Increasing the levels of insulin-like growth factor-I by an IGF binding protein inhibitor produces anxiolytic and antidepressant-like effects

The present studies were conducted to determine if increasing central levels of the neurotrophic factor insulin-like growth factor-I (IGFI) either directly or indirectly produces anxiolytic and antidepressant-like effects in the mouse. Central levels of IGF-I can be increased directly, by administering IGF-I, or indirectly by blocking the insulin-like growth factor binding proteins (IGFBPs). The IGFBP family has the unique ability to regulate IGF-I levels by sequestering IGF-I into an inactive complex. Therefore, an IGFBP inhibitor increases the level of IGF-I available to bind to its receptor. Intracerebroventricular (icv) administration of the nonspecific IGFBP inhibitor NBI-31772 ( 10 30 mu g) increases the number of punished crossings in the four-plate test and NBI-31772 (0.3-10 mu g) increases time spent in the open quadrant of the elevated zero maze (EZM), indicative of anxiolytic-like effects. NBI-31772 (3- 30 mu g) also decreases immobility time in the tail suspension test, indicative of antidepressant- like effects. Similarly, icv administration of IGF-I (0.1 mu g) produces anxiolytic-like effects in the four-plate test and IGF-I (0.3-1 mu g) produces anxiolytic-like effects in the EZM. IGF-I (10 mu g) also produces antidepressant-like effects in the tail suspension test. Coadministration of the IGF-I receptor antagonist JBI with NBI-31772 or IGF-I blocks the anxiolytic-like and antidepressant- like effects of these compounds. These results suggest that NBI-31772 produces behavioral effects by increasing levels of IGF-I that in turn activate the IGF-I receptor. The present studies demonstrate that an IGFBP inhibitor mimics the behavioral effects of IGF-I and that IGFBP inhibition may represent a novel mechanism by which to increase IGF- I to treat depression and anxiety.