Cigarettes and alcohol serve as gateway drugs, which people use before progressing to the use of marijuana and then to cocaine and other illicit substances; this progression is called the "gateway sequence" of drug use. An article in the November 2, 2011 issue of Science Translational Medicine by Drs. Amir Levine, Denise Kandel, and Eric Kandel, and colleagues at Columbia University Medical Center provides the first molecular explanation for the gateway sequence. They show that nicotine causes specific changes in the brain that make it more vulnerable to cocaine addiction -- a discovery made by using a novel mouse model. Alternate orders of exposure to nicotine and cocaine were examined. [Referential web site: http://www.dependency.net/]The authors found that pretreatment with nicotine greatly alters the response to cocaine in terms of addiction-related behavior and synaptic plasticity (changes in synaptic strength) in the striatum, a brain region critical for addiction-related rewards. On a molecular level, nicotine also primes the response to cocaine by inhibiting the activity of an enzyme―histone deacetylase―in the striatum. This inhibition enhances cocaine's ability to activate a gene called FosB gene, which promotes addiction. The relationship between nicotine and cocaine was found to be unidirectional: nicotine dramatically enhances the response to cocaine, but there is no effect of cocaine on the response to nicotine. Nicotine's ability to inhibit histone deacetylase thus provides a molecular mechanism for the gateway sequence of drug use. Nicotine enhances the effects of cocaine only when it is administered for several days prior to cocaine treatment and is given concurrently with cocaine.
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