تابع دوپامینرژیک مرکزی در بی اشتهایی عصبی و پرخوری عصبی(بولیمیا) : یک رویکرد غدد روانی

Data on central dopamine (DA) function in patients with Anorexia Nervosa (AN) and Bulimia Nervosa (BN) are contradictory. To tentatively clarify the brain secretory state of the amine and its relationship with the nutritional impairments and/or the psychopathological aspects of the two disorders, we measured the responses of growth hormone (GH) to acute stimulation with apomorphine (APO), a selective D-1 and D-2 receptor agonist, in 16 AN patients, 8 restricted (AN–R) and 8 bingeing–purging (AN–BP), in 7 BN patients and in 8 healthy controls (CTR). Interference of impairment of the somatotropic axis in the GH response to APO stimulation was excluded by measuring the GH and insulin-like growth factor-1 (IGF-1) basal levels and GH responses to growth hormone-releasing hormone (GHRH) stimulation. Psychological aspects of patients and controls were investigated by the rating scales Eating Disorder Inventory (E.D.I.), Bulimic Investigation Test Edinburgh (B.I.T.E)., and Yale–Brown Cornell Eating Disorder Scale (YBC–ED). Basal GH levels were significantly higher and those of IGF-1 lower in AN–R than in AN–BP, BN and CTR subjects. GH responses to GHRH stimulation were significantly higher in AN–R than in AN–BP and BN patients and in CTR. GH responses to APO stimulation were significantly lower in AN–R and AN–BP than in BN and CTR subjects, suggesting that at the hypothalamic level there is a subsensitivity of postsynaptic D-2 receptors and possibly a presynaptic DA hypersecretion. The altered GH responses to APO stimulation did not correlate with the Body Mass Index, while they correlated negatively with E.D.I. scores.

Central dopaminergic (DA) dysfunctions have been suggested to be involved in the development and course of Anorexia Nervosa (AN). Since DA is a physiological inhibitor of hunger, acting on D-2 receptors in the hypothalamus (Leibowitz and Brown, 1980, Morley and Blundell, 1988 and Inoue et al., 1994), an hypersecretion of the amine has been proposed to be responsible for anorexia and weight loss (Barry and Klavans, 1976). Even though changes in hunger sensation has not been always confirmed in AN (Owen et al., 1985, Nakai et al., 1987, Wash et al., 1989 and Halmi, 1996), the possibility that impairments in the very complex control of the feeding system, of which DA function is a substantial part, might be involved in the development and modulation of the Disorders of Eating Behavior (ED) has never been definitely excluded. Increased central DA activity has been suggested to be responsible also for the hyperactivity which is often present during the course of AN (Barry and Klavans, 1976). Central DA stimulates the function of the limbic–hypothalamo–pituitary–adrenal (LHPA) axis, inhibits the secretion of the hypothalamo–pituitary–gonadal (HPG) axis and of the hypothalamo–pituitary–thyroid (HPT) axis, and by acting directly on the pituitary lactotrops it inhibits the secretion of prolactin (PRL). In AN, and also in BN even though less frequently and severely, the function of the LHPA axis is increased (Gold et al., 1986, Kaye et al., 1987, Kaye, 1996, Walsh et al., 1987, Fichter et al., 1990 and Vescovi et al., 1996) and that of the HPG and HPT axes and the PRL secretion are decreased (Casper et al., 1977, Judd et al., 1978, Fichter et al., 1990, Tommaselli et al., 1995 and Altemus et al., 1996), which indirectly suggests that the hypothalamic DA stimulatory activity might be higher than normal in these disorders. A central DA hyperactivity has been observed in Obsessive Compulsive Disorder (Brambilla et al., 1997), a pathology which is frequently combined with AN and BN, and has even been suggested to represent the core of a spectrum of which ED could be part (Rothenberg, 1986, Kasvikis et al., 1986, Pigott et al., 1991 and Bellodi et al., 1992). Finally, it is well known that the mesolimbic dopaminergic system is primarily involved with modulation of natural rewards and motivations (Di Chiara and Imperato, 1988 and Di Chiara, 1999). Strong motivation in terms of feeding behavior, and feeling of high reward in successful food avoidance and weight loss are central in the pathology of AN and BN. Studies of central secretion of DA and its metabolites in AN are contradictory. During the active phase of the disease, cerebrospinal fluid (CSF) concentrations of DA and its main metabolite homovanillic acid (HVA), have been found to be normal (Gerner et al., 1984), increased (Bowers et al., 1994), or decreased, with a return to normal or maintenance of increased values after weight gain (Gross et al., 1979, Riederer et al., 1981, Gillberg, 1983, Kaye et al., 1984, Kaye et al., 1999a, Kaye et al., 1999b, Ebert et al., 1984 and Jimerson et al., 1988). Plasma concentrations of HVA are decreased (Kaplan et al., 1989), while those of DOPAC, another DA metabolite, are normal (Van Binsbergen et al., 1991). Urinary HVA values are normal or increased and those of DOPAC are decreased (Johnston et al., 1984 and Van Binsbergen et al., 1991). In BN, the CSF concentrations of HVA are normal or lower than normal, particularly in patients with high binge frequency (Jimerson et al., 1988, Jimerson et al., 1992 and Kaye et al., 1990). Plasma HVA concentrations are reduced (Kaplan et al., 1989) or increased (Bowers et al., 1994). Results of pharmacological stimulation tests probing the functional state of hypothalamic postsynaptic D-2 receptors and therefore, indirectly, of presynaptic DA secretion support the hypothesis of a central DA hyperactivity in AN. Blunted growth hormone (GH) responses to acute stimulation with the D-2 agonists L-Dopa or apomorphine have been observed in anorexics in the active phase of the disease and in some cases after weight gain (Sherman and Halmi, 1977, Casper et al., 1977, Halmi and Sherman, 1977 and Halmi and Sherman, 1979). The acute administration of the D-2 antagonists metoclopramide or chlorpromazine has resulted in blunted responses of prolactin (PRL) and luteinizing hormone (LH), the prolactin impairment lasting also after weight gain (Halmi et al., 1983, Owen et al., 1983, Caviezel et al., 1984 and Golden et al., 1992). The blunted responses to the administration of the DA agonists and antagonists may be indicative of a subsensitivity of postsynaptic D-2 receptors, and, inferentially, of a presynaptic DA hypersecretion. The contrast between the results of the direct and indirect investigation of central DA secretion in ED may be due to multiple interfering factors. Measures of CSF concentrations of the amine and its metabolite are a mirror of the entire DA brain production and not of specific areas which might be involved in the pathogenesis of AN and BN, while the neuroendocrine studies reflect the hypothalamic situation, which, in turn, can not automatically be extended to higher brain centers. CSF concentrations of DA and its metabolites are the product of their secretion, metabolization and clearance. Therefore, high, normal or low values of DA, HVA and DOPAC can be due to each one of these processes, or to their combination, and not necessarily only to the secretion of DA. In this regard, the neuroendocrine tests give better indexes of the capacity of the DA system to secrete the amine in response to the body requests. However, the probes used in the stimulation–inhibition tests in the previous studies were not pure pre- or postsynaptic D-2 receptor agonists and antagonists, acting also on the nor-ioradrenergic (NE) and on the serotoninergic (5-HT) systems (Tamminga and Gerlach, 1987). Apomorphine (APO) can be considered, at the moment, an agent acting mainly as a D-1 and D-2 receptor stimulator, the quota of the NE and 5-HT involvement being practically negligible (Ernst, 1967 and Ungerstedt et al., 1981). However, APO has been used only in one study (Casper et al., 1977), in very low doses calculated on a drug dose/body weight ratio in order to avoid the violent nausea and vomiting induced by the drug and it can not be excluded that the doses used were too low to elicit substantial GH rises, therefore resulting in blunted responses of a possibly normally functioning DA system. Finally, the previous studies have never taken into consideration the possibility that the blunted responses to the various D-2 agonists and antagonists could be due to impairments of the peripheral somatotropic axis, including secretions of GH and insulin-like growth factors (IGFs), and the GH responses to growth hormone releasing hormone (GHRH) stimulation. It is well known that the peripheral parameters of the somatotropic axis are markedly altered in AN and sometimes in BN, and this has been considered a consequence of starvation or malnutrition, even though the cause of the impairments is probably much more complex (Brambilla et al., 1987, Brambilla et al., 1989, Hochberg et al., 1992, Katelsberg et al., 1996, Scacchi et al., 1997 and Argente et al., 1998). These alterations can interfere with the responses to the stimulation–inhibition tests and be responsible for the blunted GH responses to APO. In a group of patients with AN and BN we investigated the state of secretion of GH and IGF-1 and the GH responses to GHRH stimulation, followed by the GH responses to APO stimulation. The association of the two tests should give a more precise indication of the functional state of the hypothalamic postsynaptic D-2 receptors, and indirectly of presynaptic DA secretion. The aim of our study was to see whether or not the central DA function is impaired in AN and BN, and if the alteration is a phenomenon linked to the nutritional impairments or to specific psychopathological aspects of the two disorders. If this last is the case, our data would suggest the possible involvement of DA impairments in the modulation of ED and, as a consequence, the necessity of a DA-directed therapy in the treatment of the two disorders.