Download Serotonin and Food Intake: An Overview of Experimental Research and Clinical Implications and more Study notes Neurobiology in PDF only on Docsity!
NeurophnrmacologyVol. 23, No. 12B,pp. 1537-1551, Printed in Great Britain
0028-3908/84$3.00+ 0. Pergamon Press Ltd
SEROTONIN AND APPETITE
J. E. BLUNDELL
Biopsychology Group, Psychology Department, University of Leeds, University of Leeds, Leeds LS2 9JT, England
- GENERAL BACKGROUNDTO REVIEW
1.1. Introduction
The proposition that serotonin may be involved in the control of intake of food and the expression of appetite is less than 10 years old. Indeed, in a 600 page anthology of serotonin and behaviour published in 1973 (Barchas and Usdin, 1973) neither feeding behaviour nor food intake were included in the subject index. This late development of the link between serotonin and feeding is surprising. First, serotonin systems occupy a strategic anatomical location, projecting to and coursing through hypo- thalamic zones (Azmitia, 1978), where they could be expected to contribute to the dramatic changes in food consumption and body weight following experimentally-induced hypothalamic damage. Sec- ond, serotonergic neurones are widely distributed in the gut (Gershon and Dreyfus, 1977; Ahlman, 1976; Fozard, 1984) where modifications of gastrointestinal functioning would give rise to repercussions in feed- ing activity. Although the earliest conceptualisations of neurochemical models of feeding control empha- sised noradrenaline (Grossman, 1962; Booth, 1967) or dopamine (Ungerstedt, 1971; Marshall, Rich- ardson and Teitelbaum, 1974) more recently two reviews have been specifically devoted to the role of serotonin (Blundell, 1977, 1979), whilst other reviews have given considerable attention to the issue (Hoe- bel, 1977; Coscina, 1977; Leibowitz, 1980) or have dealt with specialised aspects (e.g. Garattini, 1978). There is now no doubt that certain experimental manipulations of serotonergic metabolism produce marked effects on food consumption and less potent effects on other aspects of feeding behaviour. Do these results mean that some serotonin-containing neurones play a role in the natural regulatory system which serves to match an organism’s nutritional intake to its bodily requirements? The present review will draw together recent research findings and sug- gest an appropriate interpretation of the data. It should be mentioned immediately that research on serotonin and feeding is progressing only gradually and has not yet been embraced by work on the characterisation of receptor subtypes. There appear to be two reasons for this. First, researchers have been preoccupied with establishing the validity and reliability of the basic relationship between serotonin
adjustments and food intake. Second, there has been a concern to verify that any relationship involves a rational link between nutritional factors and neu- rochemical systems and is not dependent upon the mediation of a third factor such as changes in tem- perature, arousal or sedation. It is appropriate that a settlement of these methodological issues should precede the investigation of any association between feeding and a particular sub-type.
1.2. Summary Research over the last 10 years has given rise to a particular pattern of findings and is characterised by certain clear trends. It is appropriate to state these clearly as a basis for the present examination of the field. The most striking and consistent effect is the suppression of food intake by experimental treat- ments which directly or indirectly activate serotonin receptors. There appears to be no exception (pub- lished in the literature) to this general rule. Consequently, activation of serotonin pathways or metabolism is a suficient, though of course not a necessary, condition for the inhibition of food intake in experimental test situations. The converse of this effect, an increase in food intake resulting from an inhibition of serotonin metabolism or a blockade of receptors, is a much weaker phenomenon though it can be detected under suitable experimental circum- stances. There are both theoretical and meth- odological reasons why an increase in food intake is a more elusive phenomenon than an anorexic action (see Blundell, 1981a for a discussion of this issue). One parsimonious interpretation of the effects of serotonin-induced manipulations of food intake is that certain serotonin-containing neurones and path- ways mediate in the process of satiation (bringing an eating episode to a halt) and maintain the state of satiety (period of inhibition over further eating). One further research theme in the field of serotonin and appetite concerns the proposal that serotonin- containing neurones may be involved in the selection of particular nutritional commodities, such as protein or carbohydrate, and in the expression of preferences for these macronutrients. The evidence for this hy- pothesis arises from experiments on nutritional ma- nipulations and changes in dietary self-selection fol- lowing experimental interventions in serotonin systems. Considerable methodological and technical 1537
1538 J. E. BLUNDELL
problems confront experimentation on dietary self- selection and nutrient intake (see Blundell, 1983 for review) and it is not surprising that there is disagree- ment between different research findings. An important aspect of research on serotonin and feeding is the relative contributions of central and peripheral serotonin stores. In many studies treat- ments have been used which influence both aspects simultaneously and it appears that changes in feeding can come about after interventions in either the brain or the periphery. These brief summarising comments have been set down at this stage in order to draw attention to the major issues and to serve as a focus for the review and for the development of future research.
1.3. Clinical implications At this stage research is still directed toward estab- lishing a functional role of endogenous serotonin systems in the control of food intake. Even if there is not complete unanimity of opinion on this issue certain empirical facts are clear; pharmacological manipulation with serotoninergic drugs gives rise to both dramatic and subtle effects on feeding. Accord- ingly, such drugs can be used clinically to assist in the management of certain types of feeding disorders. Drugs for the inhibition of eating are used in the management of obesity and may find a use in the treatment of binge eating episodes which represent a major symptom of the condition named bulimia nervosa (Russell, 1979). Drugs which augment eating have been used in the treatment of anorexia nervosa (Benady, 1970), and agents which influence nutrient preferences, such as the desire for protein or carbo- hydrate, could be used in the treatment of eating disorders displaying particular aberrant patterns of eating. The demand for the development of effective drugs in this area is increasing in view of the preva- lence of disorders of feeding and body weight. It is estimated that between one quarter and one third of the adult population of the U.K. may be defined as mildly obese (Garrow, 1982) whilst about 2% of the female population between the ages of 20 and 40 suffer from the eating disorder of bulimia nervosa (Cooper and Fairburn, 1983). One further clinical implication seems important. A number of classes of psychotropic drugs, such as anxiolytic and antidepressant agents, may influence metabolism of serotonin. Such drugs also may bring about changes in eating and body weight (see Blundell, 1980). This is particularly true of benzodiazepine-type anxiolytics (e.g. Edwards, 1977) which have been characterised as hunger-mimetic agents (Cooper, 1980). It follows that a drug influencing the activity of serotonin systems and administered as treatment for a particular condition may, as a byproduct, bring about changes in appetite, eating and body weight. Consequently, there may be already in existence a sub-class of eating or weight disorders which are drug-induced.
1.4. A note on terminology In scientific research on the control of feeding, terms such as hunger, appetite, satiation and satiety have specific meanings and refer to particular states or processes (see Blundell, 1979 for discussion and review). In day-to-day discourse however, terms such as hunger and appetite may be used interchangeably as if they were different versions of the same phenom- enon. The term appetite used in the title of this chapter simply serves to connote a relationship to events controlling food consumption. In the body of the text however, the meaning of such terms will be more strictly delimited. In the study of food intake there is a clear need to separate the “urge to begin eating” from “the amount consumed”; separate pro- cesses control these aspects of feeding. There is also evidence for a disengagement between the willingness to obtain food and the willingness to eat food once it has been obtained. Accordingly, a distinction may be made between hunger, defined as the process which stimulates the onset of eating, and appetite, a process which directs and guides eating once feeding has begun. In turn, satiation can be defined as the “process” which brings eating to a halt whilst satiety is the “state” of inhibition over further eating. Assig- nation of the term satiation is problematic. Fre- quently the action of a drug to inhibit food intake is regarded as an action upon the process of satiation. However, satiation can only properly be invoked when the cessation of feeding is due to the con- sequences of ingestion of food (or to the activation of processes mediating this cessation). The mere obser- vation of reduced intake is obviously insufficient evidence to justify the use of satiation or satiety (Blundell, 1979b; Blundell and Latham, 1979a). This discussion is not simply about semantic nice- ties. The distinction between different terms reflects the operation of separate processes underlying the control of feeding behaviour. Food intake is not simply switched on and off; an episode of food consumption represents the end product of an inter- action between various distinguishable operations. There is evidence that these operations are influenced by different physiological and neurochemical events. Consequently, in proposing that serotonin influences food intake it is necessary to inquire about the particular operations which may be adjusted by this neurotransmitter. Recognition of this issue has impli- cations for the design and interpretation of experi- ments.
2. METHODOLOGICAL REQUIREMENTS
The investigation of a relationship between a neurotransmitter (serotonin) and behaviour (feeding) demands sophisticated strategies for the manipu- lation and measurement of serotonin, together with sensitive techniques for measuring and monitoring feeding behaviour. Congruence between the out-
1540 J. E. BLUNDELL
feeding animals with the measurement of meal pat- terns and feeding profiles.
- Voluntary self-selection of different diets vary- ing in macronutrient content.
- Presentation of food items characterised by their novelty, variety and palatability.
In certain cases these procedures can be combined to provide a total picture of an animal’s feeding reper- toire (Fig. 1) and the individual procedures have been fully described elsewhere (Blundell, 1981a, b; Blun- dell and Latham, 1978, 1982; Blundell and McAr- thur, 1981). Taken together, a variety of experimental strategies for manipulating or monitoring 5-HT, and sensitive procedures for measuring feeding behav- iour, should provide the basis for evaluating the proposition that serotonin is involved in the control of food intake.
3. PHARMACOLOGICAL MANIPULATION WITH PERIPHERALLY ADMINISTERED AGENTS
3.1. Agonists, releasers and reuptake blockers
A number of compounds are available whose net effect is to facilitate 5-HT synaptic activity. These compounds include fenfluramine and its derivatives, m-chloro-phenyl-piperazine (m-CPP), another piper- azine derivative 6-chloro-2( 1-piperazmyl)pyrazine (MK-212), indalpine (LM-5008). fluoxetine (Lilly 110140), dl-8-chloro-1 l-anti-amino-benzo(b)bicyclo- [3,31]nona-3, 6a(lOa)diene hydrochloride (ORG
- femoxatine (FG 4963), zimelidine and quip- azine. All of these compounds have been demon- strated to produce an inhibition of food con- sumption, an effect consistent with the hypothesis that enhancing central serotoninergic transmission
fideo 1 1 recorder
causes anorexia. In many aspects fenfluramine is representative of this category of drugs and is dis- tinguished by being widely used in research. Experi- ments with fenfluramine can be used to exemplify the characteristics of the class though it is not suggested that all produce identical effects. For fenfluramine, it has been demonstrated that the drug releases serotonin from nerve endings and inhibits reuptake into the neurone (e.g. Garattini and Samanin, 1976). However, it should be considered that the neurochemical effects vary according to whether the parent drug or the main metabolite, norfenfluramine, is given and also depend upon the administration of the d- or I-isomer. For example, it has been proposed that d-fenfluramine and d- nonfenfluramine release 5-HT from two different pools (Samanin and Garattini, 1982). This does not appear to be true for the f-forms which, in addition, have a weaker action on 5-HT. Consequently, when the racemic form of fenfluramine is administered several different mechanisms may be invoked simul- taneously. Evidence for the involvement of 5-HT in the anorexic action of fenfluramine rests on the capacity of treatments which interfere with synthesis of 5-HT or synaptic transmission to antagonise the drug- induced inhibition of food intake. For example, methysergide, which antagonized the hypothermic effect of fenfluramine in dogs (Jesperson and Scheel- Kruger, 1970) also antagonised the anorexic action of moderate (Blundell, Latham and Leshem, 1973) and large (Barrett and McSharry, 1973) doses of fenfluramine in rats. In addition, other drugs believed to block post-synaptic 5-HT receptors, such as meth- ergoline (Funderburk, Hazelwood, Ruckhart and Ward, 1971; Jesperson and Scheel-Kruger, 1973)
i Feedmg chamber Intro^ cage^ octiwty
10”
A
0 patterns
C
PRE AND POST PRANDIAL BEHAVIOUR
- ACTIVITY CYCLE
- APPETITIVE SEQUENCE
- SATIETY SEOUENCE MACRO STRUCTURE OF FEEDING AND SELECTION -MEAL AND SELECTION PERIODICITY -NUMBER OF MEALS -INTER MEAL INTERVALS -MEAL SIZE AND DURATION
MICRO STRUCTURE OF FEEDING -RATE OF EATING
- INTRA MEAL INTERVAL
- INTRA MEAL BOUT STRUCTURE
- INTRA MEAL SELECTION
Fig. 1. Plan of the technique for the computer-logged continuous monitoring of diet selection (from 2 diets varying in nutrient composition), meal patterns, locomotor activity and related behaviour.
Serotonin and appetite 1541
cinanserin (Clineschmidt, McGuffin and Werner,
- and cyproheptadine (Garattini and Samanin,
- also partially antagonise the suppressant action of fenfluramine on feeding. It is however possible that these drug interactions could arise through peripheral metabolic effects, resulting in a reduced level of fenfluramine in blood (and brain). Pretreatment of rats with intraventricular injec- tions of 5,6_dihydroxytryptamine, which is neuro- toxic for central 5-HT-containing neurones (Nobin and Bjorklund, 1978) attenuated the anorexic effect of fenfluramine (Clineschmidt, 1973), though con- tradictory results have been obtained (e.g. Hollister, Ervin, Cooper and Breese, 1975). However, the most striking reduction of the anorexic effect of fenfluramine has been achieved following electrolytic lesions of the median raphe nuclei (Samanin, Ghezzi, Valzelli and Garattini, 1972), though it should be noted that other studies have shown lesser effects (Fuxe, Farnebo, Hamberger and Ogren, 1975) or no effect (Sugrue, Goodlet and McIndewar, 1975) of this procedure. Indeed, it now seems likely that a number of experimental parameters may influence the re- lationship between anorexia induced by fenfluramine and the integrity of central serotonin systems, for two further studies have reported little or no effect on the action of fenfluramine, following raphe lesions (Carey, 1976) or depletion of S-HT by intra- ventricular injection of 5,7_dihydroxytryptamine (Hoebel, Zemlan, Trulson, Mackenzie, Ducret and Norelli, 1978). Moreover, at least two experimental reports have observed a paradoxical enhancement of anorexia induced by fenfluramine following central manipulations of 5-HT. These findings suggest a need for close scrutiny of important experimental vari- ables, including the regime used for the measurement. of food intake, the extent and location of central depletion of 5-HT, and the time interval between treatment and testing of the anorexic drug. One further approach to the understanding of the action of fenfluramine has been through the com- parison of the mechanisms underlying the sup- pressant effects of amphetamine and fenfluramine on feeding. One powerful procedure has been the use of these compounds as a drug-pair in double- dissociation designs (e.g. Blundell, Latham, McAr- thur, Moniz and Rogers, 1979). It has typically been demonstrated that procedures which ameliorate an- orexia produced by amphetamine have little effect on fenfluramine or even lead to an enhancement of its suppressant action. For example, lesions of the lateral hypothalamus (Blundell and Leshem, 1974), intra- ventricular injections of 6-hydroxydopamine and tranylcypromine (Fibiger, Zis and McGeer, 1973), or lesions of the dopamine-containing nigro-striatal tract (Carey and Goodall, 1975), all reduce the anorexic effect of amphetamine but fail to ameliorate the effect of fenfluramine. The anorexic action of the two drugs can also be dissociated after intra- hypothalamic injection (Blundell and Leshem, 1973)
and after lesions of the ventral noradrenergic bundle (Garattini and Samanin, 1976), which augment an- orexia produced by fenfluramine (Ahlskog, Randall, Hernandez and Hoebel, 1984) in a similar manner to lateral hypothalamic lesions (Blundell and Leshem, 1974). Consequently, while noradrenaline systems (Ahlskog, 1974) or dopamine mechanisms (Baez, 1974; Burridge and Blundell, 1979) seem to be impli- cated in the anorexic action of amphetamine, these amine systems do not appear to play a direct role in the action of fenfluramine. Further evidence on the mode of action of fenfluramine has been produced using a continuous monitoring procedure which has revealed effects which are inaccessible in studies using deprived rats. The initial study using the Kissileff type eatometer demonstrated that amphetamine and fenfluramine gave rise to quite distinctive behavioural profiles (Blundell and Leshem, 1975), which were not readily related to the blood levels of the drugs (Blundell, Campbell, Leshem and Tozer, 1975). The character- istic effect of fenfluramine on these free-feeding rats was a reduction in meal size (Fig. 2) and the specificity of this action suggested the operation of a 5-HT-mediated satiation process (Blundell, Latham and Leshem, 1976). Subsequently, this effect of fenfluramine has been reported in a number of sepa- rate studies (Blundell and Latham, 1978; Burton, Cooper and Popplewell, 1981; Blundell and Latham, 1982; Davies, Rossi, Panksepp, Bean and Zolovick,
- and has been shown to occur in both obese and lean Zucker rats (Grinker, Drewnowski, Enns and Kissileff, 1980). In keeping with the initial obser- vations (Blundell and Leshem, 1975) it has recently been affirmed that the “effects of fenfluramine are specific to the mechanisms which control meal size, with a nebligible effect upon meal initiation” (Davies et al., 1983). The power of the continuous monitoring procedure rests on its capacity to provide an accurate measure of moment to moment changes in consumption over long periods of time (usually 24 hr). In turn, these detailed profiles of consumption can be related to changes in the concentration of the drug in the blood and brain. In addition, the refinement of computer processing of feeding data (see Blundell and Latham, 1982 for details) has allowed the description of both inter- and intra-meal events (Fig. 3). In particular, fenfluramine has been shown to slow the rate of eating during the course of a meal (Blundell and Latham, 1978, 1982; Burton et al., 1981). This reduc- tion in rate of eating has also been revealed through the observational analysis of the micro-structure of eating following food deprivation (Blundell and Latham, 1978). Moreover, the slow rate of eating brought about by fenfluramine is counteracted by methergoline (Blundell and Latham, 1980). Taken together, studies on the structure of feeding behav- iour following administration of fenfluramine indi- cate that the drug does not produce a non-specific
Serotonin and appetite 1543
blockade of eating nor does it introduce abnormal patterns of behaviour which could interfere with the natural expression of eating. The drug exerts an action on specific components of the feeding process and appears to produce a firm re-adjustment of the pattern of eating. Unlike most anorexic drugs based on the phenyl- ethylamine configuration, fenfluramine does not pro- duce an increase in arousal but tends to display a sedative action. Since fenfluramine reduces loco- motor activity in certain test situations, it has been suggested that the inhibition of eating is simply one aspect of a more general inhibitory effect of sero- toninergic activation. However, elucidation of this issue requires the measurement of locomotion and feeding under similar test conditions. This can be achieved by monitoring both aspects of behaviour simultaneously. Under such circumstances in de- prived animals, fenfluramine reduces food intake without producing marked changes in activity or resting (Blundell and Latham, 1980). In free-feeding rats, fenfluramine does give rise to an increase in the amount of time spent resting and asleep. However the temporal analysis of behaviour from videotaped records shows that there is no change in resting during the actual consumption of a meal nor during the appetitive phase of behaviour leading up to a meal (Blundell and McArthur, 1979). Consequently eating is not impeded by animals falling asleep or showing excessive sedation. However, once the meal has finished the post-prandial period of sleep is greatly extended. In other words the state of satiety (period of inhibition over further eating) is prolonged by fenfluramine. Interestingly, a number of other compounds show similar actions. For example, fluoxetine, a more specific inhibitor of the 5-HT membrane pump than chlorimipramine (Fuller, Perry, Snoddy and Molloy,
- has been shown to potently depress food intake (Goudie, Thornton and Wheeler, 1976) and shows a behavioural profile similar to that of fentluramine in the deprived rat (Blundell and Latham, 1978). Moreover, the blocker of uptake of 5-HT, ORG 6582 produces a dose-related reduction in meal size in the free-feeding rat (Blundell and Latham, 1978). To the extent that the suppressant action of fenfluramine on feeding is sero- toninergically mediated, the experimental data sug- gest the existence of a 5-HT mechanism which is inhibitory and normally serves to bring feeding to a close. Taken together, the findings suggest that the facilitation of synaptic 5-HT through pharmaco- logical manipulation represents a sufficient, though not a necessary condition for the occurrence of anorexia.
3.2. Receptor blockers A number of compounds with affinity for 5-HT receptors have been shown to block the anorexic action of a drug such as fenfluramine (e.g. Garattini
and Samanin, 1976). Do such drugs influence food intake when administered alone? Methysergide, widely used in the treatment of migraine, has been reported to increase appetite with a resulting gain in weight (see Blundell, 1977). In addition, unwanted gains in weight of as much as 10 kg have been reported during treatment of migraine with the anti- serotonin compound pizotofen (BC-105; Speight and Avery, 1972). Surprisingly, increases in food intake of animals have been more difficult to detect. One possible reason for the comparative ineffectiveness of methysergide in animals is the tendency for drugs to be administered to deprived animals or animals on strict feeding regimes, which promote eating at a maximal rate. If 5-HT systems mediate in a satiation process, then the appropriate time to observe feeding effects evoked by a serotonin antagonist would be when satiation was maximal, not when satiety was weak. Significantly, methysergide has been shown to elevate food intake when given to hungry rats which have been allowed to feed freely for 30 min (Blundell and Leshem, 1974). This effect is consistent with the dissipation of satiation signals arising from food consumption. Cyproheptadine also increases appetite and food intake in humans (Silverstone and Schuyler, 1975) and elevations of food intake and body weight have been observed in rats (Ghosh and Parvathy, 1973) and cats (Chakkrabarty, Pillai, Anand and Singh, 1976). Interestingly, when meal taking was measured in fasting rats, using a continuous recording device, cyproheptadine significantly increased the duration of the first large meal consumed after deprivation (Baxter, Miller and Soroko, 1970). This action is the converse of that brought about by fenfluramine and similar drugs, and provides further evidence that a 5-HT mechanism is somehow implicated in the con- trol of meal size.
3.3. Percursors of serotonin Exogenously administered 5-hydroxytryptophan (5-HTP) is frequently employed as a tool to in- vestigate serotoninergic function and there are posi- tive and negative aspects to its use (see Blundell, 1979). In the few studies in which specific obser- vations of food intake have been carried out, there is genera1 agreement about the effect of 5-HTP. Joyce and Mrosovsky (1964) reported a dose-dependent reduction of food intake in satiated rats measured over a 22 hr period following interperitoneal injec- tions of dl-5-HTP, and Singer, Sanghvi and Gershon (1971) showed that I-5-HTP (50 mg/kg) significantly depressed eating during a 1 hr food test in deprived rats. Similarly, Blundell and Leshem (1975) observed a reduction in food intake which lasted for at least 4 hr following an injection of 37.5 mg/kg I-5-HTP. In addition, when 5-HTP was administered together with the peripheral decarboxylase inhibitor car- bidopa (MK-486), the suppressant effect on food intake remained, although there was a weak antago-
1544 J. E. BLUNDELL
nistic effect of MK-486 (Bhmdell and Latham, 1979). Since changes in metabolism of 5-HTP following administration of 5-HTP and MK-486 are probably restricted to events occurring in the brain, this finding suggests that the effects of 5-HTP on feeding are mediated centrally. Interestingly, the action of 5-HTP plus MK-486 on the micro-structure of eating and on meal patterns show similar effects to those of fenfluramine and related compounds. These effects are typified by a reduction in meal size (but not meal number) and a slowing of the intra-meal eating rate (Blundell and Latham, 1979). Because of certain methodological difficulties asso- ciated with the administration of 5-HTP, the tech- nique of tryptophan loading is often preferred as a means of elevating levels of 5-HT brain. One early report of a dose-dependent decrease in food con- sumption after peripheral injections of tryptophan (see Fernstrom and Wurtman, 1972, note 14), has been followed by further confirmation of this effect (Latham and Blundell, 1979; Gibbons, Barr, Bridger and Leibowitz, 1981) though negative reports have also been published (Weinberger, Knapp and Man- deli, 1978; Peters, Beliissimo and Harper, 1984). What factors could account for this disagreement concern- ing the effect of tryptophan? One possibility concerns the sensitivity of the behavioural assay used to mea- sure feeding. The effect of tryptophan on food intake is not massive (at the moderate dose normally admin- istered) and any disturbance or contamination during collection of data could easily mask the anorexic action. Significantly, when the effects of tryptophan were monitored continuously in a controlled labora- tory environment, a clear effect was demonstrated on free-feeding rats which lasted for 4 hr after adminis- tration. This effect was characterised by a reduction in meal size. Moreover, in deprived rats, tryptophan reduced the magnitude of the first enormous meal normally consumed by rats when allowed access to food (Latham and Blundell, 1979). Interestingly, the post-meal interval was significantly extended, indi- cating that tryptophan not only reduced meal size but also intensified inhibition over further eating. Taken together, the actions of precursors of serotonin are generally consistent with the effects of other pharma- cological manipulations which facilitate 5-HT syn- aptic transmission.
4. LESIONS AND DEPLETIONS OF BRAIN SEROTONIN SYSTEMS
Effects of central manipulations on the anorexia induced by peripherally-administered drugs have been described earlier. However, it is important to consider whether such manipulations, which adjust 5-HT in brain have any direct effect on food intake or feeding parameters. When injected systemically, p-chlorophenylalanine (PCPA) produces a variety of changes in food con- sumption, some of which may be dependent upon
various intestinal disturbances (see Blundell, 1979). However, when pCPA was injected bilaterally into the cerebral ventricles of rats it produced a marked depletion of serotonin in brain with only small decre- ments in noradrenaline and dopamine; more im- portantly the treatment gave rise to a clear hyper- phagia with a concomitant increase in body weight (Breisch and Hoebel, 1975; Breisch, Zemlan and Hoebet, 1976). However, since a similar effect was later observed with other methyl esters (Coscina, Daniel and Warsh, 1978; Mackenzie, Hoebel, Ducret and Trubon, 1979), it appears that the weight gain is not dependent upon a decrease in serotonin in whole brain. Using neurotoxins, it has been shown that intraventricular injections of 5,6-dihydroxytrypt- amine produced a dose-de~ndentincrea~ in food consumption (Diaz, Ellison and Masouka, 1974) whilst 5,7-dihydroxytryptamine (5,7-DHT) gave rise to a long-lasting hyperphagia and weight gain (Saller and Stricker, 1976). This last effect was also associ- ated with increased growth, consequently the effect may be only obliquely related to the regulation of food intake. In addition to the use of neurotoxins, extensive corre!ationai analyses have been performed between neurochemical changes and adjustments in food in- take following micro-knife cuts in the midbrain teg- mentum (Grossman, Grossman and Halaris, 1977) and in various segments of the media forebrain bundle (McDermott, Alheid, Halaris and Grossman, 1977). In the first study, all of the cuts significantly depleted noradrenaline and 5-HT in the hypo- thalamus and forebrain. However, the only significant correlation revealed that hyperphagia was associated with a depletion of S-HT in the forebrain. The second study revealed that ingestive behaviour (including both aphagia and hyperphagia) was posi- tively correlated with 5-HT in the forebrain. Accord- ingly, these studies provide some of the best evidence for a relationship between serotonin in brain and food intake but also suggest an interaction between S-HT in forebrain and dop~inergic pathways in the overall regulation of food intake. In view of these data, it is rather surprising that only slight changes in feeding have been noticed following lesions of the raphe nuclei, which markedly deplete 5-HT in forebrain (see Blundell, 1979 for discussion). It does appear likely that the precise location of the lesion within the raphe system is a critical factor. In keeping with this consideration, it is important to note that specific lesions of the B raphe nuclei have been shown to increase body weight whereas B7 and B9 lesions have no effect (Geyer, Puerto, Dawsey, Knapp and Bullard, 1976). Rats operated at 6 weeks of age, and sacrificed 4 weeks later, showed mean weight gains for controls, B7, B8 and B9 of 95.0, 94.9, 120.0 and 96.Og. The importance of the site of depletion is also emphasized by the results of local injections of 5,7-DHT. Bilateral micro-infusions of 5,7-DHT into
1546 J. E. BLIJNDELL
0.
-I
j 0.
“E 0. FF &I (^) 0.
0. l- r 5-HT
----^ I^ Parovantriculor
c t) (^) I-) _ -- J
I;.
NE
lnhlbltory
Perlfornical --
Factlttatory
Caudal
Fig. 4. Summary of evidence on hypothalamic neurotransmitters involved in the facilitation and inhibition of food intake (after Hoebel and Leibowitz, 1981).
azine) also suppress NA-induced and deprivation- induced feeding when injected into the para- ventricular nucleus. Taken together these data point to the existence of endogenous stores of S-HT within the paraventricular nucleus which are important in the inhibition of eating.
6. S-HT AND NUTRIENT SELECTION
In addition to a postulated action on total food intake and the structure of feeding behaviour, it has also been suggested that 5-HT plays a role in the selection of macronutrients, particularly protein and carbohydrate. The underlying principle is based on the relationship between dietary composition, plasma ratios of amino acids (particularly the ratio of tryp- tophan to large neutral amino acids), uptake of tryptophan into the brain and enhancement of the synthesis of serotonin. The evidence for this view has been set out elsewhere (e.g. Anderson, 1979; Wurt- man, Heft1 and Melamed, 1981) and the operation of the mechanism implies that the concentration of 5-HT in brain depends upon the nutrient composition of the diet consumed. Tryptophan is alleged to play a crucial role in this mechanism and a number of objections have been raised against the process (Pe- ters et al., 1984; Curzon, 1984). However, the hypoth- esis suggests that manipulations of metabolism of serotonin or of concentrations of 5-HT in brain should bring about an adjustment of the animal’s capacity to voluntarily self-select particular nutrients. Obviously, an experimental test of this possibility requires a test situation allowing animals the oppor- tunity to make dietary choices (see Section 2.2).
The first experiments (^) using peripherally- administered agents were directly related to the pro- posed role for serotonin in protein selection (Wurt- man and Wurtman, 1977). The purpose of the experiments was to separate the effects of drugs on total caloric intake from their effects on the con- sumption of a particular nutrient. In the major study male weanling rats (21-48 days old) were placed on an 8-hr cyclic feeding regimen and during the feeding period allowed to select food from two isocaloric diets, containing 5 or 45% protein. The rats were injected with one of two drugs, fenfluramine and fluoxetine, known to act on serotonin metabolism. With fenfluramine no adjustments were observed during the first hour after injection, but during the following 3 hr “fenfluramine-treated animals selec- tively decreased their consumption of the low-protein diet and increased their consumption of the high- protein food so that total caloric intake was de- pressed while protein intake was spared”. Like fenfluramine, fluoxetine suppressed food intake but spared protein consumption, thereby increasing the proportion of calories consumed as protein. On the other hand amphetamine, a drug with little known action on serotonin-mediated neurotransmission, was reported to reduce food consumption but failed to alter the proportion of total calories consumed as protein. The action of serotoninergic drugs was char- acterised as a protein sparing effect (Wurtman and Wurtman, 1977). These first studies were carried out on young rats subjected to food deprivation prior to testing. To investigate the robustness of the findings, Blundell and McArthur (1979) administered fenfluramine to
Serotonin and appetite 1547
adult rats maintained on a deprivation regimen or allowed to feed freely. For deprived animals the data were broadly in keeping with the findings of Wurt- man and Wurtman (1977); fenfluramine gave rise to an increase in the proportion of protein in the total food consumed (protein-sparing effect). However, under free feeding conditions, the protein-sparing effect of fenfluramine was not apparent. It has since been revealed that food deprivation significantly de- creases intake of protein and the ratio of protein to total energy consumed in both adult and weanling rats (McArthur and Blundell, 1982). The alteration of this baseline should be considered in evaluating the effects of drugs on nutrient intake. In addition, it has also been demonstrated that sensory characteristics of the diet can exert a significant effect on the action of drugs to alter protein intake (Blundell, 1983). This factor may have had some bearing on the outcome of a further experiment in which fenfluramine was ad- minstered to rats, offered a choice of pure separate portions of protein (casein), carbohydrate (corn starch and dextrin) and fat (vegetable fat and safflower oil). In one experiment in which the fat ration contained more calories than the other two nutrient ratios, fenfluramine reduced the intake of protein and fat and tended to spare carbohydrate. When all diets were made isocaloric, fat intake was again severely depressed with a relative and weak sparing of protein and carbohydrate (Orthen- Gambill and Kanarek, 1982). If animals are given diets containing different proportions of two nutri- ents and if the treatment selectively alters their intake of one of the diets, it may not be clear which of the nutrients the animal is choosing or avoiding. For example, if a treatment causes rats to consume less of a diet A (high-carbohydrate, low-protein) than diet B (low-carbohydrate, high protein), it can be said to be exerting either a “protein-sparing“ or a “carbohydrate-suppressing“ effect. A decision about which action is primary and which secondary requires the use of different types of test diets in which only one of the nutrients in question is varied. In experi- ments (Wurtman and Wurtman, 1979) on the effect of serotoninergic drugs on carbohydrate intake, rats were allowed to consume from two isocaloric, iso- protein diets containing either 25 or 75% dextrin. Following administration of fenfluramine or MK212, rats specifically decreased their consumption of the high (75x)-carbohydrate diet and consumed rela- tively more of the low-carbohydrate diet. Con- sequently, the absolute intake of carbohydrate was reduced, together with the proportion of total food represented by carbohydrate. The role of serotonin may be to control the proportion of carbohydrate to protein consumed rather than absolute amounts. It should be noted that the depression of fat intake by fenfluramine was not observed in these experiments; with these iso-protein diets the preferred low carbo- hydrate diet actually contained a high proportion of fat.
In a specific test of the effect of tryptophan on nutrient selection, the amino acid (100 mg/kg) was administered to rats allowed to choose between 0 and 55% or 15 and 55% protein diets (Peters et al., 1984). Although the concentrations of 5-HT and 5-HTAA in brain increased by 50x, the treatment with tryp- tophan did not modify total food intake or protein and carbohydrate selection. However, other manipu- lations of 5-HT in brain synthesis blockers, neuro- toxins and raphe lesions have produced quite different results. Following systemic administration of pCPA, intraventricular injections of 5-7,DHT or radio-frequency lesions of dorsal and medial raphe nuclei, whole brain content of 5-HT was reduced and the rats consumed a smaller proportion of protein in their total intake (Ashley, Coscina and Anderson, 1979). These data support a role for 5-HT in nutrient selection, but one puzzle is that these changes in protein intake are in the opposite direction to that predicted by some previous post hoc correlations of dietary selection and plasma tryptophan to neutral amino acid ratios (Ashley and Anderson, 1975a,b). Clearly, the overall picture is somewhat complex and the investigation of nutrient selection is beset by severe methodological difficulties (Blundell, 1983). Different studies, involving differences in the age of animals, sensory qualities of diets, concentration of nutrients, type of nutrient offered, number of choices, feeding regimens and test intervals, have produced widely varying results. The protein sparing (or carbo- hydrate suppressive) action of fenfluramine and sim- ilar drugs can be observed under certain conditions but does not appear to be a very robust phenomenon. Taken together the evidence suggests that fluctuations in S-HT in brain (probably in certain selective sites) create a disposition to modulate di- etary selection, but that this tendency may be blocked or masked by changes in physiological or environ- mental circumstances (see Blundell, 1983 for further discussions of these issues and review of human experiments).
- A NOTE ON CENTRAL VERSUS PERIPHERAL EFFECTS
Although manipulations of 5-HT in brain produce clear effects on feeding behaviour, the presence of different types of 5-HT receptors at critical sites in the gastro-intestinal region invites the supposition that at least a part of the adjustment in consumption (or selection) could be provoked by peripheral action. For fenfluramine, it has been argued that the an- orexic action, at least in non-deprived animals, may be related to a slowing of gastric emptying (Davies, 1976; Davies er al., 1983). FentIuramine does slow stomach emptying and was shown to be most effective in lengthening the post-meal interval when given immediately after feeding. In addition, it has been known for more than ten years that peripheral injections of 5-HT inhibit food intake. Bray and
Serotonin and appetite (^1549)
styles (Turner M., Ed.), pp. 21-42. Applied Science, London. Blundell J. E. (1979b) Serotonin and feeding. In: Serotonin in Health and Disease, Vol. 5 Clinical Applications (Essman W. B., Ed.), pp. 403450. Spectrum, New York. Blundell J. E. and Latham C. J. (1979a) Pharmacology of food and water intake. In: Chemical inj7uences on Behav- iour (Cooper S. and Brown K., Eds), pp. 201-254. Academic Press, London. Blundell J. E. and Latham C. J. (1979b) Serotonergic influences on food intake: effect of S-hydroxytryptophan on parameters of feeding behaviour in dkpr&d and free-feeding rats. Pharmac. Biochem. 11: 431437. Blundell J. E.: Latham C. J., McArthur R. A., Moniz E. and Rogers P. J. (1979) Structural analysis of the action of amphetamine and fenfluramine on food intake and feed- ing behaviour in animals and man. Curr. med. Res. Opin. 6: 34-54. Blundell J. E. and McArthur R. A. (1979) Investigation of food consumption using a dietary self-selection pro- cedure: effects of pharmacological manipulation and feed- ing schedules. Br. J. Pharmac. 67: 436P-438P. Blundell J. E. (1980) Pharmacological adjustment of the mechanisms underlying feeding and obesity. In: Obesity (Stunkard A. J., Ed.), pp. 182-207. Saunders, Philadel- phia. Blundell J. E. and Latham C. J. (1980) Characterisation of the adjustments to the structure of feeding behaviour following pharmacological treatment: effects of am- phetamine and fenfluramine and the antagonism pro- duced by pimozide and methergoline. Pharmac. Biochem. Behav. 12: 717-722. Blundell J. E. (1981a) Deep and surface structures: a qualitative approach to feeding. In: The Body Weight Regulatory System: Normal and Disturbed Mechanisms (Cioffi L. A., James W. P. T. and Van-Itallie T., Eds), pp. 73-82. Raven Press, New York. Blundell J. E. (1981b) Biogrammar of feeding: pharma- cological manipulations and their interpretations. In: Progress in Theory in Psychopharmacology (Cooper S. J., Ed.), pp. 233-276. Academic Press, London. Blundell J. E. and McArthur R. A. (1981) Behavioral flux and feeding: continuous monitoring of food intake and food selection and the video-recording of appetitive and satiety sequences for the analysis of drug action. In: Anorectic Agents, Mechanisms of Action and of Tolerance (Garattini S., Ed.), pp. 19-34. Raven Press, New York. Blundell J. E. (1982) Neuroregulators and feeding: impli- cations for the pharmacological manipulation of hunger and appetite. Rev. Pure appl. Pharmac. Sci. 3: 381462. Blundell J. E. and Latham C. J. (1982) Behavioural pharma- cology of feeding. In: Drugs and Appetite (Silver&one T., Ed.), pp. 41-80. Academic Press, London. Blundell J. E. (1983) Processes and problems underlying the control of food selection and nutrient intake. In Nutrition and the Brain, Vol. 6 (Wurtman R. J. and Wurtman J. J.. Eds), pp. 163-221. Raven Press, New York. Booth D. A. (1976) Localization of the adrenergic feeding system in the rat diencephalon. Science 15s: 515-517. Bray G. A. and York D. A. (1972) Studies on food intake in genetically obese rats. Am. J. Physiol. 233: 176-179. Breisch S. T. and Hoebel B. G. (1975) Hyperphagia and transient obesity following intraventricular para- cholorphenylalanine. Fedn Proc. Fedn Am. Sots exp. Biol. 34: 296. Breisch S. T., Zemlan F. P. and Hoebel B. G. (1976) Hyperphagia and obesity following serotonin depletion by intraventricular parachlorophenylalanine. Science 192: 382-384. Burridge S. L. and Blundell J. E. (1979) Amphetamine anorexia: antagonism by typical but not atypical neuro- leptics. Neuropharmacology 18: 453457. Burton M. J., Cooper S. J. and Popplewell D. A. (1981) The
effect of fenfluramine on the microstructure of feeding and drinkina in the rat. Br. J. Pharmac. 69: 621-633. Carey R. J. and Goodall E. B. (1975) Attentuation of amphetamine anorexia by unilateral nigro-striatal lesions. Nekopharmacology 14: 827-834. Carev R. J. (1976) Effects of selective forebrain depletions ofnorepinkphrine and serotonin on the activity and food intake effects of amphetamine and fenfluramine. Phar- mat. Biochem. Behav. 5: 519-523. Chakkrabarty A. S., Pillai R. V., Anand B. K. and Singh B. (1976) Effect of cyproheptadine on the electrical activ- ity of the hypothalamic feeding centres. Brain Res. 6: 561-569. Clineschmidt B. V. (1973) 5,6_Dihydroxytryptamine: sup- pression of anorexigenic effect of fenfluramine. Eur. J. Pharmac. 24: 405-409. Clineschmidt B. V., McGuffin J. C. and Werner A. B. (1974) Role of monoamines in the anorexigenic actions of fenfluramine, amphetamine and p-chloromethamphe- tamine. Eur. J. Pharmac. 27: 313-323. Cooper P. J. and Fairburn C. G. (1983) Binge-eating and self-induced vomiting in the community: a preliminary study. Br. J. Psychiat. 142: 139-144. Cooper S. J. (1980) Benzodiazepines as appetite-enhancing compounds. Appetite 1: 7-19. Coscina D. V. (1977) Brain amines in hypothalamic obesity. In: Anorexia Nervosa (Vigersky R. A., Ed.), pp. 97-107. Raven Press, New York.
Coscina D. V., McArthur R. A., Stancer H. C. and Godse D. D. (1978) Association of altered brain norepinephrine and serotonin with the obesity induced by gold- thioglucose in mice. Pharmac. Biochem. Behav. 9: 123-128.
Coscina D. V., Daniel J. and Warsh J. J. (1978) Potential non-serotonergic basis of hyperphagia elicited by intra- ventricular p-chlorophenylalanine. Pharmac. Biochem. Behav. 9: 791-797.
Curzon G., Joseph M. H. and Knott P. J. (1972) Effects of immobilization and food deprivation on rat brain tryp- tophan metabolism. J. Neurochem. 19: 1967-1974. Curzon G. (1984) Effect of food intake on brain transmitter amines. In: Psychopharmacology of Food (Sandler M. and Silverstone T., Ed.). Oxford University Press, London. In press. Davies R. F.(1976) Some neurochemical and physiological factors controlling free feeding patterns in the rat. Ph.D. thesis. McGill University, Montreal. Davies R. F., Rossi J., Panksepp J., Bean N. J. and Zolovick A. J. (1983) Fenfluramine anorexia: a peripheral locus of action. Physiol. Behav. 30: 723-730. Diaz J., Ellison G. and Masuoka D. (1974) Opposed behaviour syndromes in rats with partial and more com- plete central serotonergic lesions made (^) with 5,6-dihydroxytryptamine. Psychopharmacologia 37: 67-69, Dillettuso B. A. and Wangsness P. J. (1977) Effect of age on hyperphagia in the genetically obese Zucker rat. Proc. Sot. exp. Biol. Med. 154: l-5. Edwards J. G. (1977) Unwanted effects of psychotropic drugs. IV Drugs for anxiety. Practitioner 219: 117-121. Femstrom J. D. and Wurtman R. J. (1972) Brain serotonin content: physiological regulation by plasma neutral amino acids. Science 178: 414-416. Femstrom J. D. and Wurtman R. J. (1973) Control of brain 5-HT content by dietary carbohydrates. In: Serotonin and Behaviour (Barchas J. and Usdin E., Eds), pp. 121-128. Academic Press, New York. Fibiger H. C., Zis A. P. and McGeer E. G. (1973) Feeding and Drinking deficits after 6-hvdroxvdooamine adminis- tration in the rat: similarities to the iateial hypothalamic syndrome. Brain 55: 135-148. Finkelstein J. A., Chance. W. T. and Fischer J. E. (1983) Brain serotonergic activity and plasma amino acid levels
(^1550) J. E. BLIJNDELL
in the genetically obese Zucker rats. Phurmac. Biochem. Behav. 17: 939-944. Fletcher P. J. and Burton M. J. (1984) Effects of manipu- iations of peripheral serotonin on feeding and drinking in the rat. Pharmac. Biochem. Behav. In press. Fozard J. R. (1984) Neuronal 5-HT receptors in the periphery. Neuropharmacology 23: 1473-1486. Fuller R. W., Perry K. W., Snoddy H. D. and Molloy B. B. (1974) Comparison of the specificity of 3-(p-trifluoromethylphenoxy~N-methyl-3-phenyipropano lamine and chlo~mipramine as amine uptake inhibitors in mice. Eur. J. Pharmac. 28: 223-236. Funderburk W. H., Hazelwood J. C., Ruckhart R. T. and Ward J. W. (1971) Is 5-hydroxytr~tamine involved in the mechanism of action of fenfluramine? J. Pharm. Pharmuc. 23: 468-469. Fuxe K., Famebo C. O., Hamberger B. and Ogren S. 0. (1975) On the ‘in Y&O and ‘in vitro’ actions of fenfluramine and its derivatives on central monoamine neurons, espaially Shydroxytryptamine neurons, and their relation to the anorectic action of fenfluramine. Postgrad. med. J. 51: 35-45. Gal E. M., Morgan M and Marshall F. D. (1965) Studies on the metabolism of 5-hydroxytryptamine (serotonin) III. The effect of goldthioglucose (GTG) induced obesity. Life Set. 3: 375-378. Garattini S. and Samanin R. (1976) Anorectic drugs and neuro-transmitters. In: Food lntuke and Appetite (Silver- stone T., Ed.), pp. 82-108. Dahlem Konferenzen, Berlin. Garattini S. (1978) Importance of serotonin for explaining the action of some anorectic agents. In: Recent Advances in Obesity Research: Vol. II (Bray G. A., Ed.), pp. 433-441. Newman, London. Garrow J. (1982) Does plumpness matter? t’v’utr, BuR. 7: 49-s3. Garthwaite T. L., Kahlkoff R. K., Gaunsing A. R., Hagan T. C. and M~ahan L. A. (19791 Plasma free trvntoahan. brain serotonin and an endocrine profile of the genetically obese hyperglycaemic mouse of 4-5 months of age. Endocrinology 105: 1178-I 182. Gershon M. D. and Dreyfus C. F. (1977) Serotonergic neurons in the mammalian gut. In: Nerves and the Gut (Brooks F. P. and Evers P. W., Eds), pp. 197-206. Geyer M. A., Puerto A., Dawsey W. J., Knapp and Bullard S. (1976) Histological and enzymatic studies of the meso- limbic and mesostriatal serotonergic pathways. Brain Res. 106: 241-256. Ghosh M. N. and Parvathy S. (1973) The effect of cypro- heptadine on water and food intake and on body weight in the fasted adult and weanling rats. Br. 1. Pharmac. 48: 328-329. Gibbons J. L., Barr G. A., Bridger W. H. and Leibowitz S. F. (198 1) L-Tryptophan’s effects on mouse killing, feed- ing, drinking, locomotion and brain serotonin. Pharmac. Biochem. Behav. 15: 201-206. Goudie A. J., Thornton E. W. and Wheeler T. J. (1976) Effects of Lillv 110140. a snecific inhibitor of serotonin uptake, on food intake and on 5-hydroxytryptophan induced anorexia. Evidence for serotonergic inhibition of feeding. J. Pharm. Pharmac. 28: 318-320. Grinker J. A., Drewnowski A., Enns M. and Kissileff H. (1980) Effects of d-amphetamine and fenfluramine on feeding patterns and activity of obese and lean Zucker rats. Pharmae. Biochem. Behav. 12: 265-275. Grossman S. P. (1962) Direct adrenergic and cholinergic stimulation of hypothalamic mechanisms. Am. J. Physiol. 202: 872-882. Grossman S. P., Grossman L. and Halaris A. (I 977) Et&&s on hypothalamic and telencephalic NE and 5-HT of tegmental knife cuts that produce hyperphagia and hyper- dipsia in the rat. P/tarmac. Btochem. Behav. 6: 101-106. Hoebel B. G. (1977) Pha~acologi~ control of feeding. A. R~u. Pharmac. Toxic. 17: 605-621.
Hoebel B. G. and Leibowitz S. F. (1981) Brain monoamines in the modulation of self-stimulation, feeding and body weight. In: _&&, aeharior and BodiIy Disease (Weiner H. A., Hoffer M. A. and Stunkard A. J., Eds), pp. 103-142. Raven Press, New York. Hoebel R. G., Zemlan F. P., Trulson M. E., McKenzie R. G., Ducret R. P. and Norelli C. (1978) Differential effects of p-chlorophenylalanine and 5,7-dihydroxytryptamine on feeding in rats. Ann. N.Y. Acad. Sci. 30% 590-594. Hollister A. S., Ervin G. N., Cooper B. R. and Breese G. (1975) The roles of monoamine neural systems in the- anorexia induced by (+)-amphetamine and related com- pounds. Neuropharma~o~ogy 14: 715-723. Ishizaki F. (1974) Goldthioglu~ose-indu~d lesions and quantitative changes of monoamines in the rat brain. Yonago Acta Medica 18: l-8. Jesperson S. and Scheel-Kruger J. (1970) Antagonism by methysergide of 5”hydroxyt~ptamine-like action of toxic doses of fenfluramine in dogs. J. Phurmac. 2% 637-638. Jesperson S. and Scheel-Kruger J. (1973) Evidence for a difference in m~h~isrn of action between fen~uramine- and amphetamine-induced anorexia. J. Pharm. Phurmac. 25: 49-54. Joyce D. and Mrosovsky N. (1964) Eating, drinking and activity in rats following 5-hydroxytryptophan (5-HTP) administration. Psychophurmaco~ogja f5: 417-423. Kantak K. M., Wayner M. J. and Stein J. M. (1978) Effects of various periods of food deprivation on serotonin synthesis in the lateral h~othalamus. Pharmuc. Biochem. Behav. 9: 535-541. Latham C. J. and Blundell J. E. (1979) Evidence for the effect of tryptophan on the pattern of food consumption in free feeding and food deprived rats. Life Sci. 24: 1971-1978. Leibowitz S. F. and Papadakos P. J. (1978) Serotonin-norepin~h~ne interactions in the para- ventricular nucleus: antagonistic effects on feeding behav- iour in the rat. Neurosci. Abstr. 4: 452. Leibowitz S. F. (1980) Neurochemical systems of the hvpothalamus-control of feeding and drinking behav- i&r and water-el~trolyte excretion. In: Handbook of the oothal (Moraane P. J. and Panksevv J., Ed& DV. 29$-347. Mar&l Dikker, New York. __ __ MacKenzie R. C., Hoebel B. G., Ducret R. P. and Trulson M. E. (1979) Hyperphagia following intraventricular p-chlorophenylalanine- leucine- or tryptophan-methyl es- ters: lack of correlation with whole brain serotonin levels. Pharmac. Biochem. Behav. 10: 951-955. Marsha11 J. F., Richardson J. S. and Teitelbaum P. (1974) Nigrostriatal bundle damage and the lateral hypo- thalamic syndrome. J. romp. Physiol. Psyehol. m 8~830. McArthur R. A. and Blundell J. E. (1982) Effects of age and feeding regime on self selection of protein and carbo- hydrate. Appetite 3: 153-162. McDermott L. J., Alheid G. F., Halaris A. E. and Gross man S. D. (1977) A correlation analysis of the effects of surgical transections of three components of the MFB on ingestion behaviour and hypoth~amic, striatal and telen- cephalic amine con~ntrations. Pharmac. Biorhem. Behav. 6: 203-214. Nobin A. and Bjorklund A. (1978) Degenerative effects of various neurotoxic indoleamines on central monoamine neurons. Ann. N.Y. Acad. Sci. 385: 305-327. Orthen-Gambit1 N. and Kanarek R. B. (1982) Differ- ential effects of amphetamine and fenfluramine on dietary self-selection in rats. Pharmac. Biochem. Behav. 16: 303-309. Perez-Cruet J., Tagliamonte A., Tagliamonte P. and Gessa G. L. (1972) Changes in brain serotonin metabolism associated with fasting and satiation in rats. Life Sci. 11: 31-39. Peters J. C., Bellissimo D. B. and Harper A. E. (1984)
