Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine

Abstract

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.

Differential Roles of α6β2* and α4β2* Neuronal Nicotinic Receptors in Nicotine- and Cocaine-Conditioned Reward in Mice

“…Furthermore, the involvement of a6b2* nAChRs was confirmed by the blockade of cocaine CPP with a-conotoxin MII [H9A; L15A] given i.c.v. These results are not surprising as previous studies have shown that nicotinic agonists and antagonists modulate cocaine reward, reinforcement, and sensitization (Champtiaux et al, 2006;Horger et al, 1992;Levine et al, 2011;Reid et al, 1998;Reid et al, 1999;Zachariou et al, 2001;Zanetti et al, 2007). Our results expand on a previous study implicating a role for b2 in cocaine place preference (Zachariou et al, 2001) by suggesting that a6 is the subunit co-expressed in the nicotinic subtype that is mediating the reward like effects of cocaine.…”

“…For example, Horger et al (1992) observed increased cocaine self-administration by rats that were preexposed to nicotine. Levine et al (2011) recently observed that nicotine pretreatment increased cocaine locomotor sensitization and conditioned place preference (CPP) in mice. Similarly, the nonselective nicotinic antagonist mecamylamine decreased cocaine self-administration in rats (Levin et al, 2000;Blokhina et al, 2005) and reduced cue-induced cocaine craving in cocaine-dependent and cigarette smoking humans (Reid et al, 1998).…”

Nicotine pretreatment reduced cocaine-induced CPP and its reinstatement in a sex- and dose-related manner in adult C57BL/6J mice

“…This period of life is a very sensitive age in which the negative affective state associated with nicotine withdrawal is reduced while the rewarding action of nicotine is enhanced compared to adults (Carcoba et al, 2014;Dickson et al, 2014;Dickson et al, 2011;Hutchison and Riley, 2008;Lee et al, 2015;McQuown et al, 2009;Natividad et al, 2012;Natividad et al, 2010;Natividad et al, 2013;O'Dell et al, 2004;O'Dell et al, 2006;O'Dell et al, 2007;Shram et al, 2008;Torres et al, 2008;Wilmouth and Spear, 2004), making adolescents a vulnerable target to nicotine use and abuse as well as for use of other addictive drugs during adulthood. Consistent with this notion, previous studies have shown that nicotine exposure during adolescence can prime the use and abuse of cocaine, alcohol, and other addictive substances (Bechtholt and Mark, 2002;DiFranza and Guerrera, 1990;Horger et al, 1992;Hutchison and Riley, 2008;Kandel and Kandel, 2015;Kandel and Kandel, 2014;Kelley and Rowan, 2004;Kouri et al, 2001;Levine et al, 2011;Li et al, 2014;McQuown et al, 2007;McQuown et al, 2009;Meliska et al, 1995;Natividad et al, 2010;Rinker et al, 2011;Rosenberg, 2014;Schindler et al, 2012;Schneider et al, 2012). There is also evidence showing that about 90% of regular smokers start using tobacco at an early age, and that early onset smoking carries a major risk for the development of addiction to other drugs of abuse (Rimm et al, 1995).…”

“…Many studies have reported that nicotine may serve as a gateway drug for cocaine and other illicit drugs (Dickson et al, 2014;Dickson et al, 2011;Levine et al, 2011;Li et al, 2014;McQuown et al, 2007;Orsini et al, 2008). However, there is limited information on the effect of nicotine treatment on the rewarding action of cocaine if nicotine is administered during adulthood.…”

“…For example, previous studies have shown that nicotine exposure during adolescence can pave the way to the use and abuse of cocaine, alcohol, and other addictive substances (Levine et al, 2011;McQuown et al, 2007;Orsini et al, 2008). Interestingly, an epidemiological study has shown that, just alone in the United States, 90.4% of adults (between the ages of 18-34), who had used cocaine at least once had also smoked cigarettes before (Levine et al, 2011). Many preclinical studies have also demonstrated the effect of early nicotine use on the reinforcing and rewarding effects of cocaine.…”