某些研究提示，香煙或酒精可以是人們?cè)谵D(zhuǎn)向使用大麻或可卡因前用的“誘導(dǎo)性毒品”,。
Amir Levine及其同事探索了這一從尼古丁到可卡因的誘導(dǎo)效應(yīng)的生物學(xué)基礎(chǔ)并發(fā)現(xiàn),，在小鼠的研究中，尼古丁可增強(qiáng)機(jī)體對(duì)可卡因的反應(yīng),。
這一對(duì)可卡因的改變了的反應(yīng)只發(fā)生在當(dāng)小鼠用尼古丁進(jìn)行“預(yù)處理”并接著同時(shí)接受了尼古丁和可卡因時(shí),。
研究人員提示，尼古丁增強(qiáng)了可卡因的襲擊能力及增加FosB基因表達(dá)的能力,，F(xiàn)osB 基因控制著部分的對(duì)可卡因的行為反應(yīng),。
Levine及其同事發(fā)現(xiàn)，來自紐約州的一小組高中生的數(shù)據(jù)與那些在小鼠中的發(fā)現(xiàn)有著良好的匹配,，對(duì)這些高中生進(jìn)行追蹤的年齡為從15歲至34歲,。
該組中的大多數(shù)的可卡因使用者在他們開始用可卡因之前都吸過煙，并且當(dāng)他們是活躍的吸煙者的時(shí)候開始使用可卡因的,。
研究人員寫道：“我們的數(shù)據(jù)提示,，有效的干預(yù)措施不僅僅可防止吸煙及其對(duì)健康的負(fù)面影響，而且它還可降低進(jìn)展成為使用慢性非法藥品的風(fēng)險(xiǎn),。” 在一篇相關(guān)的《觀點(diǎn)欄目》中,，國立藥物濫用研究所負(fù)責(zé)人Nora Volkow指出，這些研究結(jié)果還可導(dǎo)致新的成癮性藥物的分子靶點(diǎn)的發(fā)現(xiàn),。(生物谷 Bioon.com)
doi:10.1126/scitranslmed.3003062
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PMID:
Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine
Amir Levine, YanYou Huang, Bettina Drisaldi, Edmund A. Griffin Jr., Daniela D. Pollak, Shiqin Xu1, Deqi Yin, Christine Schaffran, Denise B. Kandel and Eric R. Kandel
In human populations, cigarettes and alcohol generally serve as gateway drugs, which people use first before progressing to marijuana, cocaine, or other illicit substances. To understand the biological basis of the gateway sequence of drug use, we developed an animal model in mice and used it to study the effects of nicotine on subsequent responses to cocaine. We found that pretreatment of mice with nicotine increased the response to cocaine, as assessed by addiction-related behaviors and synaptic plasticity in the striatum, a brain region critical for addiction-related reward. Locomotor sensitization was increased by 98%, conditioned place preference was increased by 78%, and cocaine-induced reduction in long-term potentiation (LTP) was enhanced by 24%. The responses to cocaine were altered only when nicotine was administered first, and nicotine and cocaine were then administered concurrently. Reversing the order of drug administration was ineffective; cocaine had no effect on nicotine-induced behaviors and synaptic plasticity. Nicotine primed the response to cocaine by enhancing its ability to induce transcriptional activation of the FosB gene through inhibition of histone deacetylase, which caused global histone acetylation in the striatum. We tested this conclusion further and found that a histone deacetylase inhibitor simulated the actions of nicotine by priming the response to cocaine and enhancing FosB gene expression and LTP depression in the nucleus accumbens. Conversely, in a genetic mouse model characterized by reduced histone acetylation, the effects of cocaine on LTP were diminished. We achieved a similar effect by infusing a low dose of theophylline, an activator of histone deacetylase, into the nucleus accumbens. These results from mice prompted an analysis of epidemiological data, which indicated that most cocaine users initiate cocaine use after the onset of smoking and while actively still smoking, and that initiating cocaine use after smoking increases the risk of becoming dependent on cocaine, consistent with our data from mice. If our findings in mice apply to humans, a decrease in smoking rates in young people would be expected to lead to a decrease in cocaine addiction.
