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THE UNIVERSITY OF ROCHESTER MEDICAL CENTER 601 ELMWOOD AVENUE ROCHESTER. NEW YORK 14642 AREA CODE 716 SCHOOL OF MEDICINE AND DENTISTRY • SCHOOL OF NURSING STRONG MEMORIAL HOSPITAL DEPARTMEhT OF PHARMACOLC1G1 November 9, 1987 Ronald M. Davis, M.D. Director Office on Smoking and Health Center for Health Promotion and Education Rockville, MD 20857 Dear Dr. Davis: RE: Chapter II of Surgeon General's Report I have reviewed the manuscript edited by Neal Benowitz and find it, for the most part, satisfactory. I have made some minor modifications which are included in the body of the manuscript. The major criticism I have concerning Chapter II relates to the question of tolerance to nicotine. Although there are a number of studies indicating that tolerance to nicotine occurs in both humans and animals, there are frequently disagreements. With respect to behavioral and receptor binding studies in~rodents, little or no tolerance to nicotine-induced prostration following acute administration nicotine intraventricularly to rats chronically exposed to nicotine (1,2). Furthermore, no change was observed in the number or affinity of (-)- B-nicotine binding sites in brains of rats chronically exposed to nicotine (2,3). - It should be emphasized that although tolerance to the peripheral actions of nicotine appeas to develop in smokers, behavioral tolerance is far less evident. Once a smoker has overcome the initial adverse reactions to nicotine (nausea, dizziness, etc.) he is able to maintain satisfication with a relatively 101: level of nicotine (= 1 mg/cigarette) for indefinite periods. This pattern of drug use is quite different fromithat observed with truly addictive drugs, such as opiates, amphetamines, and barbiturates, where progressively increasing amounts are needed'to prevent abstinence or proviti- satisfaction. ~ It should also be noted that the phenomenon of tolerance is associated with virtuallyy every type of psychotropic agents: neuroleptics, anti- depressants, anti-muscarinics, muscle relaxants, and stimulants. Although drug dependence is associated with tolerance, the influence that tolerance is indicative of drug dependence is incorrect. 1

Ronald M. Davis, M.D. November 9, 1987 Page 2 Apropose to these comments, I quote from a prefatory chapter to a NIDA symposium which I wrote for a symposium entitled "Mechanisms of Tolerance and Dependence" (2). "Finally, there remains the problem of the criteria for determining whether a drug of abuse is addictive. Some might argue that any drug or substance which is abused, i.e., used compulsively, is addictive; in which case the term would be applicable to innumberable drugs, substances, and compulsive behavioral patterns. Since the degree or intensity of abuse varies greatly among drugs and substances, this definition requires a categorization in terms of their degree of addictive liability. The term "habitual", which is more generally used to describe compulsive tendencies, would be synonymous with "addictive". It may, however, be useful to reserve the term "addictive" for abused agents and tendencies exhibiting a "high degree" of compulsiveness. The problem would then be to define the psychophysical parameters associated with compulsive behavior and to decide arbitrarily when an agent is to be labeled "addictive". At the present state of our knowledge, the most characteristic psychophysical parameters associated with compulsive use of drugs are those resulting from either their abrupt withdrawal or administration or an appropriate antagonist. In the case of the opiates, barbiturates, amphetamines, and alcohol, the withdrawal signs are well-defined and severe; vhereas, with the cannabinoids and nicotine, they are not easily definable by physiological measures and tend to be far less severe. If the term "addictive" is reserved for those drugs promQting severe, definable withdrawal signs--often life-threatening in humans--the class of addictive drugs would be small; but, if the term is to be more generally applicable to abused drugs, it will be necessary to develop, in both animals and human models, the psychophysical, pharmacologic, and biochemical criteria for assessing their relative degree of compulsive liability." There are many other studies where tolerance to chronic administration of nieotine was not observed in animals.- Van Loon et al. (4) reported tht the administration of 0.1 mg/kg to rats for 7 days did not result in any diminution of adrenal catecholamine secretion on the seventh day. In studying the effects of chronic exposure to cigarette smoke on neuroendocrine function in the rat hypothalamus, it was observed that chronic exposure to cigarette smoke over a period of 9 days does not result in tolerance with regard to the ability of acute intermittent exposure to cigarette smoke to produce a reduction of serum levels of prolactin, LH. andiFSB (5). 2

,4 Ronald M. Davis, M.D. November 9, 1987 Page 3 1) Abood LG, Reynolds DT, Booth H and Bidlack JM. Sites and mechanisms for nicotine's action in the brain. Neurosci. Neurobehavior Reviews 5:479- 486, 1981. 2) Abood LG, Grassi S, Costanzo M and Junig J. Behavioral and biochemical studies in rats after chronic exposure to nicotine. NIDA Monograph 54:348-355, 1984. 3) Benwell MEM and Balfour DJK. Nicotine binding to brain tissue from drug-naive and nicotine-treated rats. J. Pharm. Pharmacol. 37:405-409, 1985. Van Loon GR, Kiritsy-Roy JA, Brown LV and Bobbi'tt FA. Nicotine regulation of sympathoadrenal catecholamine secretion in "Tobacco Smoking and Nicotine" eds. Martin WR, Van Loon GR, Iwamoto ET and Davis L. pp. 263-276, Plenum, NY, 1987. 5) Anderson K, Enroth P, Fuxe K, Mascagni F and Agnati LF. Effects of chronic exposure to cigarette smoke on amine levels and turnover to various hypothalamic catecholamine nerve terminal systems and the secretion of pituitary hormones in the male rat. Neuroendocrinology 41:462-466, 1985. Sincerely, ~ Leo G. Abood, Professor LGA!1v enclosure 3