Models of intravenous nicotine self-administration in laboratory animals are being used to investigate the behavioral and neurobiological consequences of nicotine reinforcement, and to aid in the development of novel pharmacotherapies for smoking cessation. Central to these models is the principle of primary reinforcement, which posits that response-contingent presentation of a primary reinforcer, nicotine, engenders robust operant behavior, whereas response-independent drug delivery does not. This dictum of nicotine as a primary reinforcer has been widely used to explain why people smoke tobacco-smoking results in the rapid delivery of nicotine to the brain, setting up a cascade of neurobiological processes that strengthen subsequent smoking behavior. However, there is mounting evidence that the primary reinforcement model of nicotine self-administration fails to fully explain existing data from both the animal self-administration and human smoking literatures. We have recently proposed a "dual reinforcement" model to more fully capture the relationship between nicotine and self-administration, including smoking. Briefly, the "dual reinforcement" model posits that nicotine acts as both a primary reinforcer and a reinforcement enhancer. The latter action of nicotine had originally been uncovered by showing that a reinforcing VS, which accompanies nicotine delivery, synergizes with nicotine in the acquisition and maintenance of self-administration, and that this synergism can be reproduced by combining operant responding for the reinforcing stimulus with non-contingent (response-independent) nicotine. Thus, self-administration (and smoking) is sustained by three actions: (1) nicotine, acting as a primary reinforcer, can sustain behavior that leads to its delivery; (2) nicotine, acting as a primary reinforcer, can establish neutral environmental stimuli as conditioned reinforcers through Pavlovian associations; and (3) nicotine, acting as a reinforcement enhancer, can magnify the incentive value of accompanying stimuli, be they conditioned or unconditioned reinforcers.

Although considerable progress has been made we do not yet fully understand the behavioral and neurobiological bases of nicotine reinforcement, and without this knowledge treatment strategies aimed at reducing smoking remain deficient. This dissertation provides an original perspective on nicotine reinforcement, which arises from substantial evidence of complex interactions between nicotine and nonpharmacological stimuli. The present experiments tested the hypothesis that nicotine reinforcement derives from at least two sources: 1) the primary reinforcing properties of nicotine, an action that requires response-dependent drug administration, and 2) the more prominent ability of nicotine to enhance behavior maintained by salient non-nicotine stimuli, an action that does not require a contingent relationship between drug administration and reinforced operant responding. Although novel for nicotine, this hypothesis has origins in an extensive literature on the reinforcing properties of psychostimulant drugs. Empirical support for the application of this hypothesis to nicotine reinforcement will be presented. By investigating the interaction between nicotine and nonpharmacological stimuli within the context of drug selfadministration in rats, the present research has generated new insights into the paradox of how nicotine, an apparently weak primary reinforcer, can sustain the robust behavior observed in selfadministration and in smoking. Hypotheses generated by these data provide important direction for future investigations into the neurobiology of nicotine reinforcement.iii

These data indicate that the reinforcement-enhancing effects of nicotine are very potent even when only moderate quantities of the drug are self-administered. Moreover, they provide the first demonstration that the reinforcement-enhancing and primary reinforcing effects of nicotine can be dissociated behaviorally.

Abstract:Rationale: In Pavlovian conditioning research, nicotine is typically conceptualized as the unconditioned stimulus (US) that becomes associated with an exteroceptive conditioned stimulus (CS). This research has not explored the possibility that nicotine can also function as a CS. Objectives: The present research examined whether nicotine served as a CS for the presence (CS+) or absence (CS-) of sucrose and started defi ning its specifi city. Methods and results: Rats trained in the CS+ condition had nicotine (0.4 mg/ kg, base) paired intermittently with brief access to sucrose. Intermixed were saline sessions without sucrose. Nicotine acquired the ability to evoke goal tracking. This conditioned response (CR) decreased across extinction sessions. The CR was sensitive to nicotine dose (ED 50 =0.113 mg/kg) and administration to testing interval; 0-min and 100-min delays produced no CR. The CS properties were specifi c to nicotine in that amphetamine and bupropion substitution was incomplete. Rats in the CS-condition received similar discrimination training except that sucrose was paired with saline. Nicotine also served as a CS-; the saline state CS+ acquired control of goal tracking. Mecamylamine, but not hexamethonium, blocked nicotine's ability to serve as a CS+ and CS-, indicating a role for central nicotinic acetylcholine receptors. Conclusions: Nicotine served as a signal for the presence or absence of sucrose. The extinction, CS-, and substitution results eliminated a psycho motor stimulant account. The conceptualization of nicotine as a CS suggests novel empirical research in which a drug acquires additional inhibitory and/ or excitatory value based on other outcomes present during its effects.

Compulsive smoking is a worldwide public health problem. Although research has confirmed the importance of associative learning processes in nicotine addiction, therapies targeting nicotine-associated cues still have a high relapse rate. Most theories conceptualize nicotine as an ‘outcome’ that reinforces behaviors and/or changes the affective value of stimuli. Albeit important, this view does not capture the complexity of associative processes involved in nicotine addiction. For example, nicotine serves as a conditional stimulus acquiring new appetitive/affective properties when paired with a non-drug reward. Also, nicotine functions as an occasion setter that participates in higher-order associative processes that likely permit a more pervasive influence of conditioned cues that are resistant to typically cue-exposure therapy techniques. Finally, nicotine appears to amplify the salience of other stimuli that have some incentive value resulting in enhanced nicotine selfadministration and conditioned reinforcement processes. Future smoking intervention strategies should take into consideration these additional associative learning processes.