Role of Brain Serotonin in Disease Associated Anorexia

Considering disease-associated anorexia as a pathological and persistent form of satiety, it is intuitive to speculate that the pathogenesis of anorexia could be related to a derangement of the physiological mechanism mediating satiety. As a consequence, much scientific effort has been devoted to clarify the involvement of hypothalam-ic appetite-suppressing circuits in the onset of anorexia. Many studies have been conducted in animal models of cancer anorexia, but it is reasonable to translate the results obtained to other diseases. Therefore, it appears that disease-associated anorexia is related to the inability of the hypothalamus to respond appropriately to consistent peripheral signals, primarily due to the hyperacti-vation of the melanocortin system. This derangement could be triggered by cytokines.

The mechanisms by which cytokines negatively influence energy intake are currently under investigation. As proposed by Inui, cytokines may play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signalling [9]. This could be done by persistent stimulation of the POMC anorexigenic pathway. Recent data suggest that hypothalamic serotonergic neurotransmission may be critical in linking cytokines and the melanocortin system [6]. Thus, it could be speculated that during disease, cytokines increase hypothalamic serotonergic activity, which in turn contributes to persistent activation of POMC neurons, leading to the onset of anorexia and reduced food intake. In humans, the demonstration of the involvement of brain serotonin in anorexia is more difficult since serotonergic activity cannot be easily measured in vivo. Thus, the activity of the hypo-thalamic serotonergic system is inferred by cerebrospinal fluid (CSF) levels of tryptophan.

Tryptophan is the precursor of serotonin, whose synthesis is strictly dependent on the availability of tryptophan [10]. In anorectic cancer patients, plasma and particularly CSF concentrations of tryptophan are increased when compared to controls and non-anorectic cancer patients [11, 12]. After tumour removal, plasma tryptophan normalises and food intake improves [13]. Similar data have been obtained in patients with liver cirrhosis. In this clinical setting, the presence of anorexia was associated with higher plasma levels of tryptophan than in non-anorectic patients with liver cirrhosis [14]. Also, brain tryptophan availability, which predicts brain tryptophan levels, was higher in anorectic than in non-anorectic patients. In uremic patients, persistently high brain serotonin levels appear to be related to the onset of anorexia and reduced food intake [15]. When considered together, these data suggest that brain serotonin could represent a key factor involved in the pathogenesis of cancer anorexia and thus provide an interesting therapeutic target.

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