Abstract
Based on reports that increased hypothalamic ventromedial nucleus (VMN)-serotonin (5-HT) is associated with cancer anorexia and recent findings in our laboratory that low levels of dopamine (DA) in the VMN are associated with prolonged inter meal intervals thus decreased food intake, and reports that setting up satiation is concomitant with descending levels of DA in the rostromedial hypothalamus, we hypothesized that an elevated 5-HT to low DA ratio in the VMN modulates food intake in cancer anorexia. In Expt 1: A microdialysis cannula guide was placed stereotactically into the VMN of methylcholanthrene (MCA) sarcoma tumor-bearing (TB) Fischer rats and in non-tumor-bearing (NTB) and pair-fed (PF) controls. When TB rats manifested anorexia by a decrease in food intake, VMN-5-HT, its metabolite 5-hydroxyindolacetic acid (5-HIAA), and DA with its metabolite 3,4,-dihydroxyphenylacetic acid (DOPAC) were measured by in vivo microdialysis using HPLC during baseline, in response to food, and after feeding. In Expt 2: TB rats had tumor removed and VMN microdialysis performed 7 days later. Increased 5-HT release and turnover, and significantly reduced DA release with increased DOPAC occurred in TB vs NTB or PF rats. When food was offered, intake in TB rats was significantly lower than in NTB control rats. During eating, VMN-5-HT rose and peaked significantly earlier in TB vs NTB rats, while DA release was significantly reduced. With eating, the 5-HT and DA metabolism became reduced in all rats. Seven days after surgical removal of the tumor, 24 h food intake had increased to the level of controls; and when food was offered during microdialysis, intake in TB rats increased (ns relative to control), but was not yet normal. VMN microdialysis showed that 5-HT was normal at baseline, as well as during and after eating, while DA remained depressed. The metabolic turnover of 5-HT and DA was significantly lower in TB-r and PF vs NTB rats. We conclude that increased 5-HT/DA ratio is related to the development of cancer-induced anorexia.
Highlights
Anorexia is a major initiating factor in the development of the cachectic state in cancer
We have shown that anorectic tumor-bearing rats injected into the ventromedial nucleus (VMN) with a selective IL-1 receptor antagonist (IL-1 ra) [13] increased their food intake
The results provide direct evidence that the VMN-monoamine neurotransmitters are involved in cancer-induced anorexia: 1) Higher release of VMN 5-HT and lower release of DA, with increased metabolism of both neurotransmitters as indicated by higher 5-hydroxyindolacetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC), were found in anorectic TB vs NTB rats at the baseline; 2) While the food intake in TB rats was significantly lower, they released significantly more of VMN-5-HT during eating
Summary
Anorexia is a major initiating factor in the development of the cachectic state in cancer. Considering anorexia as loss of a desire to eat, several candidates are frequently cited as putative anorectic factors in cancer anorexia (for review see 25): cytokines [27], products of glucose, fat and amino acid metabolism [9], and more recently, neuropeptide Y [11], as well as other hypothalamic neurotransmitters [7,15,16,18,20,23,25]. The brain levels of TRP, 5-HT and 5-HIAA were not elevated in the pair-fed animals vs TB rats It ACTA MEDICA (Hradec Králové) 1998;41:3-11 appeared that the elevated serotonergic activity did not continue to increase in direct proportion to the degree of malnutrition [5], suggesting that the brain 5-HT may be involved in the development of cancer anorexia
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