Matthew I. Palmatier - US grants

DESCRIPTION (provided by applicant): Concomitant drug use and polydrug abuse are often overlooked in treatment programs for compulsive drug users. Studies of drug and alcohol cessation programs have demonstrated that the use of licit drugs with which patients have access, such as caffeine or nicotine, increases during the period of treatment. Therefore, investigating the potential behavioral and pharmacological mechanisms of how drug cues modulate associations with other rewarding stimuli will help us understand the potential impact of licit drug use during and after treatment for compulsive drug use. The experiments in this proposal utilize a Pavlovian conditioning procedure in which one cue modulates conditioned responding to a second cue. Specifically, in the presence of the stimulus effects of nicotine or amphetamine, the environmental cue will always be followed by sucrose; in the presence of saline, the cue will never be followed by sucrose. Thus, the drug state sets the occasion upon which food is available after the exteroceptive cue. The experiments will examine the specificity with which the drug stimuli modulate conditioned responding and some possible associative mechanisms. For example, are the drug cues sensitive to changes in their stimulus effects? Could these modulators serve as "global" cues or are they specific to discriminative situations in which they were trained? What are the potential associative mechanisms of the modulators? Based on preliminary findings as well as research and theory, we predict that changing the physical properties of the modulators will change their stimulus effects within the organism and reduce their behavioral efficacy. In addition, the modulators will probably have little direct "associative" strength and could potentially be used to solve discriminations in which they were never trained.

DESCRIPTION (provided by applicant): There is converging evidence that environmental cues related to tobacco use are critically involved in tobacco dependence. Dr. Caggiula's laboratory is currently investigating the impact of environmental cues on nicotine (NIC) self-administration (SA) in rats. They have found that NIC enhances responding for other reinforcers (i.e., delivery of an environmental cue). However, one shortcoming of these studies is that delivery of the cue and delivery of NIC depend on the same behavior (i.e., pressing an "active" lever). Thus, the nature of the interaction between the reinforcers (NIC and cue) is not completely clear. The experiments outlined in the present proposal will begin to examine the nature of the interaction between NIC and the environmental cue using a "two-lever" paradigm. That is, NIC infusions and cue presentations will be controlled by two distinct operants (i.e., pressing different levers). This technique will provide a more sensitive assay of how NIC reinforces behavior and will expand our understanding of chronic tobacco use. Increasing the sensitivity of NIC SA models will provide useful and readily applicable information for behavioral and pharmacological tobacco cessation programs.

[unreadable] DESCRIPTION (provided by applicant): 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 NIC 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 experiment proposed below extend the testing of a model that is sensitive to both the primary reinforcing and reinforcement enhancing effects of nicotine, focusing on questions regarding the potential mechanisms by which pharmacotherapeutic interventions for smoking cessation may reduce nicotine-seeking or replace the reinforcement enhancing effects of nicotine. 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) Do pharmacotherapeutic interventions for smoking cessation share reinforcement enhancing effects with nicotine? (2) How do pharmacotherapeutic interventions with/without reinforcement enhancing properties affect primary reinforcement by nicotine in a paradigm that can isolate this effect? The answers to these questions will establish preliminary basis for future questions about how these pharmacotherapies may affect stimuli associated with the primary reinforcing effects of nicotine. PUBLIC HEALTH RELEVANCE: 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 and because it also makes more rewarding other aspects of smoking, including environmental stimuli associated with the behavior. 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. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): Flavor additives in tobacco products and e-cigarettes are familiar stimuli with 'incentive' properties - they have been paired with sweet tastes or caloric post-ingestive effects in the past. These additives are intended to increase self-administration of nicotine by increasing palatability; however, they may also interact with the potent 'reward-enhancing' effects of nicotine to promote acquisition of self-administration and compulsive use. The inclusion of flavors with conditioned rewarding properties may also promote neurochemical changes that are correlated with long-term use and dependence. The specific objectives of the proposed studies are to investigate whether these flavor additives promote harm by increasing the number of individuals who smoke or use e-cigarettes; to determine whether flavor additives promote the development of nicotine dependence using pre-clinical models that measure motivation to take the drug as well as taking the drug in the face of aversive consequences; and to determine whether inclusion of flavor additives in the nicotine self-administration paradigm increases levels of mesotelencephalic dopamine, a neurochemical change that may contribute to compulsive substance use and dependence. We predict that flavors with conditioned reinforcing properties (paired with sweeteners in the past) will promote acquisition of self-administration at low nicotine doses, will increase nicotine 'dependence', and will cause regionally specific increases in neural growth factors. This research will make a significant impact on public health as it may reveal an important feature of smoked tobacco and e-cigarettes that encourage experimentation, repeated use, and dependence. The project builds on pre-clinical self-administration with the important innovations of including flavor stimuli in te self- administration paradigm and specifically using stimuli that model flavor additives in tobacco and e-cigarettes (flavors with incentive motivational properties). The experiments will begin by 'conditioning' the additives (e.g., menthol and strawberry) with incentive properties by pairing them with a sweet reward. This models most flavor additives (e.g., menthol, licorice, cocoa) which are familiar to most individuals who smoke before they are ingested in tobacco or e-cigarette formulations (e.g., candy canes, mints, ice cream, etc.). The flavor will then be self-administered in its unsweetened form, orally, by licking at a sipper tube. Nicotine is self- administered intravenously in conjunction with oral flavor delivery. This models inclusion of flavor additives in tobacco and e-cigarettes, which do not include potent sweeteners. Based on our preliminary findings, we expect that these conditioned reinforcing flavors will 1) reduce the dose of nicotine needed to acquire self- administration and 2) increase the motivation to obtain nicotine 3) increase nicotine self-administration in the face of negative consequences and 4) increase levels of dopamine in mesotelencephalic regions in which synaptic plasticity is associated with drug self-administration and substance dependence. We anticipate that these studies will have broad impact on the nicotine self-administration paradigm and public health.