title: Insulin-like growth factor-I inhibits endogenous acetylcholine release from the rat hippocampal formation: possible involvement of GABA in mediating the effects.
abstract: Evidence suggests that insulin-like growth factor-I (IGF-I) plays an important role during brain development and in the maintenance of normal as well as activity-dependent functioning of the adult brain. Apart from its trophic effects, IGF-I has also been implicated in the regulation of brain neurotransmitter release thus indicating a neuromodulatory role for this growth factor in the central nervous system. Using in vitro slice preparations, we have earlier reported that IGF-I potently inhibits K(+)-evoked endogenous acetylcholine (ACh) release from the adult rat hippocampus and cortex but not from the striatum. The effects of IGF-I on hippocampal ACh release was sensitive to the Na(+) channel blocker tetrodotoxin, suggesting that IGF-I might act indirectly via the release of other transmitters/modulators. In the present study, we have characterized the possible involvement of GABA in IGF-I-mediated inhibition of ACh release and measured the effects of this growth factor on choline acetyltransferase (ChAT) activity and high-affinity choline uptake in the hippocampus of the adult rat brain. Prototypical agonists of GABA(A) and GABA(B) receptors (i.e. 10 microM muscimol and 10 microM baclofen) inhibited, whereas the antagonists of the respective receptors (i.e. 10 microM bicuculline and 10 microM phaclofen) potentiated K(+)-evoked ACh release from rat hippocampal slices. IGF-I (10 nM) inhibited K(+)- as well as veratridine-evoked ACh release from rat hippocampal slices and the effect is possibly mediated via the activation of a typical IGF-I receptor and the subsequent phosphorylation of the insulin receptor substrate-1 (IRS-1). The inhibitory effects of IGF-I on hippocampal ACh release were not additive to those of either muscimol or baclofen, but were attenuated by GABA antagonists, bicuculline and phaclofen. Additionally, in contrast to ACh release, IGF-I did not alter either the activity of the enzyme ChAT or the uptake of choline in the hippocampus. These results, taken together, indicate that IGF-I, under acute conditions, can decrease hippocampal ACh release by acting on the typical IGF-I/IRS receptor complex while having no direct effect on ChAT activity or the uptake of choline. Furthermore, the evidence that effects of IGF-I could be modulated, at least in part, by GABA antagonists suggest that the release of GABA and the activation of its receptors may possibly be involved in mediating the inhibitory effects of IGF-I on hippocampal ACh release.
authors.affiliation: Douglas Hospital Research Center, Department of Psychiatry, 6875 La Salle Boulevard, Verdun, QC, Canada H4H 1R3.
authors.forename: D
authors.initials: D
authors.lastname: Seto
authors.forename: W-H
authors.initials: WH
authors.lastname: Zheng
authors.forename: A
authors.initials: A
authors.lastname: McNicoll
authors.forename: B
authors.initials: B
authors.lastname: Collier
authors.forename: R
authors.initials: R
authors.lastname: Quirion
authors.forename: S
authors.initials: S
authors.lastname: Kar
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002794:Choline / Q000493:pharmacokinetics; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018755:GABA Agonists; D018756:GABA Antagonists; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D014316:Tritium; D005680:gamma-Aminobutyric Acid; D007334:Insulin-Like Growth Factor I; D002795:Choline O-Acetyltransferase; D017526:Receptor, IGF Type 1; D002794:Choline; D000109:Acetylcholine