The nAChR agonist nicotine acts on dopaminergic pathways (see Fig. 1) implicated in the rewarding or the incentive-motivational effects of stimuli such as food, play, or copulatory opportunity.70,88 Notably, nicotine's action in this "incentive/approach system" and the conditioned effect associated with this action is used to explain the acquisition and maintenance of compulsive tobacco use,44,45,80 and the over 95% relapse rate following abstinence without pharmacotherapy.16,17 Animal models such as self-administration and intracranial self-stimulation have been employed to elucidate the behavioral and neurobiological processes underlying these effects of nicotine.15,46,69,81 For example, rodents and nonhuman primates prepared with an intravenous catheter will press more on a lever that produces contiguous intravenous delivery of nicotine.22,39 The differential increase in responding (self-administration) maintained by nicotine requires normal functioning of the system outline in Figure 1. For example, nicotine self-administration in rats is decreased with bilateral 6-hydroxydopamine lesions of the dopaminergic projections between the ventral tegmental area (VTA) and nucleus accumbens,23 or by infusions of a nAChR antagonist, DHpE, into the VTA.24 Further, selective cholinergic lesioning of the pedunculopontine tegmental nucleus, a major cholinergic projection to the VTA, also attenuates nicotine self-administration.51 Finally, mice lacking the P2 subunit fail to self-administer nicotine.32
Additional empirical work has implicated nAChRs located on the cell bodies in the VTA and on the terminals of glutamatergic projections from the prefrontal cortex to the VTA.27,47,60 These excitatory glutamatergic projections stimulate VTA neurons resulting in dopamine re-lease.48 Theorists have suggested that this release of dopamine, especially in the nucleus accumbens, is important for various aspects of the rewarding/incentive effects of appetitive stimuli and the conditioned approach effects engendered by these stimuli (de Bruin, this book and refs. 3,10,27). Dopamine release in the nucleus accumbens is increased in vitro and in vivo with nicotine. This prolonged increase in dopamine release appears to be mediated by long-term potentiation ofVTA cells containing NMDA receptors—a glutamate receptor selective for the agonist V-methyl-D-aspartate.87 The a7* nAChRs located on the presynaptic terminals of projections from the prefrontal cortex are important for inducing this long-term potentiation in the VTA.60,88 The a4p2* nAChR located on the cell bodies of VTA neurons quickly desensitize to the presence of nicotine and are unlikely to contribute to the long-term enhancement of dopamine release.27,75
Although there is a massive empirical literature studying the functional effects of dopamine release in this system, there is still disagreement as to its role in incentive-related behaviors. The following quote by Dani et al27 provides a good summary that is consistent with our thinking and will serve as basis for suggesting a broad role of the nAChR-mediated neural plasticity of this system in learning and memory.
"DA [dopamine] concentrations in the NAc [nucleus accumbens] are not a scalar indication of reward. More likely, the DA signal conveys novelty and reward expectation or serves to
indicate the deviation of the environmental input from the animal's expectations, which were constructed by experience. Thus, DA may participate in the ongoing associative learning of adaptive behaviors as an animal continually updates a construct of environmental salience" (p. 350).
This conceptualization suggests that the dopamine signal that is enhanced by nicotine's action on presynaptic terminals containing a7* nAChRs plays a role in neurally attributing incentive salience to the stimulus input from a continually changing environment. This neural attribution likely occurs through associative learning processes, broadly defined.3
Recent research by Caggiula and colleagues15 provides an important behavioral example of this process. Briefly, rats were trained to self-administer nicotine such that when the response requirement was completed a 1-sec intravenous infusion of nicotine (0.03 mg/kg) was delivered; a 1-sec light co-occurred with the nicotine infusion. Upon establishing stable self-administration behavior, some rats were switched to an extinction phase in which saline replaced nicotine, but the 1-sec cue light still occurred. Although lever press rates decreased with the removal of nicotine, the nicotine-associated light still maintained responding well above controls receiving saline without the cue light. In a separate set of rats, the response-contingent nicotine infusion continued during the extinction phase, but the light signal was removed. Rates of nicotine self-administration also decreased in this group. Notably, the level of responding maintained by nicotine alone was comparable to that maintained by the cue light alone. This result is intriguing if one considers that the rate of behavior maintained by what is conceptualized as the primary reinforcer, nicotine, is similar to that controlled by a cue associated with the effects of nicotine. Caggiula et al15 concluded that, "nicotine promotes the establishment or magnifies the salience of conditioned reinforcers" (p. 526). We suggest that a plausible mechanism for this enhanced incentive salience is the action of nicotine on the a7* nAChRs located on glutamatergic presynaptic terminals of projections from the prefrontal cortex to the VTA. Of course, this proposal requires empirical attention.
Regardless of the specific neurobiological processes responsible for enhancing the incentive salience of stimuli, this enhancement provides an additional mechanism by which nAChR compounds may broadly affect learning and memory. For example, enhanced attention and/or vigilance (see earlier) may be, at least in part, the result of this process. Stimulus events that occur in the presence of nicotine (or other appropriately selective nAChR agonists) may acquire, or have potentiated, some appetitive property. Presumably this enhanced appetitive quality increases salience and may even require deeper processing given the acquired associations. Indeed, animals in a free-choice situation spend more time in a distinct environment that has been previously paired with appetitive stimuli.4
Enhanced/magnified incentive salience of cues may also play a role in the improved acquisition of new tasks observed with some nAChR agonists. For example, we found that acquisition of a T-maze visual discrimination task was faster in chronic nicotine-treated rats than in saline-treated rats.6 Perhaps nicotine potentiated the incentive effects of the food used to reinforce correct arm choice (i.e., black arm). According to this formulation the incentive salience of the black arm may also be enhanced. That is, any conditioned reinforcing value acquired by the black-arm stimuli repeatedly associated with food may be increased by nicotine. Further, these conditioned effects may be stronger because the appetitive effects of food would also be enhanced (see earlier). Finally, the black-arm stimuli may acquire additional incentive salience by direct association with nicotine. The cumulative increase in the incentive salience of the stimulus events relevant to learning the discrimination thus enhanced acquisition rates relative to saline controls. Interestingly, reversal learning (white-arm now associated with food) was not altered by nicotine pretreatment. Perhaps, the effects of nicotine on the incentive salience require the stimulus events to be relatively novel (i.e., relatively little learning history). Or, perhaps the acquired increase in the incentive salience of black arm cues competed with white arm cues that were now becoming associated with food and nicotine after a long history on nonreinforcement in a manner similar to nonmagnified cues in the saline controls.
As a final note in this section, we found that enhanced acquisition in the T-maze task was predicted by activity in an inescapable novel environment; less reactive rats learned the discrimination faster (see ref. 6 and Fig. 1). Notably, past research on individual differences predicted by reactivity to inescapable novelty has implicated the mesocorticolimbic dopamine system.82,86 The nAChR-mediated long-term potentiation of the VTA increases dopamine release within this system (see Fig. 1) and suggests a potential process responsible for the predictable difference in T-maze learning produced by nicotine. Of course, the speculations concerning incentive salience and the role of nAChR-mediated long-term potentiation in learning and memory require further research to provide independent evidence for the processes at a neurobiological and behavioral level.
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