Abstract # 3183 Treatment with rapamycin affects behavioral and brain protein expression in rats with experimentally induced glioblastoma

Neuropsychiatric comorbidities, such as depression or anxiety, are frequently seen in glioblastoma (GBM)-patients restricting their quality of life. mTOR signaling has been implicated in the development of certain neurological disorders and is also a key driver for GBM tumor progression. Against this background, the present study analyzed effects of treatment with the mTOR inhibitor rapamycin on tumor growth, behavior, and brain protein expression in a rat model of GBM. Male Fisher 344 rats received intracranial implantation of RG2 rat-GBM cells. One week following surgery animals were treated with rapamycin (3 mg/kg) for 7 days. Subsequently, mood and anxiety-related behaviors were assessed and brain and blood samples were taken for biochemical analyses. Systemic treatment with rapamycin inhibited RG2-cell proliferation in vitro and tumor growth in vivo. Compared to SHAM operated controls GBM-rats displayed less coping strategies when exposed to the forced-swim test. This result, however, was not observed in GBM-rats treated with rapamycin. Importantly, this ”preventing” effect of rapamycin on stress-coping was accompanied by anxiety-related behavior assessed in the elevated plus-maze test. Correspondingly, in rapamycin treated GBM animals’ protein expression of glucocorticoid receptors was decreased in the hippocampus but increased in the amygdala. These findings for the first time show that, as seen in humans, that GBM disease progression in an experimental preclinical setting is associated with neurobehavioral alterations, partially mediated by central mTOR-dependent mechanisms.