Nerve Growth Factor-Induced Neurite Sprouting in PC12 Cells Involves -1 Receptors: Implications for Antidepressants

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 -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 antagonist N,N-dipropyl-2-[4-methoxy-3-(2phenylethoxy)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. An emerging hypothesis suggests that the action of antidepressants likely involves neuroplasticity, i.e., antidepressants may exert their therapeutic effects by stimulating adaptive changes in the neuronal system. Indeed, stress as well as psychotropic drugs, including antidepressants, were reported to induce not only neurochemical alterations but also structural alterations and synaptic remodeling, including sprouting of neurites and changes of dendritic spines (Nakamura, 1991; McEwen, 2000; Norrholm and Ouimet, 2001). Specifically, in animal studies, several classes of antidepressants could reverse the reductions in the density of dendritic spines in hippocampal neurons induced by stress or by depression (McEwen, 2000; Norrholm and Ouimet, 2001). Additionally, chronic electroconvulsive shock, which is a treatment for severely depressed patients, induced the sprouting of hippocampal neurons (Gombos et al., 1999). Antidepressants, including tricyclic antidepressants and selective serotonin reuptake inhibitors, possess moderate-tohigh affinities at -1 receptors (Sig-1R) (Su, 1982; Narita et al., 1996; Shirayama et al., 1997). However, the physiological implication of the binding of these antidepressants to Sig-1R is unknown. Although most of antidepressants are known to inhibit serotonin and/or norepinephrine reuptake, the efficacy of these antidepressants cannot be solely explained by their actions on the monoaminergic system (Nestler et al.,