Sheri Booth

Cue dependency of nicotine self-administration and smoking

A paradox exists regarding the reinforcing properties of nicotine. The abuse liability associated with smoking equals or exceeds that of other addictive drugs, yet the euphoric, reinforcing and other psychological effects of nicotine, compared to these other drugs, are more subtle, are manifest under more restricted conditions, and do not readily predict the difficulty most smokers experience in achieving abstinence. One possible resolution to this apparent inconsistency is that environmental cues associated with drug delivery become conditioned reinforcers and take on powerful incentive properties that are critically important for sustaining smoking in humans and nicotine self-administration in animals. We tested this hypothesis by using a widely employed self-administration paradigm in which rats press a lever at high rates for 1 h/day to obtain intravenous infusions of nicotine that are paired with two types of visual stimuli: a chamber light that when turned on signals drug availability and a 1-s cue light that signals drug delivery. We show that these visual cues are at least as important as nicotine in sustaining a high rate of responding once self-administration has been established, in the degree to which withdrawing nicotine extinguishes the behavior, and in the reinstatement of lever pressing after extinction. Additional studies demonstrated that the importance of these cues was manifest under both fixed ratio and progressive ratio (PR) schedules of reinforcement. The possibility that nicotine-paired cues are as important as nicotine in smoking behavior should refocus our attention on the psychology and neurobiology of conditioned reinforcers in order to stimulate the development of more effective treatment programs for smoking cessation.

Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement.

RationaleCurrent conceptualizations of drug reinforcement assume that drug-taking behavior is a consequence of the contingent, temporal relationship between the behavior and drug reward. However, stimulant drugs also potentiate the rewarding effects of other reinforcers when administered noncontingently.ObjectivesThese studies were designed to determine whether noncontingent nicotine enhances the reinforcing properties of a nonpharmacological reinforcer and whether this direct effect facilitates operant behavior within the context of a nicotine self-administration procedure.MethodsRats self-administered nicotine or food, or received noncontingent nicotine, saline, or food either with or without a response-contingent, unconditioned reinforcing visual stimulus (VS).ResultsNoncontingent nicotine, whether delivered as discrete injections based on a pattern of self-administered nicotine or as a continuous infusion, increased response rates maintained by the VS. There were no significant differences in responding by animals that received contingent compared with noncontingent nicotine when a VS was available. This increase was not observed in the absence of the VS or as a consequence of noncontingent food delivery. Operant behavior was equally attenuated and reinstated by the removal and subsequent replacement of contingent and noncontingent nicotine. Nicotine supported self-administration in the absence of response-contingent, nicotine-paired stimuli; however, response rates were drastically reduced compared with nicotine self-administration with the VS.ConclusionsNicotine influences operant behavior in two ways: by acting as a primary reinforcer when it is contingent upon behavior, and by directly potentiating the reinforcing properties of other stimuli through a nonassociative mechanism. Nicotine self-administration and smoking may be largely dependent upon this later action.

Nicotine self-administration in rats on a progressive ratio schedule of reinforcement.

Abstract  Rationale: Robust intravenous (i.v.) nicotine self-administration (SA) in rats has been reported by several laboratories, including our own, using fixed ratio (FR) schedules of reinforcement. Studies on other drugs of abuse, however, suggest that progressive ratio (PR) schedules may provide additional information not gained using FR schedules. Objective: Here, we attempt to establish and characterize nicotine SA on a PR. Methods: One study allowed animals to acquire SA on a FR at four doses of nicotine (0.02, 0.03, 0.06, 0.09 mg/kg) before being switched to a PR. A second study examined extinction by saline substitution or pretreatment with the nicotinic antagonist, mecamylamine, including a preliminary analysis into the role of secondary reinforcers in the extinction process. Results: SA of nicotine on a PR was stable across repeated sessions. The number of infusions earned on a PR correlated with infusion rate on a FR; however, a large portion of the variance in SA on a PR could not be accounted for by infusion rate on a FR. Infusions on a PR increased across the same range of doses that produced a decrease in the infusion rate on a FR. Extinction of responding occurred after saline substitution or pretreatment with mecamylamine, and animals re-acquired when nicotine was again available without pretreatment. The presence of drug-paired stimuli appeared to lengthen the extinction process. Conclusions: Nicotine supports stable SA on a PR. Since PR and FR schedules may measure different aspects of nicotine reinforcement, PR schedules may be valuable in further characterizing group and individual differences in nicotine reinforcement.

Effects of dopamine antagonists on drug cue-induced reinstatement of nicotine-seeking behavior in rats.

Dopaminergic neurotransmission has been implicated in associative learning processes related to drugs of abuse. However, it is not clear whether blockade of activation of dopamine receptors alters conditioned incentive properties of nicotine-associated cues. Using a response-reinstatement procedure, this study examined the effects of antagonists selective for the D1 and the D2 subtypes of dopamine receptors on cue-induced reinstatement of nicotine-seeking behavior. Male Sprague–Dawley rats were trained in 30 daily 1 h sessions to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed ratio 5 schedule and associate a conditioned stimulus (cue) with each nicotine delivery. After extinction of responding by withholding nicotine (saline substitution) and its cue, the reinstatement tests were conducted following subcutaneous administration of a D1 antagonist SCH23390 (0, 5, 10, 30 μg/kg) or a D2 antagonist eticlopride (0, 5, 10, 30 μg/kg) in different groups of animals. Both SCH23390 and eticlopride significantly attenuated the magnitude of cue-elicited reinstatement of nicotine-seeking responding. These results indicate that activation of dopaminergic D1 and D2 receptors may play a role in mediating the conditioned motivational effects of nicotine-associated cues as measured in the response-reinstatement procedure. These findings suggest that manipulation of dopaminergic neurotransmission at D1 and/or D2 receptors may prove to be a potential target for the development of pharmacotherapy for prevention of environmental nicotine cue-triggered smoking relapse.