Repeated Systemic Treatment with Rapamycin Affects Behavior and Amygdala Protein Expression in Rats.

Background: Clinical data indicate that therapy with small-molecule immunosuppressive drugs is frequently accompanied by an incidence rate of neuropsychiatric symptoms. In the current approach, we investigated in rats whether repeated administration of rapamycin, reflecting clinical conditions of patients undergoing therapy with this mammalian target of rapamycin inhibitor, precipitates changes in neurobehavioral functioning. Methods: Male adult Dark Agouti rats were daily treated with i.p. injections of rapamycin (1, 3 mg/kg) or vehicle for 8 days. On days 6 and 7, respectively, behavioral performance in the Elevated Plus-Maze and the Open-Field Test was evaluated. One day later, amygdala tissue and blood samples were taken to analyze protein expression ex vivo. Results: The results show that animals treated with rapamycin displayed alterations in Elevated Plus-Maze performance with more pronounced effects in the higher dose group. Besides, an increase in glucocorticoid receptor density in the amygdala was seen in both treatment groups even though p-p70 ribosomal S6 kinase alpha, a marker for mammalian target of rapamycin functioning, was not affected. Protein level of the neuronal activity marker c-Fos was again only elevated in the higher dose group. Importantly, effects occurred in the absence of acute peripheral neuroendocrine changes. Conclusions: Our findings indicate that anxiety-related behavior following rapamycin treatment was not directly attributed to mTOR-dependent mechanisms or stress but rather due to hyperexcitability of the amygdala together with glucocorticoid receptor-regulated mechanism(s) in this brain region. Together, the present results support the contention that subchronic treatment with rapamycin may induce neurobehavioral alterations in healthy, naive subjects. We here provide novel insights in central effects of systemic rapamycin in otherwise healthy subjects but also raise the question whether therapy with this drug may have detrimental effects on patients' neuropsychological functioning during immune therapy.