Mechanisms of metabonomic for a gateway drug: nicotine priming enhances behavioral response to cocaine with modification in energy metabolism and neurotransmitter level.
Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP) models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. (1)H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc) and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Hongyu
H
Li
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Qian
Q
Bu
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Bo
B
Chen
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Xue
X
Shao
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Zhengtao
Z
Hu
Analytical and Testing Center, Sichuan University, Chengdu, Sichuan, China.
Pengchi
P
Deng
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Lei
L
Lv
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Yi
Y
Deng
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Ruiming
R
Zhu
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Yan
Y
Li
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Baolai
B
Zhang
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Jing
J
Hou
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Changman
C
Du
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Qian
Q
Zhao
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Dengqi
D
Fu
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Yinglan
Y
Zhao
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Xiaobo
X
Cen
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002755:Choice Behavior / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D016018:Least-Squares Analysis; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects; D055432:Metabolomics; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D066244:Proton Magnetic Resonance Spectroscopy
D000596:Amino Acids; D018377:Neurotransmitter Agents; D009538:Nicotine; D003042:Cocaine