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 designed to more fully capture the relationship between nicotine and self-administration, including smoking. The """"""""dual reinforcement"""""""" model posits that nicotine acts as both a primary reinforcer and a reinforcement enhancer. 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, including nicotine-associated conditioned reinforcers. The experiments proposed below will extend the testing of this model by focusing on questions regarding the role of nicotine in establishing conditioned reinforcers and the factors that moderate the ability of nicotine enhance both unconditioned and conditioned reinforcers. These questions, the answers to which will result in a much more powerful model to explore the neurobiological mechanisms of nicotine addiction and to design better smoking cessation strategies, are: (1) How does dose of nicotine and number of training sessions affect the association between nicotine and non-nicotine stimuli and thus the strength of conditioned reinforcement? (2) How does non-contingent nicotine enhance the strength of a nicotine-associated conditioned reinforcer? (3) Does self-administered nicotine also enhance the value of a nicotine-associated conditioned reinforcer as we have hypothesized occurs in smokers? (4) How does extending access to nicotine self-administration, and subsequent withdrawal from nicotine, change the ability of nicotine to enhance an unconditioned reinforcer and a nicotine-associated conditioned reinforcer?
By promoting smoking behavior, nicotine dependence increases the risk of chronic disease and mortality. Our research, which employs an animal model of nicotine use, indicates that nicotine strengthens smoking behavior because nicotine is itself rewarding but also because it makes other aspects of smoking, including the sensory properties of a cigarette and other behaviors than accompany smoking, more rewarding. The experiments proposed will continue to test this model with the long term goal of establishing its usefulness in identifying the neurobiological basis of nicotine's actions and in the development of more effective smoking cessation aids.
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