. : 303-313. Pergamon Press. Oxford. DOMINO, E. F., A. T. DREN & K. YAMAMOTO. 1966. Pharmacologic evidence for cholinergic mechanisms in neocortical and limbic activating systems. Symposium on Limbic System Progress in Brain Research, Hakone, Japan (September 1965). To be published. DOMINO, E. F. & K. YAMAMOTO. 1965. Nicotine: Effect on the sleep cycle of the cat. Science. 150: 637-638. DREN, A. T. & E. F. DOMINO. 1965. Some effects of hemicholinium (HC-3) on EEG desynchronization mechanisms in the dog. Pharmacologist. 7: 153. DUNLOP, C. W., C. STUMPF, D. S. MAXWELL & W. SCHINDLER. 1960. Modification of cortical, reticular and hippocampal unit activity by nicotine in the rabbit. Amer. J. Physiol. 198: 515-518. FLORIS, V., G. MOROCUTTI & G. F. AYALA. 1962. Azione della nicotina sulla attivita bioelectrica della corteccia del talamo e dell' ippocampo nel coniglio. Sua azione di "arousal" e convulsivante primitiva sulle strutture ippocampotalamiche. Boll. Soc. I tal. Biol. Sper. 38: 407-410. ILYUTCHENOK, R. I. 1962. The role of cholinergic systems of the brainstem reticular formation in the mechanism of central effects of anticholinesterase and cholinolytic drugs. First. Internat. Pharmacol. Meeting, Pharmacological Analysis of Central Nervous Action. W. D. M. Paton, Ed. 8: 211-216. Macmillan. New York. JEWETT, R. E. & S. NORTON. 1966. Effects of some stimulant and depressant drugs on the sleep cycle of cats. Exper. Neurol. 15: 463-474. JOUVET, M. 1961. Telencephalic and rhombencephalic sleep in the cat. In Ciha Founda- tion Symposium on the Nature of Sleep. G. E. W. Wolstenholme and M. O'Connor, Eds. : 188- 206. Little, Brown and Co. Boston. KNAPP, D. E. & E. F. DOMINO. 1962. Action of nicotine on the ascending reticular activating system. Int. J. Neuropharmacol. 1: 333-351. KNAPP, D. E. & E. F. DOMINO. 1963. Species differences in the EEG response to epinephrine, 5-hydroxytryptamine and nicotine in brainstem transected animals. Int. J. Neuropharmacol. 2: 51-55. LONGO, V. G. 1962. Rabbit Brain Research. II: Electroencephalographic Atlas for Pharmacological Research. Effect of Drugs on the Electrical Activity of the Rabbit Brain. Elsevier Publishing Co. Amsterdam. LONGO, V. G., G. P. von BERGER & D. BOVET. 1954. Action of nicotine and of the "ganglioplegiques centraux" on the electrical activity of the brain. J. Pharmacol. Exp. Therap. 111: 349--359. MICHELSON, M. J. 1961. Pharmacological evidence of the role of acetylcholine in the higher nervous activity of man and animals. Activ. Nerv. Super. 3: 140-147. SCHMITERLOW, C. G. & E. HANSSON. 1965. Tissue distribution of C"I-nicotine. In Tobacco Alkaloids and Related Compounds. U. S. von Euler, Ed. : 75-86. Pergamon Press. Oxford. SILVESTRINI, B. 1958. Neuropharmacological study of the central effects of benactyzine and hydroxyzine. Arch. Int. Pharmacodyn. 116: 71-85. SILVETTE, H., E. C. HOFF, P. S. LARSON & H. B. HAAG. 1962. The actions of nicotine on central nervous system functions. Pharmacol. Rev. 14: 137- 173.
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244 Annals New York Academy of Sciences STERMAN, M. B., T. KNAUSS, D. LEHMANN & C. D. CLEMENTE. 1965. Circadian sleep and waking patterns in the laboratory cat. Electroenceph. Clin. Neurophysiol. 19: 508-517. STONE, C. A., M. L. TORCHIANA, A. NAVARRO & K. H. BEYER. 1956. Ganglionic blocking properties of 3-methyl-amino-isocamphone hydrochloride (mecamyl- amine): a secondary amine. J. Pharmacol. Exp. Therap. 117: 169-183. STOMPF, C. 1959. Die Wirkung von Nicotine auf die Hippocampusstatigkeit den Kaninchens. Arch. Exp. Path. Pharmak. 235: 421-436. VARMA, U. K. & E. F. DOMINO. 1966. Unpublished observations. VILLARREAL, J. E. & E. F. DOMINO. 1964. Evidence for two types of cholinergic receptors involved in EEG desynchronization. Pharmacologist. 6: 192. WILLIAMS, R. L., H. W. AGNEW, JR. & W. B. WEBB. 1964. Sleep patterns in young adults: an EEG study. Electroenceph. Clin. Neurophysiol. 17: 376-381. YAMAMOTO, K. 1959. Studies on the normal EEG of the cat: comparison between the EEG of fixed cats and unfixed cats seen from the skull and subcortical leads in various consciousness levels and the corresponding behavior. Ann. Reports, Shionogi Research Laboratory_ Osaka, Japan. 9: 1125-1164. YAMAMOTO, K. & E. F. DOMINO. 1965. Nicotine-induced EEG and behavioral arousal. Int. J. Neuropharmacol. 4: 359-373. YAMAMOTO, K. & E. F. DOMINO. 1966. Cholinergic agonist-antagonist interactions on neocortical and hippocampal EEG activation. Int. J. Neuropharmacol. Submitted for publication. YAMAMOTO, K. & R. KIDO. 1962. Neurophysiological studies on the nature of sleep- neural mechanisms related to "activated sleep." Seishin-igaku. Tokyo. Japan. 11: 821-830. L ELI;CTROENCEPHALOGRAPHIC CHANGES IN MAN FOLLOWING SMOKING° Henry B. Murphree, Carl C. Pfeiffer, and Lillys M. Price Bureau of Research in Neurology & Psychiatry, N. J. Neuropsychiatric Institute Princeton, N. J. Oscar Wilde once described the Englishman in a foxhunt as "the unspeakable in pursuit of the uneatable." One might sometimes describe psychopharmacolo- gists as the indefatigable in pursuit of the indefinable. In trying to define more rigorously the actions of some drugs upon the central nervous system, we have in recent years turned to various quantitative electroencephalographic (EEG) techniques. If one accepts the postulate that there is some relationship between behavioral state and electroencephalographic activity, these methods can give numerical values to drug actions upon the brain, and thence indirectly upon behavior, which can be treated statistically, with all the advantages that this entails. There are, however, some qualifications to this, as we shall see. We have also become interested lately in what one might call the psycho- pharmacology of everyday life, the study of the effects of the numerous drugs with which huge numbers of people dose themselves, often chronically for many years, often without, or even against, medical advice, often for no discernible medical reason. It seems not presumptious to suspect that much of this intake is for some variety of mental effect. We include here ethyl alcohol, aspirin and re- lated compounds, antihistamines, various minor tranquilizers or antianxiety drugs, stimulants such as caffeine and amphetamine, and, of course, tobacco. Thus far, we have been able to define three classes of drug effects. 1) Drugs having stimulant subjective and behavioral effects tend to cause a reduction in the electrical energy (wattage, if you like) of the electroencephalogram and a con- current reduction in the variability of the energy. This can be related to a sustained flattening or absence of alpha from the EEG. When the alpha is no longer entering and leaving the record in its typical way, this varying source of energy is reduced and regulprized, if not altogether removed; and only fine, low amplitude, rather invariant background remains. Quantitative methods can de- tect such effects before they become so extreme as "alpha block," which has been described qualitativi~ly as reflecting stimulation. However, this typical stimulant effect may also have to be qualified in the future, as we shall also see. 2) Drugs having depressant. or hypnotic behavioral effects, in contrast with stimulants, tend to cause increases in the electrical energy of the EH:G and in the variability of the energy. This occurs with the advent of large, slow-wave °This work was supported in part by a grant from the American Medical Association Educa- tion and Research Foundation, by grants MH-06713 and MH-04229, from the U. S. Public Health Service, and by a grant from the Geschickter Fund for Medical Research. 245
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246 Annals New York Academy of Sciences activity which entails relatively large amounts of energy and which, even more than alpha, is highly variable. 3) The third class of drug effect upon the electroencephalogram relates to drugs having "minor tranquilizer" or "antianxiety" behavioral effects. A detailed exposition of this is given below. The present paper relates some of our efforts to study the quantitative electroencephalographic effects of smoking. There have been few studies of the electrocencephalographic effects of smoking in man,1-3 and those have been en- tirely qualitative. Initially we were thinking of smoking as having mild tranquil- izing or antianxiety effects. Our view was that smokers absorb enough nicotine chronically to go past the point of ganglionic stimulation to the point of blockade. We reasoned that if there are neurophysiological mechanisms in the brain analo- gous to those in ganglia, we should see, in the quantitative electroencephalo- gram, some evidence of depressant effects from smoking. This now appears to have been incorrect. The subjects included smokers and nonsmokers of both sexes, ages 21-43. Plain and mentholated cigarettes, with and without filters were studied, as were pipes and cigars. Trials included puffing unlighted, inhaling unlighted, puffing lighted and inhaling lighted. All trials were made with the subjects supine, eyes closed, in a quiet, partially darkened room. All EEGs were monopolar from the left or from both left and right occipital areas, with both ears as reference and ground in the midforehead. FIGURE 1 shows a block diagram of the recording setup. Three kinds of records were collected. A conventional clinical paper EEG was obtained on a Grass model 111 G electroencephalograph. The EEG was also full-wave rectified and the area under the resulting curves summated by means of solid state electronic integrators designed and built in our laboratory. By means of solid state totalizers and a counter printer, a series of numbers was ob- tained corresponding to the amounts of electrical energy for each unit of time. EEG S IGNAL DIVIDER NETWORK SOLID STATE OPERATIONAL SOLID STATE AMPLIFIER TDTALIZERS INTEGRATDRS PAPER RECORD IN GRASS III G FM MAGNETIC TAPE DATA RECORDER FIGURE 1. Block diagram of recording setup. COUNTER PRINTER PLAYBACK Murphree et al.: EEG Changes After Smoking 247 Statistical analyses were then done clerically. Finally, the EEG was also recorded with frequency modulation on magnetic tape for later playback and electronic analysis. FIGURE 2 shows a block diagram of the electronic analyzer which was also designed and built in our laboratory. The unfiltered EEG is played directly into a bank of operational amplifier integrators. At the same time, the EEG is passed through an operational amplifier filter manifold which slices the spectrum from one to 36 cps into narrow bandwidths for separate integration. The outputs of the integrators are read on digital voltmeters which drive a counter printer and which will also drive a keypunch via a parallel-to-serial converter when the latter is installed. At present, it is necessary to punch cards manually from the printed tapes. Total energy per unit time and energy from each of 28 narrow bandwidths are entered upon the punched cards which are then processed by a high-speed digital computer (IBM 1401). Several programs can be employed to make the computer process the data in a number of ways. One of these has been described in an earlier publication.4 As we accumulated data and experience, two things became clear. The first was that there appeared to be a very rapid, initial effect of an inhalation of smoke. FIGURE 3 gives an example. Here we have set the time interval for integration at 0.2 second. The subject is a heavy smoker, three or more packs per day. The vertical axis gives integrator counts per unit time, the horizontal axis gives time in seconds. Immediately after an inhalation, the number of counts per unit time drops. This occurs within five seconds, which is shorter than a chest-to-head cir- culation time. It seems reasonable that this effect might occur via some reflex ac- tion, possibly vagal. This is a frequent effect, but so far we have no statistics on the incidence; the reason for this, an important factor, became clear as the work progressed. This relates to what is sometimes called the law of initial values. As UNFILTERED EEG PLAYBACK OPERATIONAL AMPLIFIER FILTER MANIFDLD k~ DPERATIONAL AMPLIFIER INTEGRATORS IEEE D IG ITAL VOLTMETERS PR INTER a PARALLEL TO SERIAL CONVERTER ~ a _-+ U KEYPUNCH W cJa FIGURE 2. Block diagram of processing setup. DIGITAL COMPUTER
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248 Annals New York Academy of Sciences E/ectroencepha/ogram 132 2 /mmediate effect of cigarette smoke inhalation ~ a ~ 0 i 1 1 1 1 1 1 1 t I -3 -2 -I 0 1 2 3 4 5 Time (sec) FIGURE 3. Immediate, possibly reflexive, effect upon the quantitative EEG of one inhala- tion of smoke from a cigarette. our techniques have improved, it has become increasingly plain that drugs have differing effects upon the quantitative electroencephalogram, depending on the state of the subject before the drug is given. Hence, to average data from a group of subjects without taking these differences into account becomes like averaging apples and bananas. To illustrate this, and also to illustrate the effects upon the quantitative electroencephalogram associated with antianxiety drugs, some data on tripelennamine, an antihistaminic drug with typical antianxiety behavioral and subjective effects are presented as exemplary. FIGURE 4 shows strips of electroencephalographic record before and after the subject was given 50 mg of tripelennamine HCI, a usual clinical dose. In the baseline recording, the subject was behaviorally quite tense, and this was re- flected in his low-amplitude, low-alpha record. Four hours after dosage, he was more relaxed, and concurrently, his record shows more alpha activity. If he had had a high-alpha record initially, this effect would have been obscured. Five hours after dosage, he had become behaviorally drowsy, and his record corre- spondingly is flattened. These ratings were made by usual clinical criteria and are nonquantitative. Base//ne Murphree et al.: EEG Changes After Smoking 249 E/ectroe,icepha/ogrom 13 8 0 Monopolar left occipiJa/ 5hrr after Tripe%nnamine, 50 mg j soµ„ FIGURE 4. EEG recordings from the left occipital before, and four and five hours after, 50 mg of tripelennamine HCI, orally, normal male volunteer. FIGURE 5 shows a quantitative time-series plot of total energy and of energy within the alpha band only for this subject's baseline record. The energy in the 8-12 cps portion of the spectrum constitutes a fairly steady proportion of the total. FIGURE 6 shows a similar plot for the recording made four hours after dos- age. The means of total energy and of the alpha band have both increased. The total has gone from 243 to 359; alpha has gone from 78 to 142. The alpha has increased relatively more than the total. Variances have about doubled in both cases. FIGURE 7 shows a plot for the recording made five hours after dosage. Here the alpha energy has dropped from a mean of 142 (in the four-hour record) to a mean of 43, and its variance has increased from 1122 to 2071. Concurrently, the mean total energy has also decreased from 359 to 217. While the variance has de- creased somewhat, from 4008 to 3448, it is still much greater than the baseline value of 1867. Only now do we have what we previously thought of as a typical antianxiety effect. Actually, the subject has been moving along a behavioral con- tinuum from being overalert to being slightly on the drowsy side and the EEG changes have paralleled this. FIGURE 8 shows that while alpha was dropping during this five-hour record- ing, slow-wave activity in the range from one to 6 cps is increasing. The alpha is the solid line, and is the same as in the previous slide, but with an expanded verti- cal scale. The one to 6 is the broken line. The correlation coefficient between these two is -0.63. Thus, there is a kind of economy operating in which there is L
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250 Annals New York Academy of Sciences E E G 1380 6oW 6001 Alpha Baseline recording rotal 500 z= 78 x= 243 6001 s2 = 616 52= 1867 a2= 382 82= lilt 4oo-l a2/52= 0.62 0 82/02= O•595 4001 300 3001 200H 2001 Toto/ 100~ too A/pho 2 3 4 6 6 7 69 10 11 FIGURE 5. Graph of integrated EEG, unfiltered (total energy) and alpha band (8-12 cps); 10-minute baseline before any dose; normal male volunteer. Energy on vertical axis; time on horizontal axis. 600 400 3001 2001 , ~ I 2 3 4 6 6 7 8 9 1 , 10 I 2 3 4 5 s i s s lo FIGURE 8. Graph from same recording as in FIGURE 7. Here the alpha band (8-12 cps) is shown in comparison with the slow-wave band (1.0-6 cps). The vertical scale is expanded FIGURE 6. Graph as in FIGURE 5; 10-minute recording, four hours after 50 mg of tri- from FIGURE 7. There is clearly a reciprocal relationship between the activities in the two pelennamine HC), orally, same subject as in FIGURE 5. bands (r=-0.63). 1 .\ .~ Alpha X • 142 E E G 1380 rotal X • 359 S2 • 4008 82 - 2904 8Z/SZ • 0.725 SE • i122 4hr after 50mg Tripe%nnamine 82 •I1T1 82/S2 • 1.044 Alpha FIGURE 7. Graph as in FIGURE 5; 10-minute recording, five hours after 50 mg of tri- pelennamine HC(, orally, same subject as in FIGURE 5. g Mur hree et al s After Smokin p . : EEG Ch n g e a 251 Alpha X • 43 s2 , 2071 82 = 941 8z/S2• 0.454 E E G 1380 Alpha compared with s/ow activity 5 hr after 50 ma Tripe%nnamine E E G 1380 5 hr after 50 m9 Tripe%nnamine 3 4 5 6 7 8 9 10 120~ 100-I so- s0~ 401 20 1J i H I111I •~~ ~ rotal X . 217 Sz = 3448 82 . 9169 82/SZ ` 2.659 rotal
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252 Annals New York Academy of Sciences not so much a change in the total amount of electrical energy as in its distribution across the spectrum of the EEG. Now, if smoking has effects upon the central nervous system similar to those of antianxiety drugs, we should expect similar findings in EEGs after antianxiety drugs and after smoking. Careful search has not disclosed such so far. FIGURE 9 shows part of the computer's output of statistics from a subject before smoking a cigar. This man is a nonsmoker, and we expected maximal ef- fects from a nonsmoker after inhaling cigar smoke for 10 minutes. In this slide, the far left column labeled T.O presents values of electrical energy from the un- filtered EEG for each 20-second integration interval of this 10-minute recording. Columns to the right of this give values for each separate narrow bandwidth. At the bottom, the computer has calculated for each column the mean, variance, standard deviation, coefficient of variation (C.V.), the mean square successive difference of von Neumann (delta-square), and the ratio of that to variance (la- beled "Ratio D/V" in the Figure). FIGURE 10 shows a similar plot after the subject has puffed without inhaling on a cigar for ten minutes. Note that the mean for total energy has decreased from 34.7 to 25.1, and the variance for total energy has decreased from 35 to 3. Along with this, the mean for 11 cps (this subject's alpha peak) has decreased from 10.2 to 8.1, while the variance has gone from 6 to 3. There seems to be a general reduction in means and variances all across the spectrum, which is typical of stimulant rather than antianxiety effects. FIGURE 11 shows the plot after the subject has inhaled smoke from his cigar for ten minutes. There is little difference between this and the previous slide, suggesting that this subject got about as much effect from puffing as from inhaling. FIGURE 12 shows the spectrum from one to 36 cps as plotted by the Gompu- ter for a high-alpha subject during the baseline recording. Some statistics for total and alpha peak are given on the upper right. FIGURE 13 shows the spectrum for the same subject after smoking a ciga- rette with inhalations. Note that the means for total and alpha have changed little, but that the variances and the mean square successive differences or delta- squares are reduced without exception. This suggests that a reduction in variabil- ity may be the initial effect of stimulation, occurring before any change in mean energies. FIGURE 14 presents the spectrum from the baseline recording of another subject who initially had little alpha. Again note the statistics in the upper right. FIGURE 15 presents the spectrum from the same subject after smoking a cig- arette with inhalations. There is a significant reduction of the mean of total energy, from 29.7 to 25.4 (t = 3.63, P<0.01), and a reduction in the delta-square of total energy from 14 to 8; but, on the whole, the changes produced by smoking are much less impressive than in the previous cases. Of course, this subject started with the kind of record usually associated with stimulation or arousal. This Murphree et al.: EEG Changes After Smoking 253 i0 = O N N O~O O N W N O N O O O N O O O N N O P W N O Y~ W I~.~~nPld.fNd,dddN ~NhY1Y11~'m.OmNmdIP~;OY~IOU~ O"'OPINOYIOIONOOOOOONY~OOOOI00 N.+!N dUNY~OOIONr0.0 PmAA W P1`M WIP W mo W y 00 r .O 0.+~ ~Oinu100NION OION~NIf~NOIN OIOOOOPOO~n ~rP OP W P~+W .O;P W rOl.y p.IpN.rO'P TNOONPPPO Nr OOU101/~Y~Y100 OIOif1I00~NI0Y~YlU~Y~Y1Y~0 Or 4 tiPNOWmmIPmOPI~WIPNrPPrOr001~1P OrOOOONNOO0u1 O . . . Y100J1Y10OOOOO~OION ~= u~PY~PJ001~N f~ .OOOP/~I~Om~mWy1~IPW Yf.. 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DEV. 1 1.8 1.8 1.6 1.1 .9 .9 .6 .6 .7 .9 1.0 1.0 1.2 1.0 .5 C. V. 1 7.2 18.0 19.5 14.9 16.4 11.3 8.7 9.7 15.6 10.8 13.9 15.4 19.4 11.8 22.2 14.5 12.5 _ VON NEUMANN 1 6 8 5_-3_ 1__ 2 1 1 2 2 2 3 3 2 6 1 0 RATIO D/V 1 1.73 2.24 1.95 2.11 1.10 2.33 2.50 2.70 3.33 2.35 1.83 2.78 2.08 1.T9 1.69 1.35 0.00 FIGURE 10. Data and statistics as in FIGURE 9. 10-minute recording from same subject just after puffing a cigar without inhaling for 10 minutes. 4.0.- 5a0.__6sD T 0 8 n 8.5 9.0 9.5 10 O 1D 5 11 0 1J D 14_n,._ 111I11IrII11l1IlIIII1IlIII1IIIl1IIIlIlI171IL1IIIILIIIIIIIIIIILLIlI111111111IIIlIIIIl7I1111LILIlIIILI III 5 4 _ 1 01 r 26,0 H_5 __4.0 8.0 6.5 T 02 1 26.0 9.0 8.0 7.5 6.0 _ T 03 1 27.0 12.5 9.0 8.5 4.5 T104 1 30.0 11.5 9.5 9.0 6.5 0+ I 29.0 16.0_ 12.0 _6.5.. 5.5 . T 06 I 27.0 9.5 9.5 7.0 6.5 T 07 1 a0 0 9.5 11.0 1.0.0 4.0. -- -- T 08 1 27.0 12.0 9.5 9.0 5.0 A A n B 0 A 0 5 5 5 5 4 5 9 0 T OJ 1 26 0 9 0 8_5 5.0 5 O T 10 1 29.0 12.5 7.5 7.5 6.0 8.5 6.5 6.0 4.5 8.0 7.0 6.5 6.0 8.5 10.0 6.0 5.0 1 11 1 an_D t_J_o v_n--- 6-Il. 6.i._.-9.5 _-.8.5 7_5_ 5 n 9_n R_n 7_a 7_5 9_5 In_5 A_5 _--5.1 T 12 1 26.0 8.5 8.0 8.5 3.5 7.0 6.5 6.5 5.5 9.5 8.0 7.5 . 7.5 9.5 8.0 6.0 4.5 _ T 11 1 Ja_n 11_~_A.D - 7-ri__-5-5 _Z_IL-_ 7~_-.Z-S 5 n a n A 5 A 5 A 5 9 n 9 D A n .~1.D f T 14 1 27.0 10.0 8.0 7.5 7.0 9.0 7.0 7.0 6.0 10.5 9.5 9.0 8.5 10.0 7.5 7.0 5.0 7 111 1 28 0 1 5 9 5 7.5 A 5 8 n 7 D 7 n 4 5 A 5 7 5 7_5 7_n 9_0 9 n 5_5 4.5 T 16 I 27.0 11.0 8.5 8.0 6.0 7.5 6.0 6.0 4.5 8.5 8.0 7.5 7.5 9.5 9.0 6.5 4.5 __ T 17 1 26_n 12-0_-a.5___6.5-. a•5.-_ I.n S 5 4 5 9 n A n 7.5 7 n O n 6_n -_5-5 4.0 T 18 1 25.0 9.0 8.0 5.0 6.5 8.5 7.0 6.5 4.5 8.5 8.0 7.5 7.5 L0.0 8.0 7.0 5.0 _ 7 19 1_24.-Q--L.5--8._0__._.3S_- 5.0_ _6.5__. 6.5 6_4~ n v n A 5 8 n 7 5 0_n 6_0 _y0 4.0 T 20 1 28.0 8.5 7.5 8.5 5.0 7.5 8.0 6.5 4.5 9.0 8.5 6.0 8.0 10.0 9.5 6.5 4.5 _ T 21 1 77.0 12 5 9 5 8_0 5_5 8.0 7.5 7_0 4 0 7 5 6 0 5 5 5 D 7 O 7.0 4 5 1_0 T 22 1 24.0 10.0 9.0 6.5 6.0 8.0 6.5 5.5 3.5 7.5 6.5 5.5 5.0 7.5 8.0 5.0 4.5 24.Il.-_ 2-5 A_D _ 6.5 7.5 .85-5 4_5 A_n 7_n 6_5 A_n a_n ln_n_ ..5.0_ 3.5 T 24 1 26.0 9.0 8.0 7.5 6.5 7.5 6.0 5.5 4.0 8.0 7.0 6.5 6.0 8.0 7.5 4.5 3.5 ._--115_._1. Z2.0 7.I1.-_5..0 ---fL.D . 7.0 _._a+0 6 ~5 4_5 A 5 7 S T n A 5 9 n 5..5... 3.5 T 26 1 25.0 6.5 9.0 9.0 8.0 9.5 7.0 5.0 3.0 7.0 5.5 5.0 5.0 7.5 8.0 5.0 4.0 T 27 1 JS n ID_n 11__5 7_S 5_5 7.5 h 5 S 5 A 5 A n 7 n 6 S A 5 a 5 7 n 5_5 4_0 _. T 28 1 27.0 9.0 11.0 9.0 7.0 8.5 T.0 6.0 4.0 8.0 7.0 7.0 7.0 9.0 8.5 6.5 4.5 _.L 29_._.-1- .28.D__1D.S- E.0_-._6-.5. .6.0._A.5-1.0- A n a 5 R D 7 5 7 5 7 5 ln n A .5 4.5 T 30 1 31.0 11.0 9.0 7.5 7.5 8.0 8.0 7.5 5.0 9.0 8.5 - 8.5 8.5 11.0 9.0 7.0 5.0 ._l-..26.0 _.10.11 - 7.5 . 7.0 _ 5.0 -.-LS--6..D_--6.D 4 0 7 5 A 5 e n A'n R n 7 n__5-5 4.5 T 32 1 24.0 10.5 7.5 6.5 6.0 7.0 6.5 6.0 4.0 8.0 6.5 5.5 5.5 7.0 7.0 4.5 3.5 7 iz 1 J n 9 0 T 5 7 n A 5 8 n 6 5 A 5 4 5 A n 1 A 5 6 D 5 5 A D 7_n 5_n 4_n MEAN----I _26.7 10.1 8.6 7.4 5.9 7.9 6.8 6.4 4.5 8.5 7.5 7.1 6.9 9.1 8.7 5.9 4.5 --------- -.-, -- ------ ---- VARIANCE I 4 3 1 1 1 0 0 0 0 0 0 0. 1 1 3 0 STAND. UEV. 1 2.0 1.9 1.4 1.1 1.0 .8 .7 .7 .6 .7 .8 .9 1.0 1.0 1.7 .8 .6 G. V. I 7.5 18.8 16.3 14.9 16.9 30.1 10.3 10.9 13.3 8.2 10.7 12.7 14.5 11.0 19.5 13.6 13.3 VON NEUMANN 1 5 6 3 3 2 1 1 1 1 1 1 1 1 1 5 1 1 RATIO U/V 1 1.24 1.57 1.52 2:16 1.80 1.43 2.04 2.00 2.08 1.72 1.39 1.15 0.97 0.93 1.56 1.39 2.17 FIGURE 11. Data and statistics as in FIGURE 9. 10-minute recording from same subject just after inhaling from a cigar for 10 minutes. . (i.5_ 7.5 - 7,-n A 0 9 5 R_ 5 7_ S 7_ 5 9.0 _$._5-_-_.-_ -. 7.0 7.5 7.0 4.5 8.5 8.5 7.5 7.5 5.0 8.5 7.0 6.5 6.5 5.5 9.0 7.D__-_5.L -5 5 4.5 8-D 8.0 7.0 6.5 5.0 9.0 _7..5_-. 7.D-7.5_.-s_5 9_D 8.0 5.5 6.0 4.5 8.0 8.0 1.5 8.0 7_0 8.0 s.D 7.0 7.5 1...0. 7.5 Z..S 8.0 B-.D 7.0 7.5 10.0 13.0 7.P 9.5 11-D 7.0 9.5 11.0 7.0 10-0 7.5 8.0 10.5 10.0 A 0 in-n 9.5 7.0 9.5 8.5 n 10 5 1~ n 7.0 4.5 6_5 4-5 6.5' 5.0 6_.0__ 4.5 7.5 6.0 5...0_-_ 5.0 5.5 4.0 7 5 5_5 TIMN 437082

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