Lack of effects by tricyclic antidepressant and serotonin inhibitors on anorexia in MCG 101 tumor-bearing mice with eicosanoid-related cachexia☆

Abstract 

Objectives

Anorexia is a major clinical problem in large number of patients with advanced cancer disease. Serotonergic mechanisms are assumed to play a role in the process of feeding behavior during normal and pathologic circumstances, which may also involve cancer anorexia according to previous experimental and clinical studies.

Methods

In the present study, we evaluated the effect of the tricyclic antidepressants desipramine (7.5 mg · kg⁻¹ · d⁻¹, intraperitoneal) and imipramine (2 to 5 mg · kg⁻¹ · d⁻¹, intraperitoneal) the serotonin synthesis inhibitor para-chlorophenylalanine (300 mg · kg⁻¹ · d⁻¹, intraperitoneal), the serotonin receptor 5-HT_2C antagonist cyproheptadine (5 mg · kg⁻¹ · d⁻¹, intraperitoneal) and the selective serotonin reuptake inhibitor citalopram (20 mg · kg⁻¹ · d⁻¹, intraperitoneal) on anorexia in MCG-101 tumor-bearing mice, a model with significant anorexia and cachexia sensitive to cyclooxygenase inhibition. Also, MCG 101–bearing mice develop well-recognized alterations in brain tryptophan/serotonin metabolism as increased Trp, 5-HPT, and 5-HIAA during tumor progression.

Results

Daily provision of desipramine, imipramine, para-chloropheylalanine, cyproheptadine, and citalopram at doses that cause behavioral and metabolic alterations in normal mice did not alter food intake or body weight in tumor-bearing and healthy control mice. Also, the treatments did not decrease elevated plasma concentrations of interleukin-6 and prostaglandin E₂ in the tumor-bearing mice.

Conclusions

Thus, our results do not support previous observations that serotonin metabolism itself is a major factor behind anorexia in tumor-bearing animals in general. Rather, other mechanisms, such as eicosanoid and nitric oxide–dependent pathways, seem to be more important for induction of anorexia along tumor progression in the present model.

Keywords:  anorexia, cachexia, tricyclic antidepressant