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-1 (IGF-I) 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 microg) increases the number of punished crossings in the four-plate test and NBI-31772 (0.3-10 microg) increases time spent in the open quadrant of the elevated zero maze (EZM), indicative of anxiolytic-like effects. NBI-31772 (3-30 microg) also decreases immobility time in the tail suspension test, indicative of antidepressant-like effects. Similarly, icv administration of IGF-I (0.1 microg) produces anxiolytic-like effects in the four-plate test and IGF-1 (0.3-1 microg) produces anxiolytic-like effects in the EZM. IGF-I (10 microg) also produces antidepressant-like effects in the tail suspension test. Coadministration of the IGF-I receptor antagonist JB1 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.
Malberg
Jessica E
JE
Wyeth Research, Discovery Neuroscience, Princeton, NJ, USA. Jessica.Malberg@psychogenics.com
Platt
Brian
B
Rizzo
Stacey J Sukoff
SJ
Ring
Robert H
RH
Lucki
Irwin
I
Schechter
Lee E
LE
Rosenzweig-Lipson
Sharon
S
D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal; D002396:Catechols / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D019417:Hindlimb Suspension / Q000379:methods; D007276:Injections, Intraventricular / Q000379:methods; D018969:Insulin-Like Growth Factor Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects
D000928:Antidepressive Agents; D002396:Catechols; D004791:Enzyme Inhibitors; D018969:Insulin-Like Growth Factor Binding Proteins; D007546:Isoquinolines; C436731:NBI 31772; D007334:Insulin-Like Growth Factor I