Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine
| Autor: | Christine Schaffran, Yan-You Huang, Eric R. Kandel, Shiqin Xu, Deqi Yin, Amir Levine, Denise B. Kandel, Daniela D. Pollak, Edmund A. Griffin, Bettina Drisaldi |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Nicotine
medicine.drug_class media_common.quotation_subject Striatum Nucleus accumbens Pharmacology Article Histone Deacetylases Epigenesis Genetic Cocaine-Related Disorders Mice Cocaine Theophylline Animals Humans Medicine media_common business.industry Addiction Histone deacetylase inhibitor Long-term potentiation General Medicine Conditioned place preference Histone Deacetylase Inhibitors Mice Inbred C57BL business FOSB medicine.drug |
| Zdroj: | Science Translational Medicine. 3 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.3003062 |
| Popis: | 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 focused on 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 both 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 inhibiting histone deacetylase, causing global histone acetylation in the striatum. We tested this conclusion further with a histone deacetylase inhibitor and found that it similarly simulated the actions of nicotine on cocaine by priming the response to cocaine, and enhancing FosB gene expression and LTP depression in the nucleus accumbens. Conversely, in a genetic mouse model of Rubinstein Taybi’s syndrome, characterized by reduced histone acetylation, the effects of cocaine on LTP were diminished. We achieved a similar effect pharmacologically by infusing a low-dose of theophylline, an activator of histone deacetylase, into the nucleus accumbens. These data from mice prompted an analysis of epidemiological data, which indicated that most cocaine users initiate cocaine use after the onset of smoking while actively smoking and that initiating cocaine use after smoking increases the risk of becoming dependent on cocaine, consistent with our data in mice. If our findings in mice apply to humans, a decrease in smoking rates in young people could also lead to a decrease in cocaine addiction. |
| Databáze: | OpenAIRE |
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