Molecular mechanisms underlying the motivational effects of nicotine.

Cues and Nicotine Dependence Nicotine reinforcement is important for the initiation of smoking behavior, however, brain systems important for incentive motivation, such as those that control responses to reward-associated cues, may play a predominant role in maintenance of tobacco use and relapse to smoking (Robinson & Berridge, 1993). It is interesting that sensory cues provided by tobacco smoke result in increased pleasure in smokers while smoking denicotinized cigarettes (Perkins, Gerlach, Vender, Grobe, Meeker, & Hutchison, 2001; Rose & Behm, 2004) and the success of behavioral therapies that devalue cigarettes is dependent on providing the flavor that matches smokers’ regular brands (Rose & Behm, 2004). Smoking-associated cues that induce craving activate brain areas associated with liking nicotine (Brody, Mandelkern, London, Childress, Lee, Bota, Ho, Saxena, Baxter, Madsen, & Jarvik, 2002; Due, Huettel, Hall, & Rubin, 2002; Franklin, Wang, Wang, Sciortino, Harper, Li, Ehrman, Kampman, O’Brien C, Detre, & Childress, 2007). Together these studies suggest that smoking-associated cues can gain control over the areas of the brain that stimulate reward and such cues can be manipulated to aid in smoking cessation. Animal studies also suggest that cues play a prominent role in nicotine dependence. In the absence of cues, rats self-administer nicotine at a steady rate, limiting their intake to approximately 10 infusions per hour (Caggiula, Donny, Chaudhri, Perkins, Evans-Martin, & Sved, 2002a). Nicotine appears to be a weak reinforcer on its own; however, simultaneous presentation of a cue with the same dose of nicotine greatly increases self-administration (Caggiula et al., 2002a; Caggiula, Donny, White, Chaudhri, Booth, Gharib, Hoffman, Perkins, & Sved, 2001, 2002b). Environmental cues previously paired with nicotine can support self-administration behavior in the absence of nicotine reward for weeks after removal of the nicotine reinforcer (Caggiula et al., 2002a; Cohen, Perrault, Griebel, & Soubrie, 2005). Not only do such cues promote the maintenance of smoking behaviors, but smoking-associated cues can also promote relapse to smoking (Shiffman, Paty, Gnys, Kassel, & Hickcox, 1996; Waters, Shiffman, Bradley, & Mogg, 2003). Indeed, a nicotine-associated cue is a more efficient primer than the drug itself in reinstating nicotine self-administration in an animal model of relapse (Lesage, Burroughs, Dufek, Keyler, & Pentel, 2004). By virtue of being paired with nicotine, cues gain incentive salience value (Robinson & Berridge, 1993): they become conditioned reinforcers capable of eliciting self administration behavior on their own and they become triggers that lead to craving for the drug with which they were paired (Tiffany & Drobes, 1990). Prior chronic nicotine exposure enhances conditioned reinforcement Although environmental cues paired with smoking can drive nicotine intake, it is also the case that nicotine, acting through β2* nAChRs, increases the ability to make associations between rewards and novel cues in rats and mice (i.e., conditioned reinforcement), even several weeks after nicotine has been withdrawn (Brunzell, Chang, Schneider, Olausson, Taylor, & Picciotto, 2006; Olausson, Jentsch, & Taylor, 2003, 2004a, 2004b). Nicotine also facilitates the association of cues with reward by acting as an occasion setter (Palmatier, Peterson, Wilkinson, & Bevins, 2004). Thus, nicotine can increase the salience of environmental cues, which in turn increase the drive to seek nicotine, resulting in a vicious cycle that is likely to drive both smoking behavior and relapse after smoking cessation (See Fig 1). Figure 1 Nicotine drives associations with environmental cues that, in turn, drive nicotine intake The nicotine dosing regimens that lead to enhanced conditioned reinforcement have also been shown to result in locomotor sensitization, changes in intracellular signaling, upregulation of nicotine binding and increased mesolimbic dopamine turnover (Brunzell & Picciotto, 2004; Gaddnas, Pietila, & Ahtee, 2000; King, Caldarone, & Picciotto, 2004; Sparks & Pauly, 1999). Like other drugs of abuse, sensitization of the DA system might regulate nicotine associated conditioned reward (Robbins & Everitt, 2002; Robinson & Berridge, 1993; Taylor & Robbins, 1984). The ability of nicotine to promote conditioned reinforcement is blocked by systemic administration of mecamylamine (Olausson et al., 2004a). In addition, studies using knockout mice suggest that the ability of prior chronic nicotine exposure to enhance conditioned reinforcement as well as nicotine-mediated enhancement of context conditioning is mediated through nicotinic acetylcholine receptors containing the β2 subunit (β2* nAChRs) (Brunzell et al., 2006; J.A. Davis & Gould, 2006; J. A. Davis & Gould, 2007). There is an apparent dissociation between the role that β2*nAChRs play in nicotine-associated enhancement of conditioned reward and conditioned reward at baseline. β2KO mice have a tendency towards enhanced responding for a cue over wild type mice, but only when the cue was previously paired with a primary reward. This suggests that β2* nAChRs modulate conditioned reinforcement at baseline (Brunzell et al., 2006). It is known that baseline conditioned reinforcement and psychostimulant-mediated enhancement of conditioned reinforcement are controlled by DA projections to the NAc core and shell, respectively (in Robbins & Everitt, 2002) and recent data suggest that baseline contextual fear conditioning and nicotine-dependent enhancement of contextual fear are modulated by different nAChRs (J.A. Davis & Gould, 2006). It is therefore possible that baseline conditioned reinforcement and nicotine-mediated enhancement of conditioned reinforcement are regulated by nAChRs in different neuronal populations, or that long-term desensitization and activation of nAChRs is important for the ability of nicotine to increase conditioned reinforcement.