Down-Regulation of Decapping Protein 2 Mediates Chronic Nicotine Exposure-Induced Locomotor Hyperactivity in Drosophila

Abstract

Long-term tobacco use causes nicotine dependence via the regulation of a wide range of genes and is accompanied by various health problems. Studies in mammalian systems have revealed some key factors involved in the effects of nicotine, including nicotinic acetylcholine receptors (nAChRs), dopamine and other neurotransmitters. Nevertheless, the signaling pathways that link nicotine-induced molecular and behavioral modifications remain elusive. Utilizing a chronic nicotine administration paradigm, we found that adult male fruit flies exhibited locomotor hyperactivity after three consecutive days of nicotine exposure, while nicotine-naive flies did not. Strikingly, this chronic nicotine-induced locomotor hyperactivity (cNILH) was abolished in Decapping Protein 2 or 1 (Dcp2 or Dcp1) -deficient flies, while only Dcp2-deficient flies exhibited higher basal levels of locomotor activity than controls. These results indicate that Dcp2 plays a critical role in the response to chronic nicotine exposure. Moreover, the messenger RNA (mRNA) level of Dcp2 in the fly head was suppressed by chronic nicotine treatment, and up-regulation of Dcp2 expression in the nervous system blocked cNILH. These results indicate that down-regulation of Dcp2 mediates chronic nicotine-exposure-induced locomotor hyperactivity in Drosophila. The decapping proteins play a major role in mRNA degradation; however, their function in the nervous system has rarely been investigated. Our findings reveal a significant role for the mRNA decapping pathway in developing locomotor hyperactivity in response to chronic nicotine exposure and identify Dcp2 as a potential candidate for future research on nicotine dependence.

Nicotine-induced acute hyperactivity is mediated by dopaminergic system in a sexually dimorphic manner

“…To test the dosage dependent effects of nicotine on locomotor activity, we tested with four concentrations in addition to 0.6 mM of nicotine. In our previous study, we reported that 3.0 mM nicotine in food induced chronic locomotor hyperactivity (Ren et al, 2012). In this study, we found that acute treatment of nicotine at 3.0 mM induced locomotor hyperactivity in female flies, not however, in male flies.…”

“…In the startle-induced negative geotaxis assay using vertical columns, flies showed reduced climbing activity in response to nicotine treatment, and the acute and long-lasting effects were found to be mediated by dopaminergic system and cAMP/CREB pathway, respectively (Bainton et al, 2000, Hou et al, 2004. Using a video recording system where flies are tested in horizontal tubes (Zimmerman et al, 2008), our previous study revealed that chronic nicotine treatment induces locomotor hyperactivity in flies, and a protein in the decapping complex, decapping protein 2, was found to be a key factor in mediating nicotine-induced locomotor hyperactivity (Ren et al, 2012). Early onset of hyperactivity upon nicotine exposure has been observed in flies, though the mechanistic details behind this observation have so far not been studied (Bainton et al, 2000).…”

The 5′-3′ exoribonuclease Pacman (Xrn1) regulates expression of the heat shock protein Hsp67Bc and the microRNAmiR-277–3pinDrosophilawing imaginal discs

“…The mRNA level for Dcp2 is upregulated 1.3-fold in the pcm 5 mutant, while its pre-mRNA is 1.1-fold downregulated. Although these changes are statistically significant, they are very small (< 30%) and unlikely to be biologically significant, because a 4-fold increase in Dcp2 protein level (by expression of a transgene) generates no mutant phenotypes when flies are grown under normal conditions 25 . For CG7966 and CG31157 , the mRNA levels of which do not change in the pcm 5 mutant, the pre-mRNA levels also do not change.…”

A Drosophila model for developmental nicotine exposure

“…More recently, Zhang et al showed that dopamine also mediates the chronic nicotine exposure-induced locomotor hyperactivity in adult flies described by Ren et al [42,69]. In mammals and Drosophila , alpha7 receptors have been associated to biogenic amine release [41,63].…”