Antidepressant-like behavioral effects of IGF-I produced by enhanced serotonin transmission - PubMed (original) (raw)

Antidepressant-like behavioral effects of IGF-I produced by enhanced serotonin transmission

Brian A Hoshaw et al. Eur J Pharmacol. 2008.

Abstract

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.

PubMed Disclaimer

Figures

Fig. 1

Fig. 1

Blockade of antidepressant-like effects by the antagonist JB1given before but not after IGF-I. A, Rats were pretreated i.c.v. with either vehicle (aCSF) or varied doses of JB1 (5 (n = 5), 10 (n = 5), or 20 μg (n = 6); i.c.v.) 30 min before administration of either the vehicle or IGF-I (1 μg; i.c.v.). The FST session (5 min) was run 3 days later. Administration of vehicle-IGF-I (n = 12) decreased immobility and increased swimming behavior compared to the vehicle-vehicle group (n = 11). This effect was blocked by pretreatment with JB1 30 min before IGF-I, with the highest dose of JB1 blocking both the decrease in immobility and increase in swimming. ANOVAs revealed significant overall effects for immobility [F(5,39) = 7.33, P < .001] and swimming [F(5,39) = 6.25, P < .001] but not for climbing [F(5,39) = 1.25, P > .05].M B, Administration of JB1 3 days after IGF-I administration and 30 min before the FST, was not able to block the antidepressant-like effects of IGF-I. Rats were pretreated with either vehicle (aCSF) or IGF-I (1 μg) 24 h after the pretest session (15-min), and then administered either vehicle (aCSF) or JB1 (20 μg) 30 min before the FST session (5 min). Administration of IGF-I (n = 6) led to a significant decrease in immobility and a significant increase in swimming compared to the vehicle-vehicle group (n = 7), but administration of JB1 30 min before the FST (n = 7) did not block those behavioral effects. There were no significant differences between the vehicle-JB1 group (n = 6) and the vehicle-vehicle group. Two-factor ANOVA revealed that there was a significant effect for drug treatment (IGF-I vs. aCSF) in immobility [F(1,22) = 19.32, P < .001] and swimming [F(1,22) = 33.89, P < .0001], but no effect for pretreatment group (JB1 vs. aCSF) for either immobility [F(5,39) = 0.58, P > .05] or swimming [F(5,39) = 0.23, P > .05]. Values represent mean ± 1 S.E.M. * indicates P < .05 compared with the vehicle-vehicle group.

Fig. 2

Fig. 2

IGF-I did not fully produce antidepressant-like effects in the FST when tested 1 day after administration. IGF-I (1 μg; n = 7) or vehicle (aCSF; n = 7) was administered 24 h before the FST pretest (15-min), and the 5-min FST session was run 1 day after injection. Values represent mean ± 1 S.E.M.

Fig. 3

Fig. 3

Effects of antidepressants in the modified FST, either the SSRI paroxetine or the selective norepinephrine reuptake inhibitor desipramine,. A, Rats were tested in the FST 1 h after the last of 3 injections with either paroxetine (20 mg/kg), desipramine (20 mg/kg) or saline (n=10 each). One-factor ANOVA revealed significant effects for immobility [F(2,21) = 5.96, P < .001], swimming [F(2,21) = 8.35, P < .003], and climbing [F(2,21) = 6.45, P < .007]. Both drugs showed antidepressant-like effects. The SSRI paroxetine decreased immobility and increased swimming, while desipramine decreased immobility and increased climbing. B, Neither antidepressant was active in the FST when the rats were tested 3 days after the last injection. Values represent mean ± 1 S.E.M. * indicates P < .05 compared with saline.

Fig. 4

Fig. 4

Depletion of serotonin blocked the antidepressant-like effects of IGF-I in the FST. Serotonin synthesis was inhibited by administering the tryptophan hydroxylase inhibitor PCPA (300 mg/kg; i.p.) 24 h before the first 15-min session. Vehicle or IGF-I (1 μg) was then administered 24 h later, and the rats were tested in the second session of the FST 3 days later, or 96 h after PCPA pretreatment. IGF-I (n = 9) produced a significant decrease in immobility and increase in swimming compared to the saline-vehicle group (n = 9). Pretreatment with PCPA before vehicle (n = 11) had no effect on any of the three behaviors compared to the saline-vehicle group. However, PCPA pretreatment blocked the antidepressant-like effects of IGF-I (n = 11). Therefore, serotonin transmission appears to be necessary for the antidepressant-like effects of IGF-I. Values represent mean ± 1 S.E.M. * indicates P < .05 compared with the saline-vehicle group.

Fig. 5

Fig. 5

IGF-I administration increased basal serotonin levels in the ventral hippocampus 3 days, but not 1 day, after administration as measured using in vivo microdialysis. Values represent mean (pg) ± 1 S.E.M. * indicates P < .05 compared with aCSF control. A, Hippocampal serotonin levels measured 1 day after IGF-I (1 μg; n = 6) administration. Four 20-min samples were collected as a baseline measure before the systemic injection of citalopram (2.5 mg/kg; i.p.). IGF-1 did not affect basal serotonin levels compared with vehicle (aCSF; n = 4). There was a trend towards an increase in the percentage change in serotonin levels after citalopram administration (P = .07). B, Hippocampal serotonin levels measured 3 days after administration of either vehicle (aCSF; n = 6) or IGF-I (1 μg; n = 5) administration. The IGF-I-pretreated rats had significantly higher basal serotonin levels (P < .02). Although the cumulative output after citalopram injection was smaller in rats treated with IGF-1, the difference was not significant (P = .09). The time course for the ability of IGF-I to increase serotonin levels in the ventral hippocampus coincides with the time course for the appearance of behavioral effects in the FST.

Fig. 6

Fig. 6

Cell proliferation in the dentate gyrus of the hippocampus was not affected 3 days after IGF-I administration. The number of cells labeled with BrdU in the subgranular zone of the dentate gyrus were counted and compared to vehicle controls. The thymidine analog BrdU (100 mg/kg, i.p.) was injected 3 days after a single administration of either vehicle or IGF-I (1 μg; n = 7 each). Rats were perfused 2 h later and immunohistochemistry for BrdU performed to visualize labeled cells on the sectioned tissue. Values represent mean ± 1 S.E.M.

Similar articles

Cited by

References

    1. Aberg MA, Aberg ND, Hedbacker H, Oscarsson J, Eriksson PS. Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci. 2000;20:2896–2903. - PMC - PubMed
    1. Aberg MA, Brywe KG, Isgaard J. Aspects of growth hormone and insulin-like growth factor I related to neuroprotection, regeneration, and functional plasticity in the adult brain. Scientific World Journal. 2006;6:53–80. - PMC - PubMed
    1. Aguado F, Rodrigo J, Cacicedo L, Mellstrom B. Distribution of insulin-like growth factor-I receptor mRNA in rat brain. Regulation in the hypothalamo-neurohypophysial system. J Mol Endocrin. 1993;11:231–239. - PubMed
    1. Airan RD, Meltzer LA, Roy M, Gong Y, Chen H, Deisseroth K. High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science. 2007;317:819–823. - PubMed
    1. Altar CA. Neurotrophins and depression. Trends Pharmacol Sci. 1999;20:59–61. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources