Antidepressant-like behavioral effects of IGF-I produced by enhanced serotonin transmission.
Previous research has suggested that mobilization of neurotrophic factors, such as insulin-like growth factor I (IGF-I), can be involved in the effects of antidepressant treatments. The current experiments showed that IGF-I leads to antidepressant-like effects in the modified rat forced swim test when tested 3 days, but not 1 day, after i.c.v. administration. These effects were sustained longer than the antidepressants paroxetine and desipramine. In addition, blockade of the IGF-I receptor with the IGF-I antagonist JB1 30 min before IGF-I administration prevented the antidepressant-like effects of IGF-I. However, when JB1 was administered 3 days after IGF-I administration and 30 min prior to testing, the antidepressant-like effects of IGF-I were still present suggesting that IGF-1 produces a long-term activation of neural systems involved in the antidepressant response. Because the pattern of antidepressant-like effects of IGF-I resembled those of selective serotonin reuptake inhibitors, the role of serotonin in the behavioral effects of IGF-I was studied. Depletion of serotonin, by the tryptophan hydroxylase inhibitor para-chlorophenylalanine, blocked the antidepressant-like effects of IGF-I. Administration of IGF-I increased basal serotonin levels in the ventral hippocampus and altered the effects of acute citalopram. IGF-I administration did not change hippocampal cell proliferation at the 3-day timepoint when behavioral effects were seen. In addition, IGF-I did not alter the expression of mRNA levels of tryptophan hydroxylase or SERT in the brain stem, or [3H] citalopram binding in the hippocampus or cortex. Thus, IGF-I administration initiates a long-lasting cascade of neurochemical effects involving increased serotonin levels that results in antidepressant-like behavioral effects.
Hoshaw
Brian A
BA
University of Pennsylvania, Department of Psychiatry, Philadelphia, PA 19104, USA.
Hill
Tiffany I
TI
Crowley
James J
JJ
Malberg
Jessica E
JE
Khawaja
Xavier
X
Rosenzweig-Lipson
Sharon
S
Schechter
Lee E
LE
Lucki
Irwin
I
D000818:Animals; D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015283:Citalopram / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects; D003891:Desipramine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000187:drug effects; D012701:Serotonin / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism; D013550:Swimming / Q000523:psychology; D009435:Synaptic Transmission / Q000187:drug effects*; D014365:Tryptophan Hydroxylase / Q000378:metabolism
D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D015283:Citalopram; D003891:Desipramine; D007334:Insulin-Like Growth Factor I; D009414:Nerve Growth Factors; D017374:Paroxetine; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014365:Tryptophan Hydroxylase