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The pharmacology of anorexigenesis
Life Sciences Vol . 21, pp . 173-180, 1977 . Printed is the II .S .A .
Pergamoa Presa
MINIßEVISW THE PHARMACOLOGY OF ANOREXIGENESIS Roger P . Maickel and Joseph E . Zabik Section on Pharmacology Medical Sciences Program Indiana University Bloomington, IN 47401
There is no question that the clinical problem presenting as obesity has become a cortmon part of the daily practice of many physicians in the United States as well as in other countries . Rising prosperity and an elevated standard of living have increased the incidence of obesity in virtually all strata of the population . In a small percentage of the cases, obesity may be the result 'of some metabolic disorder or endocrine imbalance . However, in most cases, the increased body weight of the obese individual is the result of excessive food intake, oft coupled with a limited energy utilization . Thus, a reduction in the daily intake of nutrients with either a maintenance of prior energy utilization patterns, or even an increase in activity, should return the body fat content (and consequently, the body weight) of the obese individual to normal . Unfortunately, it is well known that rigid dietary restrictions are often only poorly followed by many obese individuals, since their pattern of excessive food intake may well be a form of habituation, or may be stimulated by some type of psychopathologic phenomena . Over the past 50 years, a number of approaches to the treatment of obesity have been utilized with more or less success . Since i
173
174
Pharmacology of Aaore~.geaesie
Vol . 21, No . 2, 1977
Food as a Controllin Influence . There seems to e no quest on t at a variety of factors, both metabolic (calories, fat, protein, carbohydrates) and senory (taste, smell, color, texture) have relevance to the quantity of food consumed in a given situation . The importance of metabolic characteristics of foodstuffs in relation to their constaription by the mammalian organism was reviewed some twenty years ago in a symposium (1) ; little has changed since then in this area as evidenced by a more recent symposium (2) . Similarly, the relative aspects of taste and other sensory factors in food intake have not changed significantly since the reviews by Hayashl (3) and Young (4) a decade ago . The Brain as a Controllin Influence . re an a a century ago, er and Sherrington (5) and Bazett and Penfield (6) showed that many simple feeding responses remain even after removal of much of the misencephalon and the more rostral portions of the brain, suggesting that some degree of satiety occurs, even at a reflex level . Since then, more than 250 reports have suggested that other brain centers, predominantly in the hypothalamus, play a major role in the control of food intake (7) . In particular, specific areas of the hypothalamus have been shown to exert unique and specific actions on food consumption by animals . Thus, Brobeck, et al (B) showed that lesions in the ventromedial hypothalamus cause overeating ân~Tc obesity, while Avand and Brobeck (9) demonstrated that lesions in the lateral hypothalamus . caused significant aphagia . Miller (10) subsequently showed that similar effects could be produced by electrical stimulation of discrete areas in these locales . Historical Develo ment of Anorexi enic A ents . n 940, r rtzmeta an es rst reported on the central nervous system actions of d-ar~hetamine, a representative of a new class of a-methyl phenylethylamines . This report followed by a few years the description of the use of dl-am hetamine as an aid in the treatment of obesity by Lesses and Meyerson (12~ . In the next 35 years, a host of compounds were developed for use as anorexigenic agents . The vast majority of these compounds were a-methylpher~ylethy amines or slight variations thereof, as can be seen from the structures presented in Figure 1 . In the course of development and use of these many agents, one unifying concept was that the anorexigenic action of the drugs, that is, their ability to reduce food consumption, was dependent upon their ability to cross the blood-brain barrier and enter the central nervous system, after any parenteral route of administratton . Thus, all of the structures shown in Figure 1 represent compounds with high partition ratios in the system benzene : pH 7 buffer . In fact, a closely related structure, p-hydroxyamphetamine, has a very similar spectrum of peripheral sympathomimetic potency to that of amphetamine but is virtually devoid of central stimulatory or anorectic activit since it does not possess the lipid solubility necessary to enter the brain (13~ . The majority of efforts in anorexigenic development have been aimed at reducing the undesirable stimulatory side effects of the drugs while maintaining their anorectic potency . However, since the developmental studies were generally performed in laboratory animals, conclusions directly relevant to human clinical situations have often been lacking . In addition, the variety of test systems used to measure CNS stimulatory action (open field, activity cages, operant systems, etc .), or~anorectic potency (decreased food consumption, lessened weight gain, etc .) in different species (mice, rats, dogs, rabbits) have made con~arisons of various agents difficult . This laboratory has recently published n comparative study of a number of anorexigenic agents in rats, using reduction of deprivatlon-induced food consumption as a measure of anorectic potency and increased response rate in a continuous avoidance responding system as a measure of CNS stimulatory potency (13) . The results separated the compounds tested into three groups on the basis of their actions on the avoidance responding
Vol. 21, No . 2, 1977
Pharmacology of Aaoreaigenesis
175
FIGURE 1
3 amphetamine
NHZ
C Nk 2
phentermine
aminoxaphen CH 3
C1 CH 3 methamphetamine
N chlorphentermine 0
H
CF3
CHZCH 3 fenfluramine CH3
C1
- CH2CH3 1 CH2CH3
diethylpropion 0
N-li
benzphetamine CH 3 NHp
3 "phenmetrazine _
mazindol
p-methylamphetamine CH3 phendimetrazine C1
Wi
NH2
p-chloramphetamine
paradigm : Inçreased Avoidances_ amtnoxaphen d-amphetamine p-chloramphetamine diethyl propion metha~hetamine phendimetrazine phenmetrazine phentermine
No Çhange benzphetamine chlorphentermine p-hydroxyamphetamine
Decreased Avoidances fenfluramine p-methyhamphetamine
176
Pharmacology of Aaoreaigeaesie
Vol . 21, No. 2, 1977
These results are basically in agreement with the clinical actions of these agents, except for the two drugs showing no change : benzphetamine and chlorphentermine . In man, benzphetamine has clear stimulatory side effects, although they are iess pronounced than equivalent anorectic doses of d-amphetamine (14,15) . In fact, some animal test systems indicate that benzphetamine increases spontaneous motor activity (16) while others do not (17) . Chlorphentermine has been reported to have an anorectic potency similar to that of d-amphetamine ; although it has some stimulatory actions in man, such side effects have been described as minimal in clinical situations (18,19) . Site s) of Action for Anorexigenesis . ss p~ y ment one , spec c rain areas in the lateral and ventromedial hypothalamus have been implicated in the control of food intake . Although the regulation of feeding behavior is a complex process involving integrative processing of information from a number of body systems, several specific points can be singled out as being of primary importance . As early as 1940 studies showed that obesity resulting from excessive food intake could be produced by placing electrolytic lesions in the ventromedial nucleus of the rat hypothalamus (20,21) . Conversely, Hoebel (22) has shown that electrical stimulation to this area leads to anorexia, aphagia, weight loss, and even starvation . As a result of these, and other, studies, the ventromedial nucleus of the hypothalamus has been assigned the role of a "satiety center" in the brain . It appears to be an area concerned with the inhibition of feeding behavior ; thus a damaged ventromedial nucleus would prevent an animal from "knowing when to stop eating," and would result in hyperphagia and consequently, obesity . In 1951, Avand and Brobeck (9) reported that bilateral electrolytic lesions placed in the lateral nucleus of the hypothalamus caused the animals to virtually cease all food intake, even to,the point of starvation . More recently, Patton (23) demonstrated a dramatic reduction in feeding behavior in animals with implanted electrodes permitting electrical stimulation of the lateral nucleus . As a result of studies such as these, the lateral nucleus of the hypothalamus has been assigned the role of a "feeding center ." That is to say, this area appears to have an ability to elicit feeding behavior in a positive manner ; furthermore, it would appear that the lateral nucleus is the dominant center of the two, with the ventromedial nucleus acting as a modifier of overall feeding activity (23,24) . It must also be recognized that other brain areas have also been implicated For example, in various ways in the control of eating behavior in mammals . Grossman (25) has reported that lesions of the amygdala can lead to a state of aphagia in a variety of mammalian species . Although this report is in opposition to that of Fulton (26) who found that amygdaloid lesiôns in monkeys elicited hyperphagia, such findings must be considered in the light of knowledge that the art~ygdala may well interact with both thé lateral and ventromedial nuclei of the hypothalamus through the stria terminalis and the ventral amygdalofugal nerves . Since the midbrain is capable of exerting significant influences on the hypothalamus through the medial forebrain bundle, it is not surprising to find that Collins (27) reported lesions of the midbrain tegmentum produce a mild aphagia, while electrical stimulation of this area facilitates existing feeding behavior . More recently, I~yrwicka and Dot (28) have reported hyperphagia after midbrain lesions, while Skultety (29~ found a similar effect resulting from midbrain stimulation . The septum can also act on the appetite regulating centers of the hypothalamus through the medial forebrain bundle (2) . Thus, electrical stimulation of the septum has been shown to elicit feeding behavior
Vol . 21, No . 2, 1977
Pharmacology of Aaora~d.geneeis
177
30), while septal lestons have been shown to produce a modest hyperphagia 31,32) . Bio enic Amines and Anorexl enesis ._ wo actors ave co ne to v r ually assure the participation of brain biogenic amines, especially catecholamines and indolealkylamines, in some way in the processes involved in feeding behavior and its supression by anorexigeniç agents . First of all, the hypothalamus is known to be rich in neuronal pathways utilizing NE and 5HT (33) ; these biogenic amines are known to be sensitive to compounds that influence biogenic amine stores and feeding behavior, such as the p-halogenated phenylethylamines (34) . Secondly, a variety of actions of anorexigenic agents such as d-amphetamine are altered by other drugs or by agents that perturb biogenic amine stores . For example, reduction of rat brain NE levels by pretreatment with aMT changed the action of a subsequent dose of d-amphetamine an rat continuous avoidance behavior from that of a stimulant to that of a depressant ; such pretreatment had no effect on the stimulatory actions of p-chloroamphetamines (35) . Even within the class of anorectic agents, differences are seen . Thus, aMT pretreatment had no effect on the anorectic action of a single dose of d-amphetamine, although the stimulant action was reduced ; a similar pretreatment was without effect on either the stimulant or anorectic actions of benzphetamine (36) . An extensive study by C1lneschmidt, et al (37) has reported the effects of various pretreatment regimens on theânôrectic actions of d-amphetamine, p-chlormethamphetamine, and fenfluramine . The authors concluded that the anorectic effect of p-chloromethart~hetamine did not involve the same biogenic pathwa s as either d-amphetamine (which they consider to act throw h catecholamines or fenfluramine (which they consider to act through serotonin~ ; close inspection of their data indicates that their conclusions may be only weakly supported . Nevertheless, other work has implicated brain NE in the anorectic activity of d-amphetamine (38), brain 5HT in the anorectic activity of fenfluramine (39), and brain dopamine in the anorectic activity of mazindol (40) . _Relevant Clinical Questions . Per aps t most s gn~fi`~rit aspects of the overall problem of anorexigenesis are those related to the clinical utilization of such agents . As recently as 1959, Stunkard and McLaren-Hums (41), in reviewing the field of treatment of obesity, stated "Most obese persons will not enter treatment, of those who do enter treatment most will not lose weight, of those who do lose weight most will regain it ." While the situation has improved somewhat since that rather pessimistic summary, the clinical use of anorectic agents remains a major problem . The uses and abuses of appetite suppressants, the problems of tolerance and .dependence, and the difficulties of m~in~aini patients gn a lann~d weightreduction schedule are well known, not on y n th~~3 country, ut t~roug out the world (42,43) . In addition to problems and questions of efficacy, especially in terms of chronic or repetitive usage, there is no doubt that the anorexigenic agents represent a class of drugs with a high incidence of _unp_leasant or even undesirable side effects . Certainly, at the present time, it would be difficult, if not impossible to categorize any agent s) as best - rather, it is more practical to consider which are "least worst"l Overview and Look to the Future . er aps t e st way to conc u e this review is to consider what must be done to develop a safe and effective agent for the control of body weight . Obviously, what has been done to date has been only moderately successful . Several specific considerations need to be made in art attempt to point out obvious problems and to characterize the complexity of the situation . First of all, studies of the effects of lesions of specific brain areas or of electrical stimulation of various brain centers are of only limited value in
17 8
Pharmacology of Anorerigeneais
Vol . 21, No . 2, 1977
terms of designing anorectic agents . This is not to say that such studies will not yield additional information regarding the neuroanatomical bases for hunger, satiety, and feeding behavior . However, in terms of drug administration in the clinical situation, it must be recognized that the brain distribution of an agent administered ~er os will be relatively uniform, and thus .stimulation may occur in one geograpTÜ~ area and repression in another. Secondly, a better understanding of the neurobiochemistry of hunger and satiety most be obtained . Such information can only be gained by appropriately designed experiments, confirmed in several species, and clearly indicative of the relative roles of specific biogenic amine systems in the anorexigenic effect as well as in the side effects of any given agent . Again, the non-specificity of drug distribution within the brain cannot be ignored . Finally, new approaches to the control of body weight by chemical therapeutic agents must be considered . The "me too" approach, creating merely new and slightly different amphetamines must be discarded . Perhaps the solution to the problem of obesity caused by excessive food intake must be sought in areas other than that of merely repressing food consur~tion . For example, the possibilities of altering patterns of food consumption, decreasing caloric substrate conversion to fat, or producing increased turnover and usage of adipose tissue triglycerides may be fruitful directions for research to take in the pharmacological control of obesity . Certainly, much remains to be done . References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 . 23 . ?.4 . 25 .
F. Hollander (ed.j, Ann . N .Y . Acad . Sci . 63 1-44 (1955) . P. J . Morgane (ed .), Ann. N.Y . Acad . Sci .,f47 1-1216 (1969) . T. Hayashi (ed .), Olfaction and Taste, Vol-TI ., Pergamon Press, New York, 835 pp . (1967) . P . T. Young, Psychol . Rev. 73 59-86 (1966) . F. R. Miller and C : S. Sherr~ngton, Quart . J . Exptl . Physiol . 9 147-156 (1916) . H . C . Bazett and W. G. Ppnfield, Brain 45 185-197 (1922) . S . P . Grossman, A Textbook of P siolo mal Ps cholo ,John Wiley & Sons, New York, 932 pp " J . R. Brobeck, J . Tepperman and C. N . H. Long, Yale J . Biol . Med. 15 831-853 (1947) . B . K. Anand and J. R. Brobeck, Yale J . Biol . Med . _24 123-140 (1951) . N . E . Miller ; Fed . Proc . 19 846-854 (1960) . M . Prinzmetal and G. Allés, Amer . J . Med . Sci . 20 0 665-673 (1940) . M . F. Lesses and A . Meyerson, New Engl . J . Med.~T8 119-124 (1938) . R . H . Cox, Jr . and R. P . Maickel, J . Pharmacol . 1:p. Therap . 181 1-9 (1972) . H . Oster and R. Medlar, Ariz . Med . 17 398-404 (1960) . B. Simkin and L . Wallace, Curr . Therâp . Res . 2 33-38 (1960) . W. Veldkamp, A. P . Tazelaar, W . A . Freyburgerând H. H. Keasling, Toxicol . Appl . Pharmacol . 6 15-22 (1964) . R . P . Maickel and A. Johnson; Res . Comm . Chem . Pathol . Pharmacol . _6 733-740 (1973) . J . Levin, J .A .P . Trafford, P . M . Newland and P .M .F . Bishop, Practitioner 191 65-69 (1963) . . C Lucey and D . R. Hadden, Ulster Med. J. 31 181-184 (1962) . A. W . Hetherington and S. W. Ranson, Anat .~ec . 78 149-172 (1940) . A. W . Hetherington and S. W. Ranson, J . Comp . Neûrol . _76 475-499 (1942) . B. G. Hoebel, Ann . N . Y . Acad . Sci . 15 7 758-778 (1969) H. D. Patton, in T . C . Ruch and H. D~atton (eds .) Physiology and Biophysics, 19th Edition, W. B. Saunders, Philadelphia, pp . 247-249 (1966) . J .A .F . Stevenson, Ann . N.Y . Acad . Sci . 15 7 1069-1083 (1969) . S.P . Grossman, Adv. Psychosomat. Med. 7âS72 (1972) .
S.
Vol . 21, No . 2, 1977 26 . 27 . 28 . 29 . 30 . 31 . 32 . 33 . 34 . 35 . 36 . 37 . 38 . ~39 . 40 . 41 . 42 . 43 .
Pharmacology of Anoreaigeneaie
179
J .F . Fulton, Frontal Lobot and Affective Behavior, W . W . Norton Co ., New York, pp . 78-82 95 E . Collins, J . Comp . Neural . 100 661-697 (1954) . W . Wyrwicka and R . W . Doty, Exp. Brain Res . 1 152-160 (1966) . F . M . Skultety, Ann . N .Y . Acad . Sci . 15 7 861=$74 (1969) . B . W . Robinson and M . Mishkin, SciencéT36 260-262 (1962) . S . A . Lorens and C . Y . Kondo, Physiol . ana Behavior 4 729-732 (1969) . D . Singh and D . R . Meyer, J . Comp . Physiol . Psychol . 6 5 163-166 (1968) . J . R . Cooper, F . E . Bloom and R . H . Roth, The Biochem~al Basics of Neuropharmacology, 2nd Edition, Oxford Univ . Press, New York, 272 pp . (1974) . F . P . Miller, R . H . Cox, Jr ., W . R . Snodgrass and R . P . Maickel, Biochem . Pharmacol . 19 435-442 (1970) . F . P . Miller, R . H . Cox, Jr . and R . P . Maickel, Neuropharmacol . _9 511-517 (1970) . R . H . Cox,'Jr . and R . P . Maickel, Res . Comm . Chem . Pathol . Pharmacol . _12 621-626 (1975) . B . V . Clineschmidt, J . C . Mc6uffin and A . B . Werner, Europ . J . Pharmacol . 27 313-323 (1974) . G . Holtzman and R . E . Jewett, Psychopharmacologie 22 151-167 (1971) . S . Garattini, W . Buczko, A . Jori and R. Samanin, Postgrad . Med . J . 51(Suppl . 1), 27-35 (1975) . J . H . Gogerty, C . Penberthy, L . C . Iorio,..and J . H . Trapold, Arch . Int . Pharmacodyn . Ther . 214(2) 285-307 (1975) . A . I . Stunkard and 1~McLaren -Hume, Arch . Intern . Med . 103 79-85 (1959) . D . A . Seaton and L . J . P . Duncan ; Brit . J . Clin . Practic~_9 89-93 (1965) . A . Levin, Postgrad . Med . J . 51 (Suppl . 1), 186-188 (1975) .
~:
Pergamoa Presa
MINIßEVISW THE PHARMACOLOGY OF ANOREXIGENESIS Roger P . Maickel and Joseph E . Zabik Section on Pharmacology Medical Sciences Program Indiana University Bloomington, IN 47401
There is no question that the clinical problem presenting as obesity has become a cortmon part of the daily practice of many physicians in the United States as well as in other countries . Rising prosperity and an elevated standard of living have increased the incidence of obesity in virtually all strata of the population . In a small percentage of the cases, obesity may be the result 'of some metabolic disorder or endocrine imbalance . However, in most cases, the increased body weight of the obese individual is the result of excessive food intake, oft coupled with a limited energy utilization . Thus, a reduction in the daily intake of nutrients with either a maintenance of prior energy utilization patterns, or even an increase in activity, should return the body fat content (and consequently, the body weight) of the obese individual to normal . Unfortunately, it is well known that rigid dietary restrictions are often only poorly followed by many obese individuals, since their pattern of excessive food intake may well be a form of habituation, or may be stimulated by some type of psychopathologic phenomena . Over the past 50 years, a number of approaches to the treatment of obesity have been utilized with more or less success . Since i
173
174
Pharmacology of Aaore~.geaesie
Vol . 21, No . 2, 1977
Food as a Controllin Influence . There seems to e no quest on t at a variety of factors, both metabolic (calories, fat, protein, carbohydrates) and senory (taste, smell, color, texture) have relevance to the quantity of food consumed in a given situation . The importance of metabolic characteristics of foodstuffs in relation to their constaription by the mammalian organism was reviewed some twenty years ago in a symposium (1) ; little has changed since then in this area as evidenced by a more recent symposium (2) . Similarly, the relative aspects of taste and other sensory factors in food intake have not changed significantly since the reviews by Hayashl (3) and Young (4) a decade ago . The Brain as a Controllin Influence . re an a a century ago, er and Sherrington (5) and Bazett and Penfield (6) showed that many simple feeding responses remain even after removal of much of the misencephalon and the more rostral portions of the brain, suggesting that some degree of satiety occurs, even at a reflex level . Since then, more than 250 reports have suggested that other brain centers, predominantly in the hypothalamus, play a major role in the control of food intake (7) . In particular, specific areas of the hypothalamus have been shown to exert unique and specific actions on food consumption by animals . Thus, Brobeck, et al (B) showed that lesions in the ventromedial hypothalamus cause overeating ân~Tc obesity, while Avand and Brobeck (9) demonstrated that lesions in the lateral hypothalamus . caused significant aphagia . Miller (10) subsequently showed that similar effects could be produced by electrical stimulation of discrete areas in these locales . Historical Develo ment of Anorexi enic A ents . n 940, r rtzmeta an es rst reported on the central nervous system actions of d-ar~hetamine, a representative of a new class of a-methyl phenylethylamines . This report followed by a few years the description of the use of dl-am hetamine as an aid in the treatment of obesity by Lesses and Meyerson (12~ . In the next 35 years, a host of compounds were developed for use as anorexigenic agents . The vast majority of these compounds were a-methylpher~ylethy amines or slight variations thereof, as can be seen from the structures presented in Figure 1 . In the course of development and use of these many agents, one unifying concept was that the anorexigenic action of the drugs, that is, their ability to reduce food consumption, was dependent upon their ability to cross the blood-brain barrier and enter the central nervous system, after any parenteral route of administratton . Thus, all of the structures shown in Figure 1 represent compounds with high partition ratios in the system benzene : pH 7 buffer . In fact, a closely related structure, p-hydroxyamphetamine, has a very similar spectrum of peripheral sympathomimetic potency to that of amphetamine but is virtually devoid of central stimulatory or anorectic activit since it does not possess the lipid solubility necessary to enter the brain (13~ . The majority of efforts in anorexigenic development have been aimed at reducing the undesirable stimulatory side effects of the drugs while maintaining their anorectic potency . However, since the developmental studies were generally performed in laboratory animals, conclusions directly relevant to human clinical situations have often been lacking . In addition, the variety of test systems used to measure CNS stimulatory action (open field, activity cages, operant systems, etc .), or~anorectic potency (decreased food consumption, lessened weight gain, etc .) in different species (mice, rats, dogs, rabbits) have made con~arisons of various agents difficult . This laboratory has recently published n comparative study of a number of anorexigenic agents in rats, using reduction of deprivatlon-induced food consumption as a measure of anorectic potency and increased response rate in a continuous avoidance responding system as a measure of CNS stimulatory potency (13) . The results separated the compounds tested into three groups on the basis of their actions on the avoidance responding
Vol. 21, No . 2, 1977
Pharmacology of Aaoreaigenesis
175
FIGURE 1
3 amphetamine
NHZ
C Nk 2
phentermine
aminoxaphen CH 3
C1 CH 3 methamphetamine
N chlorphentermine 0
H
CF3
CHZCH 3 fenfluramine CH3
C1
- CH2CH3 1 CH2CH3
diethylpropion 0
N-li
benzphetamine CH 3 NHp
3 "phenmetrazine _
mazindol
p-methylamphetamine CH3 phendimetrazine C1
Wi
NH2
p-chloramphetamine
paradigm : Inçreased Avoidances_ amtnoxaphen d-amphetamine p-chloramphetamine diethyl propion metha~hetamine phendimetrazine phenmetrazine phentermine
No Çhange benzphetamine chlorphentermine p-hydroxyamphetamine
Decreased Avoidances fenfluramine p-methyhamphetamine
176
Pharmacology of Aaoreaigeaesie
Vol . 21, No. 2, 1977
These results are basically in agreement with the clinical actions of these agents, except for the two drugs showing no change : benzphetamine and chlorphentermine . In man, benzphetamine has clear stimulatory side effects, although they are iess pronounced than equivalent anorectic doses of d-amphetamine (14,15) . In fact, some animal test systems indicate that benzphetamine increases spontaneous motor activity (16) while others do not (17) . Chlorphentermine has been reported to have an anorectic potency similar to that of d-amphetamine ; although it has some stimulatory actions in man, such side effects have been described as minimal in clinical situations (18,19) . Site s) of Action for Anorexigenesis . ss p~ y ment one , spec c rain areas in the lateral and ventromedial hypothalamus have been implicated in the control of food intake . Although the regulation of feeding behavior is a complex process involving integrative processing of information from a number of body systems, several specific points can be singled out as being of primary importance . As early as 1940 studies showed that obesity resulting from excessive food intake could be produced by placing electrolytic lesions in the ventromedial nucleus of the rat hypothalamus (20,21) . Conversely, Hoebel (22) has shown that electrical stimulation to this area leads to anorexia, aphagia, weight loss, and even starvation . As a result of these, and other, studies, the ventromedial nucleus of the hypothalamus has been assigned the role of a "satiety center" in the brain . It appears to be an area concerned with the inhibition of feeding behavior ; thus a damaged ventromedial nucleus would prevent an animal from "knowing when to stop eating," and would result in hyperphagia and consequently, obesity . In 1951, Avand and Brobeck (9) reported that bilateral electrolytic lesions placed in the lateral nucleus of the hypothalamus caused the animals to virtually cease all food intake, even to,the point of starvation . More recently, Patton (23) demonstrated a dramatic reduction in feeding behavior in animals with implanted electrodes permitting electrical stimulation of the lateral nucleus . As a result of studies such as these, the lateral nucleus of the hypothalamus has been assigned the role of a "feeding center ." That is to say, this area appears to have an ability to elicit feeding behavior in a positive manner ; furthermore, it would appear that the lateral nucleus is the dominant center of the two, with the ventromedial nucleus acting as a modifier of overall feeding activity (23,24) . It must also be recognized that other brain areas have also been implicated For example, in various ways in the control of eating behavior in mammals . Grossman (25) has reported that lesions of the amygdala can lead to a state of aphagia in a variety of mammalian species . Although this report is in opposition to that of Fulton (26) who found that amygdaloid lesiôns in monkeys elicited hyperphagia, such findings must be considered in the light of knowledge that the art~ygdala may well interact with both thé lateral and ventromedial nuclei of the hypothalamus through the stria terminalis and the ventral amygdalofugal nerves . Since the midbrain is capable of exerting significant influences on the hypothalamus through the medial forebrain bundle, it is not surprising to find that Collins (27) reported lesions of the midbrain tegmentum produce a mild aphagia, while electrical stimulation of this area facilitates existing feeding behavior . More recently, I~yrwicka and Dot (28) have reported hyperphagia after midbrain lesions, while Skultety (29~ found a similar effect resulting from midbrain stimulation . The septum can also act on the appetite regulating centers of the hypothalamus through the medial forebrain bundle (2) . Thus, electrical stimulation of the septum has been shown to elicit feeding behavior
Vol . 21, No . 2, 1977
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30), while septal lestons have been shown to produce a modest hyperphagia 31,32) . Bio enic Amines and Anorexl enesis ._ wo actors ave co ne to v r ually assure the participation of brain biogenic amines, especially catecholamines and indolealkylamines, in some way in the processes involved in feeding behavior and its supression by anorexigeniç agents . First of all, the hypothalamus is known to be rich in neuronal pathways utilizing NE and 5HT (33) ; these biogenic amines are known to be sensitive to compounds that influence biogenic amine stores and feeding behavior, such as the p-halogenated phenylethylamines (34) . Secondly, a variety of actions of anorexigenic agents such as d-amphetamine are altered by other drugs or by agents that perturb biogenic amine stores . For example, reduction of rat brain NE levels by pretreatment with aMT changed the action of a subsequent dose of d-amphetamine an rat continuous avoidance behavior from that of a stimulant to that of a depressant ; such pretreatment had no effect on the stimulatory actions of p-chloroamphetamines (35) . Even within the class of anorectic agents, differences are seen . Thus, aMT pretreatment had no effect on the anorectic action of a single dose of d-amphetamine, although the stimulant action was reduced ; a similar pretreatment was without effect on either the stimulant or anorectic actions of benzphetamine (36) . An extensive study by C1lneschmidt, et al (37) has reported the effects of various pretreatment regimens on theânôrectic actions of d-amphetamine, p-chlormethamphetamine, and fenfluramine . The authors concluded that the anorectic effect of p-chloromethart~hetamine did not involve the same biogenic pathwa s as either d-amphetamine (which they consider to act throw h catecholamines or fenfluramine (which they consider to act through serotonin~ ; close inspection of their data indicates that their conclusions may be only weakly supported . Nevertheless, other work has implicated brain NE in the anorectic activity of d-amphetamine (38), brain 5HT in the anorectic activity of fenfluramine (39), and brain dopamine in the anorectic activity of mazindol (40) . _Relevant Clinical Questions . Per aps t most s gn~fi`~rit aspects of the overall problem of anorexigenesis are those related to the clinical utilization of such agents . As recently as 1959, Stunkard and McLaren-Hums (41), in reviewing the field of treatment of obesity, stated "Most obese persons will not enter treatment, of those who do enter treatment most will not lose weight, of those who do lose weight most will regain it ." While the situation has improved somewhat since that rather pessimistic summary, the clinical use of anorectic agents remains a major problem . The uses and abuses of appetite suppressants, the problems of tolerance and .dependence, and the difficulties of m~in~aini patients gn a lann~d weightreduction schedule are well known, not on y n th~~3 country, ut t~roug out the world (42,43) . In addition to problems and questions of efficacy, especially in terms of chronic or repetitive usage, there is no doubt that the anorexigenic agents represent a class of drugs with a high incidence of _unp_leasant or even undesirable side effects . Certainly, at the present time, it would be difficult, if not impossible to categorize any agent s) as best - rather, it is more practical to consider which are "least worst"l Overview and Look to the Future . er aps t e st way to conc u e this review is to consider what must be done to develop a safe and effective agent for the control of body weight . Obviously, what has been done to date has been only moderately successful . Several specific considerations need to be made in art attempt to point out obvious problems and to characterize the complexity of the situation . First of all, studies of the effects of lesions of specific brain areas or of electrical stimulation of various brain centers are of only limited value in
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terms of designing anorectic agents . This is not to say that such studies will not yield additional information regarding the neuroanatomical bases for hunger, satiety, and feeding behavior . However, in terms of drug administration in the clinical situation, it must be recognized that the brain distribution of an agent administered ~er os will be relatively uniform, and thus .stimulation may occur in one geograpTÜ~ area and repression in another. Secondly, a better understanding of the neurobiochemistry of hunger and satiety most be obtained . Such information can only be gained by appropriately designed experiments, confirmed in several species, and clearly indicative of the relative roles of specific biogenic amine systems in the anorexigenic effect as well as in the side effects of any given agent . Again, the non-specificity of drug distribution within the brain cannot be ignored . Finally, new approaches to the control of body weight by chemical therapeutic agents must be considered . The "me too" approach, creating merely new and slightly different amphetamines must be discarded . Perhaps the solution to the problem of obesity caused by excessive food intake must be sought in areas other than that of merely repressing food consur~tion . For example, the possibilities of altering patterns of food consumption, decreasing caloric substrate conversion to fat, or producing increased turnover and usage of adipose tissue triglycerides may be fruitful directions for research to take in the pharmacological control of obesity . Certainly, much remains to be done . References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 . 23 . ?.4 . 25 .
F. Hollander (ed.j, Ann . N .Y . Acad . Sci . 63 1-44 (1955) . P. J . Morgane (ed .), Ann. N.Y . Acad . Sci .,f47 1-1216 (1969) . T. Hayashi (ed .), Olfaction and Taste, Vol-TI ., Pergamon Press, New York, 835 pp . (1967) . P . T. Young, Psychol . Rev. 73 59-86 (1966) . F. R. Miller and C : S. Sherr~ngton, Quart . J . Exptl . Physiol . 9 147-156 (1916) . H . C . Bazett and W. G. Ppnfield, Brain 45 185-197 (1922) . S . P . Grossman, A Textbook of P siolo mal Ps cholo ,John Wiley & Sons, New York, 932 pp " J . R. Brobeck, J . Tepperman and C. N . H. Long, Yale J . Biol . Med. 15 831-853 (1947) . B . K. Anand and J. R. Brobeck, Yale J . Biol . Med . _24 123-140 (1951) . N . E . Miller ; Fed . Proc . 19 846-854 (1960) . M . Prinzmetal and G. Allés, Amer . J . Med . Sci . 20 0 665-673 (1940) . M . F. Lesses and A . Meyerson, New Engl . J . Med.~T8 119-124 (1938) . R . H . Cox, Jr . and R. P . Maickel, J . Pharmacol . 1:p. Therap . 181 1-9 (1972) . H . Oster and R. Medlar, Ariz . Med . 17 398-404 (1960) . B. Simkin and L . Wallace, Curr . Therâp . Res . 2 33-38 (1960) . W. Veldkamp, A. P . Tazelaar, W . A . Freyburgerând H. H. Keasling, Toxicol . Appl . Pharmacol . 6 15-22 (1964) . R . P . Maickel and A. Johnson; Res . Comm . Chem . Pathol . Pharmacol . _6 733-740 (1973) . J . Levin, J .A .P . Trafford, P . M . Newland and P .M .F . Bishop, Practitioner 191 65-69 (1963) . . C Lucey and D . R. Hadden, Ulster Med. J. 31 181-184 (1962) . A. W . Hetherington and S. W. Ranson, Anat .~ec . 78 149-172 (1940) . A. W . Hetherington and S. W. Ranson, J . Comp . Neûrol . _76 475-499 (1942) . B. G. Hoebel, Ann . N . Y . Acad . Sci . 15 7 758-778 (1969) H. D. Patton, in T . C . Ruch and H. D~atton (eds .) Physiology and Biophysics, 19th Edition, W. B. Saunders, Philadelphia, pp . 247-249 (1966) . J .A .F . Stevenson, Ann . N.Y . Acad . Sci . 15 7 1069-1083 (1969) . S.P . Grossman, Adv. Psychosomat. Med. 7âS72 (1972) .
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J .F . Fulton, Frontal Lobot and Affective Behavior, W . W . Norton Co ., New York, pp . 78-82 95 E . Collins, J . Comp . Neural . 100 661-697 (1954) . W . Wyrwicka and R . W . Doty, Exp. Brain Res . 1 152-160 (1966) . F . M . Skultety, Ann . N .Y . Acad . Sci . 15 7 861=$74 (1969) . B . W . Robinson and M . Mishkin, SciencéT36 260-262 (1962) . S . A . Lorens and C . Y . Kondo, Physiol . ana Behavior 4 729-732 (1969) . D . Singh and D . R . Meyer, J . Comp . Physiol . Psychol . 6 5 163-166 (1968) . J . R . Cooper, F . E . Bloom and R . H . Roth, The Biochem~al Basics of Neuropharmacology, 2nd Edition, Oxford Univ . Press, New York, 272 pp . (1974) . F . P . Miller, R . H . Cox, Jr ., W . R . Snodgrass and R . P . Maickel, Biochem . Pharmacol . 19 435-442 (1970) . F . P . Miller, R . H . Cox, Jr . and R . P . Maickel, Neuropharmacol . _9 511-517 (1970) . R . H . Cox,'Jr . and R . P . Maickel, Res . Comm . Chem . Pathol . Pharmacol . _12 621-626 (1975) . B . V . Clineschmidt, J . C . Mc6uffin and A . B . Werner, Europ . J . Pharmacol . 27 313-323 (1974) . G . Holtzman and R . E . Jewett, Psychopharmacologie 22 151-167 (1971) . S . Garattini, W . Buczko, A . Jori and R. Samanin, Postgrad . Med . J . 51(Suppl . 1), 27-35 (1975) . J . H . Gogerty, C . Penberthy, L . C . Iorio,..and J . H . Trapold, Arch . Int . Pharmacodyn . Ther . 214(2) 285-307 (1975) . A . I . Stunkard and 1~McLaren -Hume, Arch . Intern . Med . 103 79-85 (1959) . D . A . Seaton and L . J . P . Duncan ; Brit . J . Clin . Practic~_9 89-93 (1965) . A . Levin, Postgrad . Med . J . 51 (Suppl . 1), 186-188 (1975) .
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