Neuropharmacology of drugs affecting food intake

Pharmac. Ther. Vol. 32, pp. 145 to 182, 1987 Printed in Great Britain. All rights reserved

0163-7258/87 $0.00+0.50 Copyright © 1987 Pergamon Journals Lid

Specialist Subject Editors: J. T. SILVERSTONEand M. F. SUGRt~

NEUROPHARMACOLOGY FOOD

OF DRUGS INTAKE

AFFECTING

MICHAEL F. SUGRUE* Centre de Recherche Laboratoires Merck, Sharp & Dohme-Chibret, 63203 Riom C~dex, France

ABBREVIATIONS Alpha-MT CNS DA 5,6-DHT 5,7-DHT DOPAC EPI

EOS GABA GVG 5-HIAA 5-HT 5-HTP HVA MAO MHPG MMTA NE 6-OHDA PCPA

alpha-methyl-p-tyrosine central nervous system dopamine 5,6-dihydroxytryptamine 5,7-dihydroxytryptamine dihydroxyphenylacetic acid epinephrine ethanolamine-O-sulphate gamma-aminobutyric acid gamma-vinyl GABA 5-hydroxyindoleacetic acid serotonin 5-hydroxytryptophan homovanillic acid monoamine oxidase 3-methoxy-4-hydroxyphenylethylene glycol alpha-methyl-meta-tyramine norepinephrine 6-hydroxydopamine p -chlorophenylalanine

1. INTRODUCTION All anorectic drugs in current use for the treatment of obesity act centrally. The importance of the CNS in ingestive behavior was clearly shown following the destruction of well-defined hypothalamic areas. The hypothalamus is the area of the brain that has been historically viewed as playing a definitive role in appetite regulation. Whereas bilateral destruction of the ventromedial hypothalamus leads to hyperphagia and weight gain (Hetherington and Ranson, 1942; Brobeck et al., 1943), damage to the lateral hypothalamus results in hypophagia and weight loss (Anand and Brobeck, 1951a,b). As a result of these observations, the concept emerged that the ventromedial and lateral hypothalamic nuclei represented the satiety and feeding centers in the brain (Stellar, 1954). However, a number of subsequent observations were difficult to equate with this hypothesis which is now viewed as an oversimplification (Grossman, 1975). The observation that the direct injection of NE into the rat hypothalamus stimulated eating (Grossman, 1960) focused attention on the role of this monoamine in eating. The significance of DA first became apparent when it was found that rats with lesions of the nigrostriatal dopaminergic system became aphagic (Ungerstedt, 1971b). The other monoamine believed to play a pivotal role in ingestive behavior is 5-HT (Blundell, 1977). All three monoamines are considered to be implicated in the mechanism of action of anorectic drugs and this facet of their pharmacology will be discussed in depth in this review. 2. ROLE OF PUTATIVE NEUROTRANSMITTERS IN INGESTIVE BEHAVIOR The importance of central monoamines in feeding was first realized when Grossman (1960) showed that the intrahypothalamic injection of NE stimulated eating in rats. Not *Present address: Merck, Sharp and Dohme Research Laboratories, WP 26-208, West Point, PA 19486, U.S.A. 145

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only has interest in the role of monoamines remained unabated, but now there is also considerable evidence to implicate neuropeptides in ingestive behavior. The major neurotransmitters implicated in feeding are NE, DA, 5-HT, GABA and a variety of neuropeptides for which evidence ranges from weak to convincing. The latter not only coexist but also modulate the release of the classical neurotransmitters. The roles of the major neurotransmitters implicated in eating will be reviewed in this section in order to provide appropriate background information prior to discussing the mechanisms of action of anorectic drugs.

2.1. NOREPINEPHRINE The two main ascending NE pathways are the dorsal and the ventral bundle. The ventral bundle receives axons from the A1, A2, A5 and A7 cell bodies which are located in the medulla oblongata and pons. The axons ascend to the mid-reticular formation and then continue mainly within the medial forebrain bundle. The system gives rise to NE nerve terminals in the lower brainstem, mesencephalon and diencephalon. At the diencephalic level, the ventral pathway innervates the thalamus and the hypothalamus. Areas of the hypothalamus with a dense innervation include the dorsomedial, periventricular and paraventricular nuclei. The density of NE terminals within the ventromedial and lateral hypothalamus is relatively low. Cell bodies in the locus coeruleus (A6) contribute predominantly to the dorsal ascending NE pathway. Following its separation from the ventral bundle at the pons, the dorsal bundle ascends in the dorsal tegmentum and, at the diencephalic level, turns ventrally to join the ascending DA axons in the medial forebrain bundle. Terminals are found in the diencephalon, limbic system and cortex (Ungerstedt, 1971a). Radioligand binding studies have revealed the presence of alphas- (U'Prichard et al., 1977), alpha2- (U'Prichard et al., 1977) and beta-adrenoceptors (Bylund and Snyder, 1976) in the hypothalamus. The central injection of NE into the hypothalamus of brain-cannulated animals has been shown to stimulate feeding in several species (Grossman, 1960; Booth, 1967, 1968a; Slangen and Miller, 1969; Kruk, 1973). In an extensive mapping study of over 30 different brain areas in the satiated rat, Leibowitz (1978a) demonstrated that the hypothalamic paraventricular nucleus is the most sensitive brain site for initiating feeding behavior following central NE injection. NE-induced eating is attenuated by lesioning the paraventricular nucleus (Leibowitz et al., 1983a). The site of action of NE in the paraventricular nucleus would appear to be postsynaptic because the destruction of NE nerve terminals by the intrahypothalamic injection of the neurotoxin, 6-OHDA (Breese, 1975), has no effect on NE-induced feeding (Leibowitz and Brown, 1980a; Goldman et al., 1985). Tests with NE or the alpha2-adrenoceptor agonist, clonidine, injected into the paraventricular nucleus have revealed that the enhanced eating of satiated rats is blocked in a dosedependent fashion by the local injection of alpha2-adrenoceptor antagonists, such as rauwolscine or yohimbine. In contrast, the alphal-adrenoceptor antagonist, prazosin, is ineffective (Goldman et aL, 1985). Clonidine-induced eating is also attenuated by electrolytic lesions of the paraventricular nucleus (McCabe et al., 1984). Radioligand binding studies have revealed that the burst of feeding which naturally occurs in the rat at the beginning of the dark cycle is associated with a peak in alpha2-binding in the paraventricular nucleus (Jhanwar-Uniyal et al., 1986). In contrast, food deprivation results in a rapid and dramatic downregulation of alpha2-adrenoceptors in this nucleus (Leibowitz, 1985). These observations indicate that feeding elicited by noradrenergic stimulation in the region of the paraventricular nucleus is mediated through alphaEadrenoceptors which, based on the evidence cited above, are located postsynaptically. The activation of alphaE-adrenoceptors in the paraventricular nucleus preferentially increases the ingestion of carbohydrate with fat and protein intake being little affected (Leibowitz et al., 1985).

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The activation of postsynaptic alpha2-adrenoceptors in the paraventricular nucleus elicits feeding. Paradoxically, small electrolytic lesions essentially restricted to the paraventricular nucleus were found to produce overeating and to increase rat bodyweight (Leibowitz et al., 1981). In earlier experiments it had been shown that lesions of the ventral ascending NE bundle in rats also led to hyperphagia and obesity (Ahlskog and Hoebel, 1973; Ahlskog, 1974; Ahlskog et al., 1975). This was also the case after the midbrain injection of 6-OHDA which resulted in the destruction of all ascending noradrenergic tracts to the forebrain. Pretreatment with desipramine blocked the 6-OHDA-induced loss of forebrain NE and prevented overeating (Ahlskog, 1974; Hernandez and Hoebel, 1982). Hence, the overeating following the midbrain injection of 6-OHDA is not due to nonspecific damage by the neurotoxin and is, in fact, due to the destruction of NE and/or EPI neurones that are necessary for the inhibition of food intake. These observations imply that a NE system is necessary for satiety and, in order to explain NE-induced eating, it has been proposed that NE may serve an inhibitory function at the cellular level in the hypothalamus; by inhibiting a neural satiety function, the monoamine would disinhibit feeding (Hoebel, 1977a,b). Overeating elicited by the injection of NE into the paraventricular nucleus of satiated rats is abolished by hypophysectomy or adrenalectomy. The response to NE could be restored by corticosterone replacement therapy (Leibowitz et al., 1984). An intact vagus nerve, in particular its pancreatic branch, is necessary for NE-induced eating (Sawchenko et al., 1981). Hence, it is apparent that NE-induced feeding is not due solely to the activation of alpha-adrenoceptors in the vicinity of the paraventricular nucleus, it is also dependent upon other inputs. In contrast to its effect at the paraventricular nucleus, NE, when injected into the lateral perifornical hypothalamus, decreases eating. This is also true for EPI and DA, and the reduced food intake is attributed to the activation ofbeta-adrenoceptors and DA receptors (Leibowitz, 1978b; Leibowitz and Rossakis, 1978a,b, 1979). The doses required to produce the catecholamine-induced suppression of food intake appear to be higher than the threshold doses needed for alpha-adrenoceptor-induced overeating. The betaadrenoceptor involved would appear to belong to the beta2-subtype because the injection of the beta2-agonist, salbutamol, into the rat lateral perifornical hypothalamus suppressed feeding whereas the alphal-agonist, phenylephrine, was ineffective (Leibowitz, 1978b). Rat food intake is also decreased by peripherally administered salbutamol, an effect blocked by the central administration of propranolol (Borsini et al., 1982b) or by systemic pretreatment with the beta2-adrenoceptor antagonist, IPS-339 (Bendotti et al., 1986). In contrast to amphetamine, salbutamol-induced anorexia is unaltered by lesioning the ventral NE bundle (Borsini et al., 1982b). The results obtained for salbutamol provide further evidence for the role of perifornical beta2-adrenoceptors in ingestive behavior. Physiologic evidence that endogenous NE may be released from hypothalamic nerve endings comes from experiments in which it was found that an increased release of NE from the ventromedial and anterior hypothalamus of the rat occurred during feeding (Martin and Myers, 1975). In a more detailed anatomic study, it was found that the release of NE from the dorsomedial and perifornical areas was increased when rats were feeding. This effect was considered to be specific because NE release from the perifornical area was unaltered during drinking. In contrast to NE, the release of DA from the cited areas was unaltered during feeding (Van Der Gugten and Slangen, 1977). The precise link between the increased release of NE from the perifornical area during feeding and the inhibition of eating following the injection of NE into the lateral perifornical area is unclear. 2.2. DOPAMINE The main DA cell bodies in the brainstem are the A9, A10 and A12 cell groups and they give rise to the nigrostriatal, mesolimbic-mesocortical and tuberoinfundibular pathways, respectively. Axons from the A9 cell bodies, located in the zona compacta of the substantia nigra, proceed rostrally in a prominent pathway that passes anteriorly

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through the lateral hypothalamus just dorsal to the median forebrain bundle. They enter the internal capsule at the mid-hypothalamic level and then pass through the globus pallidus to terminate in the caudate-putamen. The A10 cell bodies of the mesolimbicmesocortical pathway are located dorsolateral to the nucleus interpeduncularis. Axons ascend together with the axons of the nigrostriatal system and at the anterior hypothalamic level the pathways separate; the axons do not enter the internal capsule but continue in a rostral direction just dorsal to the median forebrain bundle to innervate limbic structures, such as the nucleus accumbens, olfactory tubercle and amygdala. Cortical DA innervation is most probably an extension of this innervation. The tuberoinfundibular DA system has cell bodies (A 12) located within the arcuate nucleus of the hypothalamus and these cells innervate the external layer of the median eminence (Ungerstedt, 1971a). The importance of DA in ingestive behavior was first demonstrated by Ungerstedt (1971b) who showed that the injection of the neurotoxin, 6-OHDA, into the rat nigrostriatal pathway results in aphagia and adipsia, the condition being very similar, although not identical, to the classic lateral hypothalamic starvation syndrome. Anorexia can also be induced in rats by the intraventricular injection of 6-OHDA (Zigmond and Stricker, 1972). This procedure depletes the brain of NE and DA (Breese, 1975). However, the 6-OHDA-induced anorexia would appear to be DA-mediated because it was present in rats whose brain DA stores were selectively decreased by 6-OHDA (Breese, 1975). The selective depletion of brain DA was achieved by pretreating the rats with an NE uptake inhibitor; such a procedure prevents the accumulation of the neurotoxin in NE neurons. Additional evidence implicating DA was the finding that anorexia was absent in rats in which 6-OHDA was injected in such a manner that NE and not DA was depleted (Fibiger et al., 1973). Some electrophysiological evidence is available to implicate the mesolimbic DA system in ingestive behavior (Mogenson and Wu, 1982). The above observations imply that a lack of DA is associated with anorexia. As a corollary of this, the activation of DA receptors would be expected to result in eating. This is not so. The intraventricular injection of large concentrations of DA decreases the food intake of rats (Hansen and Whishaw, 1973; Kruk, 1973). The rostral perifornical region of the lateral hypothalamus is the most sensitive region of the rat brain to locally applied DA. In contrast, extrahypothalamic sites including the DA-rich corpus striatum and limbic forebrain were totally insensitive to the effect of DA on food intake. The injection of DA antagonists, such as haloperidol, chlorpromazine and pimozide, into the rat perifornical hypothalamus several minutes prior to DA resulted in a dose-dependent inhibition of DA-induced anorexia (Leibowitz and Rossakis, 1979. The injection of the DA agonist, apomorphine, into the perifornical hypothalamus of food-deprived rats also resulted in a reduced food intake (Leibowitz, 1978b). The systemic administration of apomorphine elicits a reduction in rat food intake; this action can be attenuated by pretreatment with DA receptor antagonists, such as haloperidol, thioridazine and pimozide (Barzaghi et al., 1973; Heffner et al., 1977; Willner et al., 1985; Muscat et al., 1986). Anorexia is also elicited by other systemically administered DA receptor agonists, such as piribedil (Carruba et al., 1980a), lisuride (Carruba et al., 1980b) and pergolide (Greene et al., 1985). DA receptors in the CNS have been subdivided into D~ and D 2 receptors (Kebabian and Calne, 1979; Stoof and Kebabian, 1984). The ability of the selective D~ receptor agonist, SKF-38393 (Setler et al., 1978), to decrease the food consumption of free-feeding rats points to the involvement of the D~ receptor subtype (Gilbert and Cooper, 1985). 2.3. SEROTONIN

Nine major groups of 5-HT cell bodies are present in the raph6 and reticular systems of the rat brainstem with groups B7 and B8 being localized in the raph6 nuclei dorsalis and medianus, respectively (Dahlstr6m and Fuxe, 1964). The most medial ascending pathway into the forebrain innervates the hypothalamic, preoptic and septal areas. It follows the medial forebrain bundle with most of the fibres coming from B7 and B8. The next pathway, slightly more lateral, innervates the cerbral cortex. It also runs through the

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medial forebrain bundle, then sweeps dorsally along the cingulate gyrus and curves laterally into the hippocampus. Again the cell bodies are mainly groups B7 and B8. The third system primarily innervates the corpus striatum. This pathway is in the region slightly lateral to the medial forebrain' bundle. Its origin is from groups B8 and B9 (Fuxe and Johnsson, 1974). The 5-HT innervation of the hypothalamus (Saavedra et al., 1974; Palkovits et al., 1977), together with the presence of 5-HT radioligand binding sites (Bennett and Snyder, 1976; Peroutka and Snyder, 1979; Seeman et aL, 1980; Leysen et al., 1982), have catalyzed interest in the involvement of 5-HT in feeding. Early attempts to show an effect of intracranially injected 5-HT on the food intake of both deprived and satiated animals were unsuccessful (Wagner and De Groot, 1963; Myers and Yaksh, 1968; Slangen and Miller, 1969). However, others have subsequently observed that the intrahypothalamic injection of the monoamine decreases the food consumption of deprived rats (Goldman et al., 1971; Singer et al., 1971). The appetite-suppressant effect of a large intraventricular dose of 5-HT was blocked by the prior administration of the 5-HT receptor antagonist, cyproheptadine (Kruk, 1973). In hindsight, the lack of effect of 5-HT in satiated rats is not unexpected when one considers the role of 5-HT systems in regulating satiety. An added complication is that exogenous 5-HT can be accumulated by central catecholaminergic neurons and may conceivably act as a false transmitter (Shaskan and Snyder, 1970). An alternative approach to activating central 5-HT systems is that of precursor loading. 5-HTP, the immediate precursor of 5-HT, is rapidly decarboxylated by the enzyme /-aromatic amino acid decarboxylase and the administration of 5-HTP raises central levels of 5-HT (Udenfriend et al., 1957). A 5-HTP-induced diminution in food intake has been observed in a number of studies (Joyce and Mrosovsky, 1964; Singer et al., 1971; Blundell and Leshem, 1975; Goudie et al., 1976; Sugrue et al., 1978). The anorectic effect of 5-HT would appear to be central in origin because pretreatment with the/-aromatic amino acid decarboxylase inhibitor, carbidopa (MK-486), did not antagonize the effect of 5-HTP on eating (Blundell and Latham, 1979). However, 5-HTP can be decarboxylated at non-5-HT sites and this may cloud any interpretation of results (Yunger and Harvey, 1976). The use of l-tryptophan offers the advantage that its biosynthetic route to 5-HT is confined to 5-HT neurons. Exogenous tryptophan has been observed in some (l~ernstrom and Wurtman, 1972; Barrett and McSharry, 1975; Latham and Blundell, 1979) but not in other studies (Weinberger et al., 1978; Peters et al., 1984) to reduce food consumption. It has been shown that, under free-feeding conditions, tryptophan reduces total food intake and consistently decreases the size of meals with no effect on meal numbers (Blundell et al., 1980). 5-HT is inactivated by an uptake process present at the level of the 5-HT neuronal membrane, and selective inhibitors of 5-HT uptake have played a significant role in attempting to elucidate the function of 5-HT in feeding. Experiments investigating the effects of the compounds per se have yielded contradictory results. Large does of fluoxetine (Fuller et al., 1975), i.e. 10 or more mg/kg, decrease the food intake of deprived rats (Goudie et al., 1976; Sugrue et al., 1978). In contrast, the compound was found to be devoid of effect in free-feeding animals (Fuller et al., 1981). Org 6582 (Sugrue et al., 1976) and zimelidine (Ross et al., 1976), both at 30 mg/kg, reduced the intake of deprived rats (Sugrue et al., 1978), as did RU-25591 (Dumont et al., 1981). In contrast, LM 5008 (Le Fur and Uzan, 1977) was ineffective (Samanin et al., 1980a). In an elegant series of experiments, Blundell and his colleagues (Blundell and Latham, 1978; Blundell et al., 1980; Blundell, 1984) showed that femoxetine (Buus Lassen et al., 1975), fluoxetine and Org 6582 achieved their effect by slowing the rate of eating. Femoxetine has been observed to be an anti-obesity agent in one open clinical study (Smedegaard et al., 1981). A factor that complicates the results of the preclinical studies cited above is the fact that in all cases the doses required for activity are well in excess of those needed for blockade of 5-HT uptake in vivo. For example, the dose of Org 6582 required for a 50% inhibition of rat brain 5-HT uptake, as assessed in a paradigm in vivo, is 1.7 mg/kg, yet a dose of 5 mg/kg fails to alter food intake (Sugrue et al., 1978). Increasing the dose of Org 6582 to 10 or more mg/kg

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results in anorectic activity (Sugrue et al., 1978). Moreover, no temporal correlation exists between both phenomena (Goudie et al., 1976; Dumont et al., 1981). More important are the results of experiments in which 5-HTP and selective inhibitors of 5-HT uptake are co-administered. Org 6582, at a dose devoid of effect on the intake of deprived rats, markedly potentiated the effect of a marginally effective dose of 5-HTP and the effect of the combination was attenuated by metergoline (Sugrue et al., 1978). Others have independently shown that the anorectic effect of 5-HTP was enhanced by fluoxetine (Goudie et al., 1976). However, the dose of fluoxetine employed, 10 mg/kg, was relatively large and it also exhibited some anorectic activity. The results of both these studies are in harmony with the concept that 5-HT plays an important role in feeding. If the assumption that the activation of 5-HT receptors at hypothalamic sites reduces food intake is true, then the converse should hold; the effect of depleting the brain of 5-HT on eating has been the subject of numerous studies. The tryptophan hydroxylase inhibitor, PCPA, is a good depletor of brain 5-HT (Koe and Weissman, 1966) and it has been observed to decrease food consumption in some (McFarlain and Bloom, 1972; Panksepp and Nance, 1974) but not in other studies (Funderburk et al., 1971; Borbely et al., 1973; Clineschmidt, 1973; Sugrue et al., 1975). PCPA has been reported to produce gut irritation (Funderburk et al., 1971; Breisch et al., 1976) and, perhaps, this could explain the different findings. In contrast to these observations, the intraventricular injection of PCPA resulted in overeating and weight gain (Breisch et al., 1976). The PCPA-induced hyperphagia could be reversed by the administration of 5-HTP (Hoebel et al., 1978). The intraventricular injection of PCPA achieved a reduction of approximately 75% in forebrain 5-HT content; NE and DA levels were unaltered (Breisch et al., 1976). However, others have shown that PCPA-induced overeating can be dissociated from forebrain 5-HT depletion (Coscina et al., 1978; Mackenzie et al., 1979). An alternative procedure for reducing brain 5-HT content is to inject the neurotoxins, 5,6-DHT or 5,7-DHT, centrally (Baumgarten et al., 1971, 1973); an enhanced food consumption has been observed in rats following the intraventricular injection of 5,6-DHT (Diaz et al., 1974). In addition, hyperphagia and increased growth have also been observed after intraventricular 5,7-DHT (Sailer and Stricker, 1976, 1978), but this observation has not been confirmed (Hoebel et al., 1978; Baez et al., 1980). In a more recent study, it has been shown that the depletion of 5-HT in the septum, hippocampus and hypothalamus by the micro-infusion of 5,7-DHT into the ventrolateral hypothalamus at the level of the ventromedial nucleus resulted in hyperphagia and increased bodyweight, the latter being due to increased adiposity (Waldbillig et al., 1981). The increase in food intake was also more marked during the day than at night, as had been previously observed by Breisch et al. (1976). Increased eating and weight gain have also been observed after the administration of 5-HT receptor antagonists. For example, cyproheptadine increased both parameters (Baxter et al., 1970; Ghosh and Parvathy, 1973), while elevated food consumption has been observed after methysergide (Blundell and Leshem, 1974). However, these observations are the exception rather than the rule because 5-HT receptor antagonists are generally devoid of effect on the food consumption of deprived rats (Clineschmidt et al., 1974; Barrett and McSharry, 1975; Sugrue et al., 1978; Samanin et al., 1979). Perhaps this is due to methodologic factors because an increase in food intake may be more difficult to measure than an anorectic action (Blundell, 1984). Radioligand binding studies point to the heterogeneity of postsynaptic 5-HT receptors in the CNS. Central 5-HT receptors can be labeled with 3H-5-HT, 3H-d-LSD and 3H-spiroperidol. 3H-spiroperidol labels almost exclusively DA receptors in the corpus striatum, but in the cerebral cortex it binds to 5-HT receptors. Differential drug potencies in competing for 3H-5-HT and 3H-spiroperidol binding sites suggest that the two radioligands label two distinct populations of receptors. The 3H-5-HT and 3H-spiroperidol binding sites have been termed 5-HT1 and 5-HT2 sites, respectively (Peroutka and Snyder, 1979; Seeman et al., 1980). In general, agonists display higher affinities for 5-HT~ sites whereas antagonists prefer 5-HT2 sites (Peroutka et al., 1981). Radioligand binding studies suggest that 5-HTI binding sites can be differentiated into 5-HT~A and 5-HT m subtypes

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(Pedigo et al., 1981). 8-OH-DPAT shows high selectivity for 5-HTIA receptors (Middlemiss and Fozard, 1983) and also binds to presynaptic 5-HT autoreceptors in certain regions of rat brain (Hall et ai., 1985). The administration of low doses of 8-OH-DPAT to free-feeding rats has been observed to increase food intake significantly, spontaneous motor activity being unaltered. This effect of 8-OH-DPAT was attributed to an agonist action on the 5-HT autoreceptor (Dourish et al., 1985a,b). Support for this hypothesis fs the observation that the ability of 8-OH-DPAT to increase the food intake of free-feeding rats was attenuated by the prior intraventricular injection of 5,7-DHT (Bendotti and Samanin, 1986). A final indicator of the importance of 5-HT transmission in appetite control is the increased synthesis of the monoamine in fasted rats (Perez-Cruet et al., 1972). However, it is apparent that this is not consistent with the concept of 5-HT regulating satiety. Food deprivation has also been shown to increase brain tryptophan levels (Curzon et al., 1972). This observation correlates with the increased turnover of 5-HT since procedures that elevate rat brain 5-HT biosynthesis are generally associated with increased brain levels of tryptophan (Tagliamonte et al., 1971; Schubert and Sedvall, 1972; Goodlet and Sugrue, 1974). Unlike other putative neurotransmitters, the rate-limiting factor in 5-HT synthesis, under normal circumstances and within certain limits, is the availability of tryptophan, although it is most likely that this represents an oversimplifcation (Costa and Meek, 1974). Although changes in brain 5-HT turnover can be correlated with dietary tryptophan, no correlation exists between the latter and the functional activity of central 5-HT neurons (Trulson, 1985). The systemic administration of 5-HT decreases the food intake of rats and rabbits (Bray and York, 1972; Rezek and Novin, 1975; Clineschmidt et al., 1978a; Pollock and Rowland, 1981; Fletcher and Burton, 1984, 1985). The anorectic effect of 5-HT is not due to nonspecific effects, such as conditioned taste aversion and decreased spontaneous motor activity (Pollock and Rowland, 1981). Moreover, it is blocked by the prior administration of the peripheral 5-HT receptor antagonist, xylamidine (Clineschmidt et al., 1978a). 2.4. GABA GABA is an important inhibitory neurotransmitter in the CNS (Enna, 1981) and current preclinical evidence indicates that it can regulate food intake (De Feudis, 1981). The amino acid is present in high concentrations in the hypothalamus (Tappaz et al., 1977) and eating is associated with an increase in hypothalamic GABA content (Cattabeni et al., 1978). As stated elsewhere (section 1) the ventromedial and lateral hypothalamus have been implicated in ingestive behavior. The microinjection of GABA and the GABA antagonist, bicuculline, into the ventromedial and lateral hypothalamus, respectively, increased feeding by satiated rats. In contrast, food consumption was decreased following the injection of bicuculline into the ventromedial hypothalamus, as was the case following the injection of GABA into the substantia nigra. Based on these observations, it has been proposed the GABAergic neurons in the lateral and ventromedial hypothalamus may serve as modulators of afferent inputs to feeding control neurons (Kelly et al., 1977). The above data are consistent not only with the report that GABA concentrations in the lateral and ventromedial hypothalamus vary inversely with changes in blood glucose (Kimura and Kuriyama, 1975), but also with the observation that the threshold for eating induced by electrical stimulation of the lateral hypothalamus was decreased by the GABA antagonist, picrotoxin (Porrino and Coons, 1980). The paraventricular nucleus is considered to be a key site in mediating the adrenergic stimulation of feeding, see section 2.1, and the daytime eating of rats was observed to be enhanced by the microinjection of the GABA agonist, muscimol (Krogsgaard-Larsen et al., 1975), into this nucleus; in contrast, nocturnal feeding was reduced by bicuculline or picrotoxin (Kelly and Grossman, 1979; Kelly et al., 1979). The injection of muscimol into the ventromedial hypothalamus was also found to stimulate eating, an effect sensitive to antagonism by bicuculline (Grandison and Guidotti, 1977). Hyperphagia is also elicited by both intraventricular (Olgiati et al., 1980; Morley et al., 1981) and intranigral (Redgrave et al., 1984) muscimol and by the injection of THIP,

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another GABA agonist (Enna, 1981), into the caudal portion of the ventral tegmental area (Arnt and Scheel-Kruger, 1979). In contrast, a bicuculline-insensitive reduction in food intake was present after intraventricular GABA (Olgiati et aL, 1980). The dichotomous findings between GABA and muscimol are not confined to eating. For example, muscimol increases the activity of the DA nigrostriatal system (Walters and Lakoski, 1978) which is, on the contrary, inhibited when GABA levels in the substantia nigra are enhanced by EOS, vide infra, treatment (Racagni et aL, 1977). A bicuculline-sensitive stimulation of eating in satiated rats was elicited by the local injection of muscimol into the nucleus raph6 dorsalis (Przewlocka et al., 1979). Projections from these cell bodies pass to the hypothalamus, see section 2.3, and, based on electrophysiologic findings (Gallager and Aghajanian, 1976), it would appear that receptor activation by GABA results in a decreased activity of 5-HT systems originating from the nucleus raph6 dorsalis. However, eating following the injection of muscimol into the nucleus raph6 dorsalis was not significantly modified in rats pretreated with 5,7-DHT. Thus, the effect would not appear to the dependent upon the integrity of 5-HT neurons. Muscimol-induced eating was blocked by fenfluramine, an observation that further complicates the issue (Borsini et al., 1983). Rat food consumption has been reported to be reduced by i.p. muscimol (Cooper et al., 1980) and by both i.v. and oral THIP (Blavet and De Feudis, 1982; Blavet et al., 1982). Oral, but not i.v., THIP was blocked by s.c. bicuculline (Blavet and De Feudis, 1982; Blavet et aL, 1982). The effect of both GABA agonists would appear to be centrally mediated in the rat since the i.v. injection of GABA, a poor penetrator of the rat blood-brain barrier, did not influence food intake (Blavet et al., 1982). However, the administration of GABA in the diet of mice resulted in decreased food consumption and weight loss and, in part, this was attributed to the ability of large doses of GABA to increase the concentration of the amino acid in the mouse brain (Tews, 1981). Efforts at producing significant long-lasting elevations in central GABA levels have centered on the development of GABA-transaminase inhibitors (Metcalf, 1979; Palfreyman et aL, 1981). The first of these agents to be studied for its effects on eating was EOS. Both intraventricular (Olgiati et al., 1980) and intracisternal EOS (Cooper et al., 1980) produced a long-lasting, dose-related reduction in food consumption and bodyweight. The effect was central in origin as evidenced by the lack of activity of a large i.p. dose (Cooper et al., 1980). Hyperphagia following the acute administration of 2-deoxyglucose or insulin was c_mpletely abolished by intracisternal EOS (Nobrega and Coscina, 1982). A similar pretreatment with EOS also reversed the chronic overeating induced by diet palatability, bilateral medial hypothalamic lesions or genetic disposition (Coscina, 1983; Coscina and Nobrega, 1984). GVG is a specific-enzyme-activated irreversible-inhibitor of GABA-transaminase (Metcalf, 1979) and a dose-related decrease in food intake was present after both its acute and repeated i.p. injection (Gale and Iadarola, 1980; Huot and Palfreyman, 1982). Tolerance did not develop to a 2-week repeated administration of GVG (Huot and Palfreyman, 1982). The anorectic action of GVG is not dependent on NE, DA and 5-HT systems, as indicated by its effectiveness in rats pretreated with metergoline or intraventricular 6-OHDA (Huot and Palfreyman, 1982). Another GABA-transaminase inhibitor reported to cause aphagia following oral or i.p. dosing is BW357U (White et aL, 1982). A clear difference exists between locally applied and systematically administered GABA agonists on ingestive behavior. The reason for this is not clear. The dramatic elevation in whole brain GABA levels by GABA-transaminase inhibitors must to a greater or lesser degree perturb the neuronal circuitry in many brain regions. Perhaps the modifications in neuronal function after the intracranial administration of GABA and its agonists are more localized. As stated above, the local microinjection of GABA into the ventromedial hypothalamus enhances eating. Results following the injection of GABA into the lateral hypothalamus were equivocal (Kelly et al., 1977) and, as an alternative explanation, it is possible that the systemic administration of GABA agonists or GABA-transaminase inhibitors inhibits the lateral hypothalamic feeding center and that this inhibition

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surmounts any action at the ventromedial hypothalamic feeding center. The role of GABA in feeding is both complicated and intriguing. It remains to be resolved if GABA plays an equivalent functional role in man as in the rat since in one report it is stated that the administration of GVP for up to 8 weeks to patients with a variety of neuropsychiatric conditions failed to alter appetite and body weight (Huot and Palfreyman, 1982). 2.5. PEPTIDES The classical neurotransmitters have been estimated to account for approximately 40% of known synapses within the CNS. Neuropeptides probably account for the occupancy of the presently unclassified synaptic sites and approximately 40 different peptides have been found to be present in the mammalian brain (Krieger, 1983). Neuropeptides coexist in certain neurons with classical neurotransmitters and such a coexistence may represent a rule rather than an exception (Hokfelt et al., 1984). Attempts to define the mechanism of action of anorectics have focused on classical neurotransmitters. Such an approach may be restrictive because neurons may produce and release multiple messengers at their synapses. The effects of neuropeptides on ingestive behavior is a rapidly expanding area which will have undoubted ramifications on the drug therapy of obesity; an overview of their effects on eating is presented in this section. Certain neuropeptides stimulate eating whereas others decrease it. Two families of peptides have been demonstrated to enhance food intake after central administration. These are the opiate peptides and members of the pancreatic polypeptide family. Recent preliminary experiments indicate that centrally administered hypothalamic growth hormone-releasing factor stimulates food intake in rats (Vaccarino et al., 1985). The central administration of opiate peptides like beta-endorphin (Grandison and Guidotti, 1977; McKay et al., 1981), a stable met-enkephalin analog (McKay et al., 1981) and dynorphin (Morley and Levine, 1981) increase the feeding of satiated rats. Eating induced by beta-endorphin (Leibowitz and Hor, 1982) or dynorphin (Morley and Levine, 1981) is attenuated by the local administration of the opiate antagonist, naloxone. In addition, the increase in feeding following the injection of beta-endorphin into the hypothalamic paraventricular nucleus is blocked by the local administration of phentolamine (Leibowitz and Hor, 1982). Furthermore, clonidine-induced feeding is blocked by opiate antagonists (Katz et al., 1985). These observations suggest a potential association between beta-endorphin and NE. However, a number of dissociations also exist. For example, opiate agonists, in contrast to NE, preferentially stimulate fat and protein intake and this effect is unaltered by the prior 6-OHDA-induced destruction of NE nerve terminals. Moreover, beta-endorphin is less anatomically specific than NE and exerts reliable effects at multiple hypothalamic sites (Leibowitz, 1985). Opiate receptors can be characterized in terms of mu, delta, kappa and epsilon selectivity (Akil et al., 1984), and compounds that activate kappa receptors are more potent than mu agonists in stimulating feeding (Morley et al., 1984). In contrast to agonists, opiate antagonists, such as naloxone, decrease rat food intake (Holtzman, 1974; Panksepp et al., 1979). Although naloxone and its longer-acting analog, naltrexone, markedly decreased carbohydrate intake in man this is offset by an increase in fat intake and little weight loss is observed (Morley et al., 1984, 1985a). Neuropeptide Y is a member of the pancreatic polypeptide family. It occurs in mammalian brain in higher concentrations than all other peptides studied to date and high concentrations are present in the hypothalamic paraventricular nucleus (Gray and Morley, 1986). The intraventricular administration of neuropeptide Y markedly increases feeding in rats (Clark et al., 1984). This is also true after its direct injection into the paraventricular nucleus (Stanley and Leibowitz, 1984). Neuropeptide Y, like NE, is highly selective for carbohydrate-rich foods (Morley et al., 1985a,b). However, the observation that the local pretreatment of phentolamine has no effect on neuropeptide Y-induced feeding (Stanley and Leibowitz, 1985) indicates that this peptide can function independently of NE. Another difference between NE- and neuropeptide Y-induced eating is the fact that only in the case of the former is the enhanced feeding response blunted by either vagotomy or J,P.T, 32/2--E

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adrenalectomy (Gray and Morley, 1986). The effect of neuropeptide Y on feeding is decreased by pretreatment with either naloxone or haloperidol (Morley and Levine, 1985). In contrast to opiate peptides and neuropeptide Y, most other neuropeptides appear to inhibit feeding. This list includes calcitonin, cholecystokinin, corticotrophin-releasing factor, glucagon and neurotensin, but it is not clear if the reduction in feeding is a true effect or is the result of the nonspecific disruption in behavior (Morley and Levine, 1985, Morley et al., 1985b; Leibowitz, 1986). Centrally and systemically administered calcitonin decreases eating in rats, and the hypothalamic sites where locally applied calcitonin is the most effective are the paraventricular nucleus, the perifornical area and the supraoptic nucleus. However, extrahypothalamic sites also exist because injection into the nucleus accumbens also elicits an inhibition of eating (Freed et al., 1984). Cholecystokinin-induced satiety is probably mediated by both peripheral and central effects (Morley, 1982; Smith, 1983). The general doubt about the specificity of these peptides in suppressing feeding prevents the attribution of a key role in central appetite regulation to any of them. 3. ANORECTIC D R U G S AND BRAIN NEUROTRANSMITTERS Currently available anorectic drugs are fenfluramine, mazindol, diethylpropion, phen; termine, phenmetrazine and amphetamine. The most extensively investigated of these are fenfluramine, mazindol and amphetamine and each of these compounds will be discussed in detail. 3.1. AMPHETAMINE Amphetamine has long been recognized as an efficacious appetite suppressant, and it is generally regarded as the compound of reference when comparing compounds for anorectic activity. Its use as an appetite suppressant is severely curtailed by problems, such as central stimulation, loss of efficacy on repeated administration and abuse. The compound is a racemic mixture and d-amphetamine is approximately 3-4 times more potent than its l-enantiomer in suppressing food intake in both humans (Douglas and Munro, 1982) and animals (Baez, 1974). In this section, the word amphetamine is used synonymously for d-amphetamine and only in cases where both enantiomers are the subject of a comparison will the enantiomer by specified. 3.1.1. Acute Effects on Monoaminergic Systems A welter of preclinical evidence is available to indicate that the anoretic effect of systemically administered amphetamine is indirect and dependent upon an intact, central CA system. For example, prior treatment with the tyrosine hydroxylase inhibitor, alpha-MT, attenuates amphetamine-induced anorexia in rats (Weissman et al., 1966; Holtzman and Jewett, 1971; Frey and Schulz, 1973; Baez, 1974; Clineschmidt et al., 1974; Heffner et al., 1977; Zigmond et al., 1980). The restoration of the anorectic action of amphetamine in alpha-MT-treated rats by the CA precursor, e-dopa, indicates that the effect of alpha-MT is due to the depletion of DA and NE (Baez, 1974). The question as to whether amphetamine-induced anorexia is mediated via DA or NE cannot be answered by these experiments because both monoamines are depleted after alpha-MT administration. However, the observation that the anorectic effect of amphetamine was unaltered in rats selectively depleted of NE by pretreatment with the dopamine-beta-hydroxylase inhibitor, FLA-63, would favor the involvement of DA (Franklin and Herberg, 1977). Further support for DA comes from experiments in which amphetamine-induced anorexia was blunted by the prior administration of the DA receptor antagonist, haloperidol (Frey and Schulz, 1973; Clineschmidt et al., 1974; Heffner et al., 1977), although haloperidol was ineffective in one study (Sanghvi et al., 1975). Central DA receptors have been classified into D1 and D2 subtypes (see Section 2.2) and information is available to suggest that DI receptors are involved in the anorectic effect of amphetamine as evidenced by the ability of the D~ receptor antagonist, SCH-23390 (Iorio et al., 1983), to blunt the effect of

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amphetamine on food intake (Gilbert and Cooper, 1985). Experiments using the alphaadrenoceptor antagonist, phentolamine, have yielded contradictory results (Frey and Schulz, 1973; Sanghvi et al., 1975). Evidence to suggest that the site of action of amphetamine is central comes from experiments in which central monoamine stores have been depleted by either selective lesioning or by the local administration of neurotoxins, such as 6-OHDA. Amphetamineinduced anorexia is blunted in rats by the intracisternal (Hollister et al., 1975) or the intraventricular injection (Fibiger et al., 1973; Samanin et al., 1975; Heffner et al., 1977; Zigmond et al., 1980) of 6-OHDA. Animals with selective DA depletions were less sensitive than normal animals to the anorectic effect of amphetamine implying that DA neuronal systems are implicated in the ability of amphetamine to decrease food intake (Hollister et al., 1975; Heffner et al., 1977; Zigmond et al., 1980). The anorectic effect of amphetamine in the rat is attenuated by lateral hypothalamic lesioning (Carlisle, 1964; Fibiger et al., 1973; Russek et al., 1973; Blundell and Leshem, 1974). A similar phenomenon results from lesioning the ascending ventral NE bundle (Ahlskog and Hoebel, 1973; Ahlskog, 1974; Samanin et al., 1977a; Leibowitz and Brown, 1980b). Selective forebrain NE depletion by brainstem (Carey, 1976) and ventral midbrain lesioning (Ahlskog et al., 1984) are also effective. The conclusion to be drawn from all these studies is that the locus of action of amphetamine is presynaptic. The question of whether DA or NE is the primary monoamine involved is more difficult to answer. Again some support for DA comes from studies showing that amphetamine-induced anorexia is blunted by lesioning the substantia nigra (Fibiger et al., 1973; Carey and Goodall, 1975). In contrast, 6-OHDA-induced degeneration of mesolimbic DA nerve terminals failed to alter the ability of the drug to decrease rat food intake (Koob et al., 1978). Presynaptic 5-HT systems are not involved in the anorectic effect of systemically administered amphetamine because this action of the drug is unaltered in raph6-1esioned rats (Samanin et al., 1972, 1977a; Carey, 1976). This is also true for rats which have previously received either 5,6-DHT (Clineschmidt et al., 1978a) or 5,7-DHT (Hollister et al., 1975; Hoebel et al., 1978). The intraventricular (Kruk, 1973) or the direct injection of amphetamine in the rat lateral hypothalamus (Booth, 1968b) results in a suppression of food intake. The effect of intraventricular amphetamine is blocked by the prior i.p. injection of the DA receptor antagonist, pimozide (Kruk, 1973). In a series of experiments in which amphetamine was directly injected into 20 different rat brain areas, Leibowitz (1975a,b) and her associates (Leibowitz and Rossakis, 1978b) found that the most sensitive region to amphetamine was the prefornical region of the rat lateral hypothalamus. The anorectic action of locally administered amphetamine was blocked by a 10-min local pretreatment with either propranolol or haloperidol. In contrast, phentolamine, cyproheptadine and atropine were ineffective. In addition, the lateral hypothalamic injection of propranolol or haloperidol was found to block the anorexia induced by peripherally administered amphetamine. Moreover, on lateral hypothalamic injection, amphetamine was ineffective in rats which had been treated locally with alpha-MT 3 hr previously (Leibowitz, 1975a,b). The ventral adrenergic fiber system and DA projections from A8 and possibly A9 cell bodies contain the crucial fibers that innervate the prefornical region of the lateral hypothalamus (McCabe et al., 1984). Destruction of these fibers by discrete electrolytic or 6-OHDA lesioning attenuates the decrease in rat food intake following the injection of amphetamine into the prefornical hypothalamus (Leibowitz and Brown, 1980a,b). The constellation of these observations would imply that the suppressive effect of amphetamine on feeding is dependent on the functional integrity of prefornical hypothalamic beta-adrenoceptors and DA receptors. The paraventricular nucleus does not appear to be involved in the anorectic effect of amphetamine because not only was feeding unaffected after the injection of the drug into this site (Leibowitz, 1975a,b) but also electrolytic lesions left unaltered or even potentiated the anorectic effect of peripherally administered amphetamine (McCabe and Leibowitz, 1984). The i.p. injection of amphetamine 10 or 45 min before sacrifice decreased the concentration of DA in the rat prefornical hypothalamus by 50%. However, any interpretation

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of this finding is clouded by the fact that DA turnover, as assessed by the alpha-MT method, was unchanged (Leibowitz et al., 1983b). In addition to the ascending NE and nigrostriatal pathways, there is evidence to suggest that some other pathways, for example amygdalo-hypothalamic connections, may also contribute to the anorectic effect of amphetamine (Cole, 1978). At first sight, the facts that DA hypofunctioning, e.g. as a result of lesioning, results in decreased feeding and that an amphetamine-induced increase in DA activity elicits the same response would appear incompatible. In order to explain this apparent paradox, an inverted U-shaped curve relating central DA activity and feeding behavior has been proposed. In other words, excessive hypo- and hyperfunctioning of the DA system would result in anorexia. In an extension of this concept, the hypothesis has been proposed that amphetamine-induced anorexia may not reflect a selective loss of appetite but rather an altered brain state in which the ability to respond in a selective manner is lost (Stricker and Zigmond, 1984). Since the observation that large doses of amphetamine can decrease the concentration of NE in the rat brain (McLean and McCartney, 1961), much effort has been expended in attempting to delineate precisely the neurochemical profile of amphetamine. Statements to the effect that the anorectic effect of amphetamine is due to an action on central NE and/or DA systems are oversimplifications because the effects of the drug on central CA systems are complex and confusing. The ensuing description of the neurochemical actions of amphetamine is restricted because this agent is one of the most extensively employed tools in CNS research and a detailed review of the literature is outside the scope of this review. Although large doses of amphetamine can lower brain NE levels (McLean and McCartney, 1961; Baird and Lewis, 1964; Moore, 1963; Calderini et al., 1975), low doses generally have no effect (Costa et al., 1972; Groppetti et al., 1972). Central DA levels are also resistant to change after amphetamine administration (Jori and Bernardi, 1969; Costa et al., 1972; Heffner et al., 1977). However, steady-state levels of monoamines in the CNS give very little indication of the functional dynamics of the system. This is aptly reflected in the case of DA. Despite the lack of change in central DA steady-state levels, DA turnover is increased by the drug (Costa et al., 1972; Groppetti et al., 1972; Heffner et al., 1977). This is also reflected in the increased concentrations of the DA metabolite HVA which are frequently observed after amphetamine administration (Jori and Bernardi, 1969; Jori et al., 1973; Braestrup, 1977). HVA is formed extraneuronally and this reflects an increased release of DA. In contrast to HVA, the formation of DOPAC, the other major metabolite of DA, occurs intraneuronally and possibly reflects the metabolism of DA that has been released and recaptured (Roth et al., 1976). Central DOPAC values are invariably lowered after amphetamine administration (Roth et al., 1976; Westerink and Korf, 1976; Clemens and Fuller, 1979; Speciale et al., 1980). The ability of amphetamine to increase DA turnover may not extend to all DA-rich regions of the brain because the failure of the drug to increase limbic DA turnover has been reported (Lawson-Wendling et al., 1981). By means of various cannulation techniques, systemically administered amphetamine has been demonstrated to release endogenous DA (McKenzie and Szerb, 1968; Besson et al., 1971). Strong evidence exists to indicate that central DA-containing neurons contain two distinct transmitter pools: namely a small, readily releasable pool representing mainly newly synthesized amine and a larger more inert storage pool (McMillen et al., 1980). Biochemical and behavioral evidence indicate that amphetamine releases DA from the former. For example, the stimulant effects of the drug are blocked by pretreatment with alpha-MT (Weissman et al., 1966). In contrast, the depletion of the large storage pool by reserpine results in an enhanced behavioral response to amphetamine (Rech, 1964). In contrast, the behavioral effects of nonamphetamine stimulants, such as methylphenidate and mazindol, are attenuated by reserpine pretreatment (Scheel-Kruger, 1971; Ross, 1979a). A further distinction between amphetamine and nonamphetamine stimulants is their effect on the ability of a neuroleptic, such as haloperidol or spiperone, to elevate rat brain levels of DOPAC and HVA. Amphetamine tends to blunt the neuroleptic-induced

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increase whereas this is markedly enhanced by administering compounds, such as methylphenidate and mazindol (Shore, 1976; Fuller et al., 1978c; Fuller and Snoddy, 1979). The enhancement of the response to the neuroleptic was attributed to a facilitation of the impulse mediated release of DA. A further distinction between the two classes of compounds comes from experiments in which 3H-DA uptake into reserpinized and nonreserpinized isolated brain tissue was compared. The inhibitory effect of amphetamine and amphetamine-like compounds, such as phenmetrazine, on 3H-DA accumulation was found to be considerably greater after reserpinization. In contrast, the activity of compounds, such as methylphenidate and mazindol, was unaltered by reserpine pretreatment (Ross, 1979a; Ross and Kelder, 1979). Experiments in which the rotational behavior of rats with unilateral 6-OHDA-induced destruction of the nigrostriatal pathway points to the existence of an amphetamine-sensitive newly synthesized DA storage pool and a reserpine-sensitive DA storage pool (Oberlander et al., 1979). The ability of amphetamine to enhance the release of newly synthesized DA has been shown in experiments in which the caudate nucleus of the anaesthetized cat was continuously perfused with artificial CSF containing 3H-tyrosine; the perfusate was analyzed for 3H-CAs. The addition of amphetamine to the perfusing CSF evoked an immediate increase in the efflux of 3H-DA. The amphetamine-induced release of 3H-DA was abolished by prior treatment with alpha-MT whereas reserpine pretreatment was devoid of effect (Chiueh and Moore, 1975a). In contrast, the ability of methylphenidate to increase 3H-DA efflux from the cat caudate was prevented by reserpinization (Chiueh and Moore, 1975b). The efflux of 3H-DA evoked from central DA synapses by amphetamine is primarily dependent upon impulse activity in DA neurons (Von Voigtander and Moore, 1973). Both the spontaneous and the amphetamine-induced release of 3H-DA from preloaded striatal synaptosomes is blocked by DA uptake inhibitors, such as nomifensine and benztropine (Raiteri et al., 1979; Liang and Rutledge, 1982). This suggests that DA released by amphetamine may be dependent on the membrane pump for transport out of the neuron. This nonexocytotic release of DA has been termed 'exchange diffusion' (Paton, 1973). Pretreatment with DA uptake inhibitors, such as mazindol and methylphenidate, has been shown to antagonize amphetamine-induced hyperactivity in reserpinized mice (Ross, 1979a; Heikkila, 1981), an action that may be due to their ability to block the amine pump with a resultant decreased release of DA. The alternative possibility is that the uptake inhibitors prevent the active uptake of amphetamine into the DA neuron. It is apparent that it is difficult to state unequivocally that amphetamine blocks DA uptake because of the obvious technical difficulty in distinguishing between two processes, namely uptake and release, that are taking place concomitantly. In experiments in which effort has been directed at separating the two processes, there is a common consensus that amphetamine is a releaser of DA from striatal preparations (Heikkila et al., 1975; Raiteri et al., 1975; Bowyer et al., 1984). The question of uptake inhibition has its proponents (Bowyer et al., 1984) and opponents (Heikkila et al., 1975; Raiteri et al., 1975). Perhaps the complexity of the situation accounts for the confusion regarding the effect of the enantiomers of amphetamine on striatal DA uptake. The initial report that d- and /-amphetamine were equipotent at inhibiting the uptake of DA into isolated striatal tissue (Coyle and Snyder, 1969) has not been confirmed in a number of studies (Ferris et al., 1972; Thornburg and Moore, 1973; Harris and Baldessarini, 1973; Heikkila et al., 1975; Ferris and Tang, 1979; Matthews and Shore, 1984). d-Amphetamine was observed to the approximately 3-10 times more potent than its l-enantiomer in blocking DA uptake. NE storage in the CNS would appear to exist in the form of a single storage pool and, in contrast to DA, central stores of NE require to be depleted by more than 50% before the system cannot cope with demands placed on it (McMillen et al., 1980). This can be illustrated for amphetamine. For example, alpha-MT does not inhibit the amphetamineinduced reduction in NE neuronal impulse flow in the rat locus coeruleus, whereas reserpine is effective (Engberg and Svensson, 1979). This contrasts with the ability of alpha-MT to reverse the potent inhibitory action of amphetamine on impulse flow in

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DA-containing neurons of the zona compacta of the substantia nigra (German et al., 1979). An amphetamine-induced increased release of NE has been observed in experiments in which the brain of rat (Stein and Wise, 1969) and cat (Carr and Moore, 1969) has been artificially perfused. A similar observation has been made in studies in vitro using rat brain tissue (Ziance et al., 1972a; Azzaro et al., 1974; Heikkila et al., 1975, Arnold et al., 1977); the amphetamine-induced release of NE has been attributed to exchange diffusion (Paton, O 1973). However, an inability of amphetamine to release 3H-NE from rat hypothalamic synaptosomes has been observed in an investigation in which uptake and release could be separated (Raiteri et al., 1975). The ability of amphetamine to inhibit 3H-NE accumulation in rat hypothalamic synaptosomes was found to be unaltered by reserpinization. This contrasts with the effect of reserpine on striatal synaptosomal 3H-DA accumulation (vide supra); the finding was interpreted to indicate that amphetamine was more potent in inhibiting NE uptake than in releasing the monoamine (Ross, 1979b). An amphetamineinduced inhibition of NE accumulation in the CNS has been recorded in numerous studies in vivo and in vitro (Ross and Renyi, 1964; Carlsson et al., 1966; Glowinski and Axelrod, 1966; Haggendal and Hamberger, 1967; Coyle and Snyder, 1969; Ferris et al., 1972; Ziance et al., 1972a; Azzaro et al., 1974; Heikkila et al., 1975; Raiteri et al., 1975). An additional, and frequently overlooked, property of amphetamine is its ability to block MAO. An inhibition of the enzyme has been observed in rat brain after the i.p. injection of a large dose (20 mg/kg) of the compound (Glowinski and Axelrod, 1966). Direct evidence for a MAO inhibitory action after the administration of lower doses of the drug has been difficult to obtain because amphetamine is a reversible inhibitor of MAO type A (Mantle et al., 1976; Callingham and Parkinson, 1977) with the d-form being about five times more potent than the l-enantiomer (Miller et al., 1980). However, pretreatment with the drug prevents the irreversible inhibition of mouse brain MAO by phenelzine (Green and E1 Hait, 1978). This observation has been confirmed in the rat brain and ancillary experiments indicate a reversible intraneuronal MAO inhibition by amphetamine (Miller et al., 1980). The effects of amphetamine on serotoninergic systems are considered to be outwith the brief of this review because this monoamine does not play a pivotal role in the anorectic action of the drug (vide supra) and, in this respect, amphetamine differs from fenfluramine (Section 3.2). In addition to 5-HT, amphetamine exerts secondary effects on brain cholinergic systems (Moore, 1977). The anorectic profile of amphetamine has been shown to be dissimilar to that of fenfluramine in a number of experimental models (Section 3.2). This is also true in the case of salbutamol. For example, amphetamine has no effect on food-rewarded behavior whereas this is blunted by salbutamol (Garattini and Samanin, 1984). 3H-Amphetamine binds to a membrane fraction of rat brain and the highest density of binding sites was found to be present in the hypothalamus. The relative affinities of a series of phenylethylamine derivatives for hypothalamic 3H-amphetamine binding sites highly correlated with their potency as anorectic agents; these observations were interpreted to suggest the presence of specific receptor sites in the hypothalamus that mediate the anorectic effect of amphetamine and related drugs (Paul et al., 1982; Hauger et al., 1984). In follow-up studies, it has been observed that the binding of 3H-amphetamine to hypothalamic membranes is reduced during periods of food deprivation and that exposure of these rats to food rapidly reverses the decreased 3H-amphetamine binding, this reversal being dependent upon glucose (Angel et al., 1985). The assumption that amphetamine-induced anorexia is mediated solely via the CNS may not be totally true because the suppressant effect of low doses of amphetamine on food intake was blunted in rats which had been subjected to coelic ganglionectomy to produce a visceral sympathetic denervation. The liver was viewed as the most likely site for the peripheral action of amphetamine with the induced glycogenolysis resulting in the subsequent stimulation of hepatic metabolic receptors that inhibit feeding (Tordoff et al., 1982).

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3.1.2. Effects of Repeated Administration

The repeated administration of amphetamine to experimental animals results in a reduction of its initial anorectic effect (Tormey and Lasagna, 1960; Lewander, 1971, 1978; Ghosh and Parvathy, 1976; Gotestram and Lewander, 1976; Opitz, 1978). This contrasts with the unchanged (Jackson et al., 1981) or the enhanced (Segal et al., 1980; Rebec et al., 1982) behavioral response following the repeated administration of the drug. Presynaptic DA receptors appear to become subsensitive after repeated amphetamine administration, as indicated by the finding that the ability of amphetamine to release DA from rat striatal tissue was enhanced after repeated injection of the drug (Robinson and Becker, 1982). Subsensitive DA autoreceptors in the ventral tegrnental area of the rat have been demonstrated electrophysiologically after long-term amphetamine administration (Kamata and Rebec, 1984). A similar treatment reduced the sensitivity of rat neostriatal neurons to iontophoretically applied DA, thus suggesting the induction of subsensitive postsynaptic DA receptors (Kamata and Rebec, 1985). However, results from radioligand binding studies are inconclusive because the number of rat striatal DA binding sites has been observed to be either decreased (Howlett and Nahorski, 1979; Nielsen et aL, 1980) or unchanged (Burt et aL, 1977; Muller and Seeman, 1979; Jackson et aL, 1981). The relevance, if any, of such binding data to amphetamine-induced anorexia is unclear because in a study where striatal DA radioligand binding was decreased by repeated amphetamine, the anorectic response to the drug was unchanged (Bendotti et al., 1982). Although there is evidence to suggest that the selective depletion of rat forebrain DA delays the onset and the full development of tolerance to amphetamine (Bhakthavatsalam et aL, 1985), the nature and the rapidity of the onset of tolerance to amphetamine depend upon myriad factors, such as the dose, the time of dosing in relation to eating, the frequency and duration of dosing, the eating environment, etc. (Demellweek and Goudie, 1983). The unexpected observation has been made that one week after a large dose of amphetamine (20 mg/kg, i.p.) rats began to overeat and gain weight. The hyperphagia persisted for 2 months (Hoebel et al., 1981). In follow-up studies, it was found that the same phenomenon was elicited by the intraventricular injection of 0.5 mg of the drug every 12hr for 3 days. This was also the case after the lateral hypothalamic injection of amphetamine (50 #g) every 6 hr for 3 days. The observed hyperphagia was attributed to a local neurotoxic effect o f the drug (Hernandez et al., 1983). A slight increase in eating has been observed in some experiments after the administration of low doses of amphetamine (Holtzman, 1974; Dobrzanski and Doggett, 1976; Winn et al., 1982). Differences exist in the anorectic profiles of amphetamine and salbutamol (vide supra) and this is also the case after their repeated administration because cross-tolerance does not exist (Bendotti et aL, 1983). To view the anorectic effects of salbutamol in terms of beta2-adrenoceptor agonism may be restrictive because the repeated administration of salbutamol to rats is associated with an increased central turnover of 5-HT (Hallberg et aL, 1981; Sugrue, 1982). 3.2. FENFLURAMINE Fenfluramine is the most commonly used anorectic in clinical practice (Douglas and Munro, 1982), and preclinical pharmacologic studies distinguish the anorectic effect of fenfluramine from that of amphetamine. For example, procedures that deplete central stores of NE, such as intravehtricular or intracisternal injections (Fibiger et al., 1973; Hollister et aL, 1975; Samanin et al., 1975; Ahlskog et al., 1984) of the neurotoxin 6-OHDA or lateral hypothalamic lesions (BIundell and Leshem, 1974), reduce the anorectic action of amphetamine while leaving unaltered, or, in fact, enhancing the response to fenfluramine. This is also the case after lesioning the nigrostriatal pathway (Fibiger et aL, 1973; Carey and Goodall, 1975). A similar conclusion has been reached using appropriate receptor antagonists (Clineschmidt et aL, 1974). In addition, fenfluramine antagonizes both insulin= and 2-deoxy-d-glucose-induced overeating in rats whereas amphetamine attenuates only the hyperphagia induced by the latter (Carruba et

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aL, 1985). The eating patterns of rats are markedly dissimilar after the administration of either amphetamine or fenfluramine (Blundell et al., 1976). Preclinical data are available

to indicate that fenfluramine selectively suppresses appetite for carbohydrates (Wurtman and Wurtman, 1977, 1979; Moses and Wurtman, 1984). At 3-12hr post fenfluramine administration, the converse occurs, namely rats display a selective preference for carbohydrates (Li and Anderson, 1984). However, the carbohydrate suppressive role of fenfluramine has been questioned (Blundell, 1984). Fenfluramine is rapidly deethylated by the rat to norfenfluramine, a compound with marked anorectic properties (Beregi et aL, 1970; Broekkamp et al., 1975). Plasma levels of fenfluramine in the rat peak at 2 hr after oral dosing and then decrease rapidly. In contrast, plasma levels of norfenfluramine remain relatively constant between 2 and 24 hr after dosing and then decline abruptly be.ween 24 and 48hr. Concentrations of fenfluramine and norfenfluramine in rat brain mirror those in plasma except that levels are approximately 10-20 times greater (Clineschmidt et al., 1978b). Subtle differences exist between the pharmacologic profiles of the two compounds (vide infra) and the time-gap between administration and testing obviously plays an important role in experiments employing fenfluramine. The anorectic effect of fenfluramine in the rat has been attributed principally to its d-isomer since this is more potent than the corresponding l-enantiomer in decreasing food intake (Le Douarec and Neveu, 1970; Hirsch et al., 1982). However, this conclusion is partially clouded by the fact that, following the oral administration of d, l-fenfluramine to rats, the d-isomer is present in higher concentrations in plasma and disappears more slowly than the l-stereoisomer; this is due to the preferential metabolism of t-fenfluramine (Caccia et al., 1981). This is not the case in man because there is no difference in the half-lives of the two enantiomers following their acute administration (Caccia et aL, 1979, 1982). This contrasts with results following repe~ed dosing, the elimination half-life of l-fenfluramine being increased whereas that of d-fenfluramine is unchanged (Caccia et al., 1985). 3.2.1. Acute Effects on Central 5 - H T Systems The view was generally held during the 1970s that fenfluramine elicited its anorectic action by enhancing 5-HT transmission in the brain. The drug did this indirectly by releasing the monoamine from its storage sites in the nerve terminal (Garattini et aL, 1975; Garattini and Samanin, 1976). The tenet that 5-HT is implicated in the response to the anorectic still holds. However, to attribute the effect solely to 5-HT release would now appear to be questionable, and this issue will be addressed in detail in this section. A critical determinant in any pharmacologic experiment is the dose. In many of the experiments in which fenfluramine has been used, the dose employed is well in excess of that needed for anorectic activity and it is inevitable that this may result in conclusions that have little to do with the mechanism of action of the drug. In 1967, two groups reported independently that the acute administration of fenfluramine resulted in rapid reduction in the concentration of 5-HT in the brain (Duhault and Verdavainne, 1967;Opitz, 1967). A decreased level was also observed for 5-HIAA (Duhault and Verdavainne, 1967). The effect of fenfluramine on 5-HT and 5-HIAA is dose-dependent and occurs in all parts of the brain (Ghezzi et al., 1973), although quantitative regional differences have been reported (Costa et aL, 1971). Norfenfluramine also decreases brain 5-HT (Cattabeni et al., 1972; Morgan et al., 1972). However, fenfluramine acts per se since it lowers brain 5-HT levels in rats pretreated with SKF-525-A (Anders, 1971) to block its dealkylation (Garattini et al., 1975). 5-HT levels in the brains of genetically obese rats are decreased by a 5-day treatment with fenfluramine (Orosco et al., 1984). Fenfluramine achieves its effect by releasing the monoamine from its storage sites in the nerve terminal. A fenfluramine-induced release of 5-HT has been demonstrated in vitro using slices (Fuxe et al., 1975) and synaptosomes (Kannengiesser et al., 1976; Offermeier and du Preez, 1978) obtained from rat brain. Serum prolactin levels are

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partially regulated by central 5-HT functioning (Quattrone et al., 1978) and the fenfluramine-induced elevation in the concentration of prolactin in serum has been attributed to the 5-HT releasing properties of the anorectic (Fuller et al., 1981). Consistent with this postulate is the finding that analogs of norfenfluramine which deplete rat brain 5-HT raise serum prolactin values whereas the latter is unchanged by analogs devoid of effect on rat brain levels of the monoamine (Fuller et al., 1982). A fenfluramine-induced rapid release of 5-HT has also been demonstrated in behavioral studies (Trulson and Jacobs, 1976). Besides releasing 5-HT, fenfluramine has been shown to be an apparent inhibitor of 3H-5-HT uptake into slices (Fuxe et al., 1975), minces (Clineschmidt et al., 1978b) and synaptosomes (Belin et al., 1976; Kannengiesser et al., 1976; Offermeier and du Preez, 1978). 5-HT uptake into platelets is also inhibited (Buczko et al., 1975a). Synaptosomal studies in vitro suggest that d-fenfluramine is a true inhibitor of 3H-5-HT uptake. On the other hand, the inhibition of 3H-5-HT uptake by d-norfenfluramine is artifact due to the release of 3H-5-HT from an extravesicular pool (Borroni et al., 1983; Mennini et al., 1985). In order to release 5-HT, fenfluramine must be transported into the 5-HT nerve terminal by the so-called membrane amine pump. Compounds that block this carrier mechanism prevent the 5-HT-lowering action of fenfluramine; this point will be discussed in greater detail later. The fenfluramine-induced release of 5-HT is associated with a reduced turnover of the monoamine (Fuller et aL, 1978a; Fuller and Perry, 1983), although an increase in rat brain 5-HT turnover has been observed following the administration of either fenfluramine (Costa et al., 1971) or norfenfluramine (Costa and Revuelta, 1972). Perhaps the latter finding may be related to methodology, i.e. precursor labeling. In the study of Fuller and Perry (1983), a reduction in 5-HT turnover was found to be present in striatum, hypothalamus and brainstem, d-Fenfluramine is more effective than its/-enantiomer in reducing rat brain 5-HT turnover (Invernizzi et al., 1986). The fenfluramine-induced diminution in brain 5-HT content is rapid. However, the depletion by the acute administration of relatively large doses, e.g. 15 mg/kg, of the drug is long lasting with concentrations remaining below the normal values for at least 30 days (Harvey and McMaster, 1975; Sanders-Bush et al., 1975; Clineschmidt et al., 1976). This effect has been attributed to a neurotoxic action of fenfluramine on both 5-HT cell bodies (Harvey and McMaster, 1975) and nerve terminals (Clineschmidt et aL, 1978b; Steranka and Sanders-Bush, 1979). Convincing evidence is available to support the contention that the anorectic effect of fenfluramine is mediated by an action on central 5-HT systems. Various groups have shown that the behavioral and appetite suppressant effects on the compound in species, such as mouse, rat and dog, are attenuated by pretreatment with 5-HT receptor antagonists, such as cyproheptadine, metergoline and methysergide (Jespersen and ScheelKruger, 1970, 1973; Funderburk et al., 1971; Southgate et al., 1971; Blundell et al., 1973; Clineschmidt et al., 1974; Barrett and McSharry, 1975; Huot and Palfreyman, 1982). However, blockade of postsynaptic 5-HT receptors by various antagonists does not answer the question whether fenfluramine, or its metabolite norfenfluramine, is acting directly on these receptors or if the drug acts indirectly via released 5-HT. The advocates of the indirect mechanism of action base their claim on the following points. First, the 5-HT uptake inhibitor, chlorimipramine, prevents both the depletion of brain 5-HT and the anorectic response to fenfluramine (Ghezzi et al., 1973; Jespersen and Scheel-Kruger, 1973; Clineschmidt et al., 1974; Duhault et al., 1975, 1978). Second, the partial reduction of brain 5-HT content by the intraventricular injection of the neurotoxin 5,6-DHT (Baumgarten et al., 1971) has been observed to blunt fenfluramine-induced anorexia (Clineschmidt, 1973). Third, destruction of the nucleus raph6 medianus, an area rich in 5-HT cell bodies (Section 2.3), by either an electrolytic lesion or the local injection of 5,7-DHT, attenuates the response to the anorectic (Samanin et al., 1972; Fuxe et al., 1975). The reduced effect cannot be attributed to differences in brain levels of fenfluramine because lesioning has no effect on the concentrations of the stereoisomers of fenfluramine and norfenfiuramine (Mennini et al., 1980). However, for each of the above points there are an equal number of counter-

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propositions. The tryptophan hydroxylase inhibitor, PCPA (Koe and Weissman, 1966), is extremely effective at lowering brain 5-HT content yet it is universally agreed that pretreatment with PCPA fails to modify the ability of fenfluramine to suppress food intake (Opitz, 1967; Funderburk et al., 1971; Clineschmidt, 1973; Duhault et al., 1975; Sugrue et al., 1975). One could argue that fenfluramine acts in PCPA-treated rats as a result of its ability to release 5-HT from a residual storage pool. Evidence against this is the observation that a modest reduction of approximately 40% in brain 5-HT by PCPA prevents p-chloroamphetamine from eliciting its characteristic behavioral syndrome which is the result of 5-HT release (Marsden et aL, 1979). Furthermore, the attenuation of fenfluramine-induced anorexia by either raph~ lesioning or by the intraventricular injection of 5,6-DHT or 5,7-DHT has not been confirmed (Sugrue et al., 1975; Carey, 1976; Hollister et al., 1975; Hoebel et aL, 1978; Carlton and Rowland, 1984). All potent inhibitors of 5-HT uptake mimic chlorimipramine in preventing the fenfluramine-induced depletion of brain 5,HT. The same cannot be said for the effects of these compounds on various pharmacologic responses to fenfluramine. The administration of fenfluramine, 7.5 mg/kg, to rats housed at 27-28°C results in an elevation in core body temperature of approximately 1-2°C (Frey, 1975; Sulpizio et al., 1978). Pretreatment with 5-HT receptor antagonists, such as metergoline, methysergide and mianserin, markedly blunts the hyperthermic response to fenfluramine as does chlorimipramine (Sulpizio et al., 1978; Pawlowski et al., 1980; Sugrue, 1984). An extremely unexpected observation was the failure of the potent, selective 5-HT uptake inhibitors, Org 6582 (Sugrue et aL, 1976) and zimelidine (Ross et aL, 1976), to blunt the response to fenfluramine (Pawlowski, 1981; Sugrue, 1984). In contrast, other compounds with a similar profile, namely citalopram (Hyttel, 1977), femoxetine (Buus Lassen et al., 1975) and fluoxetine (Fuller et al., 1975), were effective (Sugrue, 1984). Why some, but not other, selective inhibitors of 5-HT uptake can prevent fenfluramine-induced hyperthermia remains to be resolved. The dichotomy cannot be explained in terms of differences in the effects of the agents on 5-HT uptake, storage and release mechanisms. Nor is it due to an action of the compounds on postsynaptic 5-HT receptors (Sugrue, 1984). In a similar vein, it has been observed that the sleep-suppressant action of fenfluramine in rats was unaltered by pretreatment with either PCPA or fluoxetine (Fornal and Radulovacki, 1983b). In contrast, metergoline was effective in this paradigm (Fornal and Radulovacki, 1983a). The results of the above studies indicate that responses to fenfluramine can be, and are, complex and that it may be totally unwarranted to relate the pharmacologic actions of the drug unequivocally to 5-HT release. An alternative mechanism of action of fenfluramine, and/or its deethylated congener norfenfluramine, is the direct activation of postsynaptic 5-HT receptors. Their stimulation by putative 5-HT receptor agonists results in a reduction in food intake. This has been shown for MK-212 (Clineschmidt et aL, 1977a, 1978a), quipazine (Samanin et al., 1977b,c; Carlton and Rowland, 1984) and m-chlorophenylpiperazine (Samanin et al., 1979; Cohen et al., 1983). The reduction of food intake in both cats and rats by MK-212 was antagonized by pretreatment with metergoline (Clineschmidt et al., 1977a). In contrast, the peripheral 5-HT receptor antagonist, xylamidine, was ineffective (Clineschmidt et al., 1978a), thus indicating that MK-212 has a central site of action. In contrast to fenfluramine, the anorectic action of MK-212 was found to be unchanged after chlorimipramine. Surprisingly, MK-212-induced anorexia was observed to be blunted in rats depleted of brain 5-HT by either raph6 lesions or intraventricular 5,6-DHT, but it should be added that the former procedure also attenuated amphetamine-induced anorexia; hence, its specificity in this study may be questionable (Clineschmidt et al., 1978a). In contrast, electrolytic lesions of the nucleus raph6 medianus failed to alter m-chlorophenylpiperazine-induced anorexia; the response to m-chlorophenylpiperazine was blocked by metergoline (Samanin et al., 1979). These observations are consistent with a post synaptic site of action. Metergoline also attenuates the anorectic action of quipazine (Samanin et al., 1977b). The reduction in food intake elicited by a low dose, i.e. 5 mg/kg (but not by l0 mg/kg) of quipazine was

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partially blunted by electrolytic lesions of the nucleus raph6 medianus (Samanin et al., 1977c, 1980d). Radioligand binding studies point to the heterogeneity of postsynaptic 5-HT receptors in the CNS (Section 2.3). The affinities of MK-212, m-chlorophenylpiperazine and quipazine for rat brain 5-HT radioligand binding sites have been assessed in terms of their abilities to displace 3H-5-HT. The ICs0 values were 15/~M (Fuller et al., 1978b), 2-4/zM (Fuller et al., 1978b; Samanin et al., 1980a) and 0.6/ZM (Samanin et aL, 1980a), respectively. Hence, the affinities of the three so-called piperazine-containing agonists for 5-HT~ binding sites are not spectacular and contrast with those of the so-called indole-containing agonists, e.g. 5-methoxy-N,N-dimethyltryptamine, which are in the nanomolar range (Bennett and Snyder, 1976; Whitaker and Seeman, 1978; Leysen et al., 1982). The affinity of quipazine for rat brain 5-HT2 sites, IC50 of 1/~M, is comparable to that at 5-HT~ sites (Leysen et al., 1982). In spite of their apparent modest affinity for 5-HT~ and 5-HT2 binding sites, the piperazine-containing agonists, such as MK-212, have been demonstrated to be very active in tests in vivo that are believed to reflect postsynaptic 5-HT receptor activation (Clineschmidt et aL, 1977b, 1978a; Clineschmidt and McGuffin, 1978; Clineschrnidt, 1979; Clineschmidt and Bunting, 1980). However, it should be borne in mind that this compound can inhibit 5-HT uptake and it also influences central catecholaminergic systems as indicated by changes in brain concentrations of HVA and MHPG (Clineschmidt, 1979). Quipazine has also been shown to interact with brain catecholaminergic systems (Francrs et aL, 1980; Ponzio et al., 1981). Fenfluramine possesses negligible affinity for central 5-HTt binding sites (Whitaker and Seeman, 1978; Garattini et aL, 1979; Samanin et al., 1980b). In contrast, the affinity of d-norfenfluramine for these sites is comparable to those of piperazine-containing agonists (Garattini et al., 1979) and this raises the distinct possibility that fenfluramine-induced anorexia, especially in rats, may be partially due to the direct stimulation of postsynaptic 5-HT receptors by d-norfenfluramine. Evidence in vivo for postsynaptic 5-HT receptor activation by d-norfenfluramine is the observation that its depleting effect on rat brain 5-HT content was blocked by metergoline. In contrast, metergoline did not modify the effect of d-fenfluramine (Invernizzi et al., 1982). Furthermore, the anorectic action of d-norfenfluramine, but not that of d-fenfluramine, was found to be unaltered by the prior administration of chlorimipramine. In contrast, both d-fenfluramine and dnorfenfluramine were antagonized by metergoline (Borsini et al., 1982a). Depletion of central 5-HT stores results in supersensitive postsynaptic 5-HT receptors (Trulson et al., 1976; Carruba et al., 1979; Ortmann et aL, 1981; Carlton and Rowland, 1984) and the discordant observations regarding the effect of 5-HT depletion on fenfluramine-induced anorexia may, in part, reside in the degree of receptor sensitization. Supersensitive 5-HT receptors would obviously by much more responsive than normal receptors to stimulation by active metabolites of fenfluramine, such as d-norfenfluramine. Another factor is the time between fenfluramine administration and testing. As stated above, fenfluramine is rapidly deethylated in the rat and in experiments that employ a time-gap of 3 hr, for instance, one could be studying the effect of norfenfluramine. At shorter time periods, e.g. 1 hr, the converse would occur. The effect of quipazine on the food intake of rats with denervation-induced supersensitive postsynaptic 5-HT receptors has been studied and, surprisingly, food intake was suppressed to the same degree as that in controls (Carlton and Rowland, 1984). Perhaps quipazine is not a full agonist for postsynaptic 5-HT receptors. This could explain the result since the response of denervation-induced supersensitive receptors does not mimic the response of normosensitive receptors to compounds that are not full agonists (Carlsson, 1983). 3.2.2. Acute Miscellaneous Effects In addition to its effects on central 5-HT systems, fenfluramine affects other classical neurotransmitter systems by both direct and indirect actions.

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A study of the enantiomers of both fenfluramine and norfenfluramine has revealed that d-norfenfluramine was the most effective of the four compounds at increasing the striatal content of acetylcholine followed by d-fenfluramine and l-norfenfluramine, whereas l-fenfluramine was inactive (Consolo et al., 1979a). In contrast to the striatum, d- and l-fenfluramine were equiactive in elevating acetylcholine concentrations in the hippocampus and nucleus accumbens (Consolo et al., 1980). The induced increase in the striatum is thought to be indirectly mediated by 5-HT systems since the action of d-fenfluramine was completely prevented by treatments interfering with 5-HT transmission, i.e. raph6 lesioning and PCPA or metergoline pretreatment. In contrast, the response to dfenfluramine was unaltered by nigrostriatal lesions (Consolo et al., 1979b; Crunelli et al., 1980). Hence, it would appear that there is a population of cholinergic neurons intrinsic to the striatum that is under inhibitory 5-HT regulation. Although it would appear that the ability of fenfluramine to incre~.se striatal acetylcholine levels is an indirect effect, the anorectic is capable of blocking central DA receptors as evidenced by its ability to increase striatal HVA content (Jori and Bernardi, 1969, 1972) and to antagonize apomorphine-induced stereotypes (Jori et al., 1974; Bendotti et al., 1980). Moreover, the augmentation in striatal HVA levels by fenfluramine is blocked by the prior administration of the DA agonist, piribedil (Jori and Dolfini, 1977). A study of the stereoisomers of fenfluramine and norfenfluramine has revealed that the l-enantiomers are more effective than the d-forms in elevating striatal HVA (Jori et al., 1973). This is the converse of that observed for inhibition of food intake (vide supra), and this would imply that DA receptor blockade does not play a functional role in the anorectic effect of the drug. In addition, the doses required for an effect tend to be on the high side. The ability of fenfluramine to block central DA receptors is also reflected in its ability to elevate brain DOPAC concentrations (Fuller et al., 1976, 1981). When used in anorectic doses, fenfluramine does not produce significant effects on brain NE levels (Duhault and Verdavainne, 1967; Costa et al., 1971). However, large doses can decrease brain NE concentrations (Duhault and Verdavainne, 1967; Ziance et al., 1972b) with a concomitant increase in MHPG-SO4 levels (Calderini et al., 1975), the metabolite that is thought to reflect changes in NE turnover (Meek and Neff, 1972). In contrast to its action of 3H-5-HT uptake, fenfluramine is essentially devoid of effect on the synaptosomal uptake of 3H-DA (Kannengiesser et al., 1976; Sugrue and Mireylees, 1978). Its effect on 3H-NE uptake in vitro ranges from weak to modest (Ziance and Rutledge, 1972; Sugrue and Mireylees, 1978). 3.2.3. Effects o f R e p e a t e d Administration The rapid development of tolerance to fenfluramine is a well-documented phenomenon (Le Douarec and Neveu, 1970; Kandel et al., 1975; Ghosh and Parvathy, 1976; Lewander, 1978; Opitz, 1978; Heffner and Seiden, 1979). Tolerance of fenfluramine-induced anorexia is not due to a reduction in body weight or to a concurrent increase in food deprivation (Carlton and Rowland, 1985). Cross-tolerance generally does not exist with amphetamine (Kandel et al., 1975; Lewander, 1978; Opitz, 1978), although contradictory data exist (Hunsinger et al., 1981; Hunsinger and Wilson, 1985). In harmony with the lack of cross-tolerance between the two drugs is the observation that the fenfluramine-induced increase in striatal HVA levels was unaffected in rats which had received repeated amphetamine (Jori and Bernardi, 1972; Jori et al., 1978). Again, this indicates that both drugs possess different mechanisms of action. Rats tolerant to fenfluramine showed good cross-tolerance to both quipazine and MK-212. In contrast, rats which were tolerant to both the 5-HT agonists showed no cross-tolerance to either fenfluramine or norfenfluramine (Rowland et al., 1982). This discrepancy has been attributed to differences in the nature of the acquired tolerance: fenfluramine-induced tolerance is of a biochemical nature whereas that to quipazine is learned as revealed by the lack of tolerance when quipazine was administered after feeding (Rowland and Carlton, 1983). In substitution tests in rats, both MK-212 and quipazine substituted for fenfluramine (White and Appel,

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1981). Tolerance to the anorectic effect of both fenfluramine and quipazine developed similarly in controls and in rats depleted of brain 5-HT by intraventricular 5,7-DHT (Carlton and Rowland, 1984). Efforts to explain fenfluramine-induced tolerance have concentrated on the effect of the long-term administration of the anorectic on central 5-HT binding sites, 3H-5-HT being the ligand. The twice-daily administration of d-fenfluramine (2.5 mg/kg) for at least 14 days decreased the number of binding sites in both the diencephalon (after 14 days) and the cortex (after 28 days). Moreover, in apparent harmony with this observation, rn-chlorophenylpiperazine-induced anorexia was partially antagonized in animals pretreated with fenfluramine for 28 days (Samanin et al., 1980b,c). The downregulation of central 5-HTj binding sites by the repeated administration of fenfluramine has been confirmed in one study (Dumbrille-Ross and Tan, 1983) but not in another (Rowland et al., 1983). It is unwarranted to correlate fenfluramine-induced tolerance to changes in the number of 5-HT1 binding sites because no temporal relation exists between both events; namely, tolerance appearing rapidly (less than 7 days) and the neurochemical change occurring much later. There is considerable evidence to implicate neuropeptides in ingestive behavior (see Section 2.5) and the short-term (5 days) repeated administration of d-fenfluramine results in augmented hypothalamic concentrations of metS-enkephalin and beta-endorphin (Harsing et al., 1982a). However, the dose used (15 mg/kg) is well in excess of those capable of reducing food intake, namely 2.5-5 mg/kg (Cox and Maickel, 1972; Pinder et al., 1975; Garattini and Samanin, 1976). The fenfluramine-induced elevation in the levels of both. peptides was found to be blunted by concurrently administered metergoline and the proposition was made that the augmented levels reflected a decreased utilization of endorphins that could be critical to the anorectic effect of fenfluramine (Harsing et al., 1982b). Confirmation of decreased enkephalin utilization comes from experiments that revealed that fenfluramine did not affect enkephalin synthesis (Mocchetti et al., 1985a,b). An increased hypothalamic content of met-enkephalin-like immunoreactive material has been observed as early as 24 hr after the injection of a large dose (20 mg/kg) of fenfluramine (Dellavedova et al., 1982). Of interest is the recent observation that morphine restored the efficacy of fenfluramine in rats made tolerant to the anorectic effect of the drug. The ability of fenfluramine to release 5-HT was also restored by morphine. One interpretation of these observations is that the exogenously administered opioid, namely morphine, surmounts the depressed opiate tone, and these findings would certainly appear to implicate endogenous opiates in the mechanism by which tolerance develops to fenfluramine (Groppetti et al., 1984). 3.2.4. Peripheral Effects Fenfluramine exerts a number of peripheral effects which may, in part, contribute to its anorectic action. These include enhanced lipolysis and increased glucose utilization (Pinder et al., 1975); a discussion of this facet of the pharmacology of fenfluramine is outwith the scope of this review. However, it has been proposed that fenfluramine may elicit a number of peripheral actions by means of its ability to release 5-HT from peripheral stores (Rowland et al., 1982; Davies et al., 1983; Carlton and Rowland, 1984; Rowland and Carlton, 1984)'. It has been claimed that fenfluramine-induced responses in gastrointestinal tissue are due, in part, to the release of 5-HT (Mottram and Patel, 1979), and systemically administered 5-HT can decrease food intake (Section 2.3). Fenfluramine probably does possess peripheral actions that are mediated by 5-HT. However, one factor that tilts the evidence in favor of the activation of central 5-HT receptors to account for its mechanism of action is the finding that the peripheral 5-HT receptor antagonist, xylamidine (Mawson and Whittington, 1970), is devoid of effect on anorexia induced by MK-212 (Clineschmidt et al., 1978a), d-fenfluramine and d-norfenfluramine (Borsini et al., 1982a). Additional evidence dissociating fenfluramine-induced anorexia from the peripheral release of 5-HT comes from experiments revealing that, whereas peripherally administered 5-HT produced

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a greater suppression of food intake in vagotomized rats than in sham-operated controls, fenfluramine evoked an equivalent degree of anorexia in both groups of animals (Fletcher and Burton, 1985). Thus, a dissociation is indicated between the anorectic effects of 5-HT and fenfluramine. 3.3. MAZINDOL Mazindol decreases the food intake of both humans (Silvertone, 1983) and animals (Gogerty et al., 1975; Iorio et al., 1976; Zambotti et al., 1976; Babbini et al., 1977; Sakata et al., 1984). A unique feature of mazindol is the fact that it is an imidazo-isoindole and, thus, it is considerably different in chemical structure from phenylethylamines such as fenfluramine and amphetamine. The drug has been found in numerous studies to be a very potent inhibitor of 3H-NE uptake into tissue slice or synaptosomal preparations from rat cortex or hypothalamus (Koe, 1976; Heikkila et al., 1977, 1981; Sugrue and Mireylees, 1978). This property has been confirmed in vivo, and mazindol is one of the most potent inhibitors of NE uptake available at present (Engstrom et al., 1975; Samanin et al., 1977a; Sugrue et al., 1977; Fuller et al., 1979). The compound is devoid of effect on NE release both in vivo (Engstrom et al., 1975) and in vitro (Heikkila et al., 1977). Rat brain steady-state levels of NE are unaltered by acutely administered mazindol (Engstrom et al., 1975; Carruba et al., 1976; Sugrue et al., 1977); a reduction in NE turnover has been observed (Carruba et al., 1976) which is the consequence of NE uptake inhibition. Mazindol is a modest inhibitor of 5-HT uptake into both synaptosomes (Koe, 1976; Carruba et al., 1977c; Sugrue and Mireyless, 1978; Heikkila et al., 1981) and blood platelets (Buczko et al., 1975b; Picotti et al., 1977). Unlike fenfluramine, mazindol is not a releaser of 5-HT in vitro (Carruba et al., 1977c; Heikkila et al.,1977; Picotti et al., 1977). Experiments studying the effect of the drug on the uptake of the monoamine in vivo and e x vivo have yielded contradictory results. In some studies, mazindol has been observed to be a modest inhibitor of 5-HT uptake (Carruba et al., 1977b,c; Samanin et al., 1977a). In contrast, others have reported that the drug is essentially devoid of effect (Sugrue et al., 1977; Sugrue and Mireylees, 1978; Fuller et al., 1979). It is generally agreed that mazindol has no effect on both the steady-state levels and the turnover of 5-HT in the rat brain (Carruba et al., 1976; Sugrue et al., 1977). Brain levels of 5-HT were also unaltered by the repeated administration of mazindol (Carruba et al., 1977c). The inability of mazindol to alter 5-HT turnover would be consistent with a failure to block uptake in vivo because compounds possessing this property decrease the turnover of the monoamine (Fuller, 1980). Why mazindol can block 5-HT uptake in vitro but not in vivo is not readily apparent. One possibility is that the drug is rapidly converted in vivo to metabolites that possess a reduced propensity to block 5-HT uptake. To test this, rats were pretreated with the liver microsomal enzyme inhibitor, SKF-525A (Anders, 1971), and the effect of mazindol on the uptake of 3H-5-HT e x vivo was studied. A slight enhancement of the action of mazindol was observed but this was insufficient to explain the anomaly between the effects of mazindol on the uptake of 5-HT in vivo and in vitro (Sugrue and Mireylees, 1978). The uptake of DA is blocked by mazindol both in vitro (Koe, 1976, Kruk and Zarrindast, 1976; Carruba et al., 1977a; Heikkila et al., 1977, Sugrue and Mireylees, 1978; Ross and Kelder, 1979) and in vivo (Sugrue et al., 1977; Samanin et al., 1977a). The drug has been observed in some (Kruk and Zarrindast, 1976; Carruba et al., 1977c) but not in other experiments (Heikkila et al., 1977; Ross and Kelder, 1979) to be a releaser of DA in vitro. This point is important since the anorectic action of mazindol has been attributed to this property (vide infra). Possible evidence of a release of DA in vivo is the elevation in striatal HVA levels following the administration of large doses of mazindol (Jori and Dolfini, 1977). Dorris and Shore (1974) have shown that MMTA acts as a false transmitter in DA neurons and that its decline rate reflects DA neuronal impulse flow both under normal conditions and after the administration of agents that alter impulse flow. In a study comparing the effects of d-amphetamine and mazindol on rat striatal concentrations of MMTA, it was found that mazindol was appreciably weaker than d-amphetamine in

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lowering MMTA levels which indicates that mazindol is a weak releaser of DA in vivo (Sugrue et aL, 1978). Additional in vivo evidence is available to confirm this observation. A characteristic feature of agents that block DA uptake and do not release the monoamine is their ability to enhance markedly the increased turnover of DA in the rat brain elicited by neuroleptics. This phenomenon was first observed by Shore (1976) and it has been proposed that a DA interpool regulatory mechanism exists in the rat brain such that free axoplasmic DA may regulate the transfer of DA from a storage to a releasable pool. As a consequence of uptake blockade, axoplasmic DA levels are decreased and the resultant effect is a reduced inhibition of interpool transfer (McMillen and Shore, 1979). Obviously, this does not occur with compounds that release DA, and the ability of haloperidol to elevate rat brain DOPAC levels is unaltered by d-amphetamine (Fuller et al., 1978c). In contrast, mazindol has been observed to potentiate the action of haloperidol (Fuller and Snoddy, 1979), thus indicating that mazindol does not release DA in vivo. Mazindol has been observed to increase rat striatal DA turnover (Carruba et al., 1976), while leaving whole brain steady-state levels of the monoamine unchanged (Carruba et al., 1976; Sugrue et al., 1977). The anorectic action of mazindol is dependent upon the presence of intact catecholaminergic stores, as indicated by a blunted response in rats pretreated with either intraventricular 6-OHDA (Samanin et al., 1975) or alpha-CT (Carruba et aL, 1978). An electrolytic lesion at the level of the ventral NE bundle also attenuates mazindol-induced anorexia (Samanin et al., 1977a; Leibowitz and Brown, 1980b). The reduction in food consumption elicited by mazindol has been shown in several studies to be antagonized by pretreatment with pimozide (Kruk and Zarrindast, 1976; Zambotti et al., 1976; Duhault et al., 1980). In contrast, phenoxybenzamine, l-propranolol and metergoline were all ineffective (Kruk and Zarrindast, 1976). Surprisingly, methysergide has been observed to block the anorectic action of mazindol (Barrett and McSharry, 1975). The diminution in food intake following the microinjection of mazindol into the perifornical hypothalamus was found to be attenuated by local pretreatment with either haloperidol or l-propranolol (Leibowitz and Rossakis, 1978b). In rats with unilateral lesions of the nigrostriatal DA pathway, mazindol, like d-amphetamine, induces a pimozide-sensitive rotation to the lesioned side (Kruk and Zarrindast, 1976; Zambotti et al., 1976; Carruba et al., 1978; Heikkila et al., 1981). This observation would imply that mazindol, like d-amphetamine, releases DA. However, the neurochemical data cited above are not in harmony with this logical conclusion and it is difficult to rationalize why an anomaly exists between the behavioral and neurochemical data. Germane to this, are the reports that several analogs of mazindol are potent inhibitors of DA uptake in vitro (Heikkila et al., 1981) yet they are devoid of anorectic activity (Aeberli et al., 1975a,b) and fail to elicit ipsilateral rotation in rats with unilateral lesions of the nigrostriatal system (Heikkila et al., 1981). Of interest is the recent report of the presence of specific sites for 3H-mazindol in the rat hypothalamus (Angel and Paul, 1985). The molecular identity of the recognition site is unknown. However, it is not located on catecholaminergic nerve terminals because the number of binding sites are not reduced after 6-OHDA lesions. 4. SUMMARY The importance of the central monoamines NE, DA and 5-HT in ingestive behavior has inevitably resulted in considerable effort being expended in attempting to implicate these monoamines in the mechanism of action of anorectic drugs. The statements that amphetamine-induced anorexia is unlikely to be due to central serotoninergic systems and that central noradrenergic and dopaminergic systems are not implicated in the appetite suppressant effect of fenfluramine are in all probability correct. However, to attribute the ability of drugs to decrease food intake unequivocally to a specific effect on central monoaminergic systems is almost certainly an oversimplification, due to the fact that other putative neurotransmitters, such as GABA and peptides, play a critical role in eating. This

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can be achieved either directly or by modulating the release of other transmitters. An added complication in attempting to correlate a specific neurochemical process to a behavioral effect, such as anorexia, is the complexity of the central actions of the drug. At best, a predominant but not an exclusive process can be identified. Perhaps the in-built constraint of. attempting to correlate a specific neurochemical effect to the desired action of a drug is accountable for the absence of a second generation of centrally acting anorectic drugs. Dramatic progress has been made in elucidating the factors involved in ingestive behavior over the last 5-10 years. This information should, and must, provide the catalyst for more efficacious anorectic drugs because obesity represents one of the few major diseases for which adequate drug therapy does not exist. Acknowledgement--Sincerest thanks are extended to Nicole Delorme for excellent secretarial assistance.

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