Repetitive exposures to nicotine induce a hyper-responsiveness via the cAMP/PKA/CREB signal pathway in Drosophila.
Nicotine, in addition to acute effects, has long-lasting effects on mammalian behaviors, such as those leading to addiction. Here we present genetic and pharmacological evidence in Drosophila suggesting that repetitive exposures to nicotine induce a hyper-responsiveness through synthesis of new protein(s) via CREB-mediated gene transcription. Single exposure to volatilized nicotine dose-dependently inhibited the startle-induced climbing response. Compared with this effect of nicotine in wild-type flies, it was stronger in dunce, which has defective phosphodiesterase, and in wild-type flies treated with a phosphodiesterase inhibitor, whereas it was weaker in DC0, which has defective protein kinase A (PKA), and in wild-type flies treated with a PKA blocker. Thus, the effect of nicotine is enhanced by a mechanism involving the cAMP/PKA cascade. However, in wild-type flies, an increase in head cAMP was not detected within 2 min after single exposure to nicotine, during which the nicotine effect on the behavior was maximal. In wild-type flies, after repetitive exposures to nicotine, the nicotine effect was significantly enhanced and the head cAMP was elevated. The responsiveness to nicotine at second exposure increased with a 4 h interval but not with a 2 h interval, suggesting that the observed hyper-responsiveness was not due to accumulation of residual nicotine. Both enhancement of the nicotine effect and elevation of cAMP during repetitive exposures to nicotine were blocked by a protein synthesis inhibitor. Induction of a dominant negative CREB transgene also blocked the enhancement, suggesting that CREB-mediated gene transcription is required for the hyper-responsiveness.
Hou
Jiamei
J
Institute for Behavioral Sciences, Gunma University School of Medicine, 3-39-22, Showa-machi, Maebashi 371-8511, Japan.
Kuromi
Hiroshi
H
Fukasawa
Yohko
Y
Ueno
Kohei
K
Sakai
Takaomi
T
Kidokoro
Yoshiaki
Y
D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D001923:Brain Chemistry; D002227:Carbazoles / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000032:analysis; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004330:Drosophila; D029721:Drosophila Proteins / Q000172:deficiency / Q000502:physiology; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D002227:Carbazoles; D017362:Cyclic AMP Response Element-Binding Protein; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D018722:Nicotinic Agonists; D011500:Protein Synthesis Inhibitors; D011758:Pyrroles; C057416:KT 5720; D009538:Nicotine; D003513:Cycloheximide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020889:Rolipram