Nerve Growth Factor-Induced Neurite Sprouting in PC12 Cells Involves ς-1 Receptors: Implications for Antidepressants
- Cellular Pathobiology Unit, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland
- Dr. Tsung-Ping Su, Intramural Research Program, National Institute on Drug Abuse-National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Dr., Baltimore, MD 21224. E-mail: tsu{at}intra.nida.nih.gov
Abstract
One theory concerning the action of antidepressants relates to the drugs' ability to induce an adaptive plasticity in neurons such as neurite sprouting. Certain antidepressants are known to bind to ς-1 receptors (Sig-1R) with high affinity. Sig-1R are dynamic endoplasmic reticulum proteins that are highly concentrated at the tip of growth cones in cultured cells. We therefore tested the hypotheses that Sig-1R might participate in the neurite sprouting and that antidepressants with Sig-1R affinity may promote the neuronal sprouting via Sig-1R. The prototypic Sig-1R agonist (+)-pentazocine [(+)PTZ], as well as the Sig-1R-active antidepressants imipramine and fluvoxamine, although ineffective by themselves, were found to enhance the nerve growth factor (NGF)-induced neurite sprouting in PC12 cells in a dose-dependent manner. A Sig-1R antagonistN,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE100) blocked the enhancements caused by these Sig-1R agonists. In separate experiments, we found that NGF dose and time dependently increased Sig-1R in PC12 cells. Chronic treatment of cells with (+)PTZ, imipramine, or fluvoxamine also increased Sig-1R. These latter results suggested that NGF induces the neurite sprouting by increasing Sig-1R. Indeed, the overexpression of Sig-1R per se in PC12 cells enhanced the NGF-induced neurite sprouting. Furthermore, antisense deoxyoligonucleotides directed against Sig-1R attenuated the NGF-induced neurite sprouting. Thus, when taken together, our results indicate that Sig-1R play an important role in the NGF-induced neurite sprouting and that certain antidepressants may facilitate neuronal sprouting in the brain via Sig-1R.
Footnotes
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This study was supported by the Intramural Research Program, and in part, by the Basic Neurobiology and Biological Systems Research Branch of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services.
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DOI: 10.1124/jpet.102.041970
- Abbreviations:
- Sig-1R
- ς-1 receptors
- ER
- endoplasmic reticulum
- (+)PTZ
- (+)-pentazocine
- NE100
- N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride
- NGF
- nerve growth factor
- AS ODN
- antisense oligodeoxynucleotide
- MS ODN
- mismatched oligodeoxynucleotide
- ANOVA
- analysis of variance
- FVX
- fluvoxamine
- IMP
- imipramine
- Trk
- tropomyosin-related kinase
- MAPK
- mitogen-activated protein kinase
- [Ca 2+]i
- intracellular Ca2+
- PLC
- phospholipase C
- AP
- activator protein
- BD1047
- N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine
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- Received July 19, 2002.
- Accepted September 4, 2002.
- U.S. Government
