gms | German Medical Science

Objective: Mood disorders are severe neuropsychiatric comorbidities of glioblastoma patients significantly restricting quality of life. Long-term glucocorticoid treatment, side effects of surgical resection or radio-chemotherapy, the poor prognosis or disturbances of neuronal signaling induced by the tumor itself are possible modulatory aspects. However, the underlying pathophysiology of these central side effects is still unclear. Against this background, we established an orthotopic glioblastoma (GBM) model to analyze neurobehavioral alterations occurring during brain tumor progression. To our knowledge, this is the first experimental approach to assess mood-related behavior in GBM.

Methods: Male Fischer 344 rats (n=20) were sham operated or implanted intracranially with RG2 cells. Anesthetized rats (isoflurane/oxygen mixture with 1–3 % isoflurane) were placed in a stereotaxic frame. Intracranial GBM was established by injection of 2 x 104 RG2 cells into the right dorsal striatum. Following surgery, animals were individually housed with free access to food and tap water. All rats were monitored daily for symptoms such as difficulty in ambulating, feeding, or grooming, or appearance of neurological disturbances as body weight loss. Tumor growth was permitted for 14 days. Mood-related behavior was assessed by the Forced-Swim test (FST), which is one of the most commonly used assays for the study of depressive-like behavior in rodents. Performance in the FST was analyzed at day 13 (priming) and 14 (testing trial).

Results: Implantation of 2 x 104 RG2 cells resulted in large tumor growth in the right hemisphere. No weight loss or difficulties in ambulating, feeding, or grooming emerged. More importantly, no neurological disturbances occurred throughout the whole experiment. Thus, exclusion of an animal due to violation of local ethical requirements was not necessary. In the FST, no sign of drowning was seen during performance. Compared to SHAM controls RG2-implanted rats displayed increased depressive-related behaviors.

Conclusion: Syngen orthotopic RG2 cell implantation (2 x 104) in the male Fisher rat leads to a stabile tumor growth over 14 days without any effect on the general conditions of the animals. Moreover, the FST is a suitable neurobehavioral test to assess mood-retated behavior in experimental GBM. We here present a novel robust GBM model that provides investigating behavioral disturbances occurring comorbid or as a consequence of brain tumor progression.