Extinction with varenicline and nornicotine, but not ABT-418, weakens conditioned responding evoked by the interoceptive stimulus effects of nicotine

Department of Psychology, University of Nebraska-Lincoln, Lincoln NE 68588-0308, USA.
Neuropharmacology (Impact Factor: 5.11). 03/2010; 58(8):1237-45. DOI: 10.1016/j.neuropharm.2010.03.005
Source: PubMed


The interoceptive stimulus effects of nicotine acquire control over behavior. This observation, among others, suggests that the stimulus effects of nicotine are important in the development and tenacity of tobacco dependence. Despite this importance, there has been little research examining whether non-reinforced presentations (extinction) of a ligand that share stimulus effects of nicotine will weaken responding controlled by nicotine. Rats were trained to discriminate nicotine (0.4 mg/kg) from saline using a discriminated goal-tracking task in which nicotine signaled intermittent access to sucrose; sucrose was withheld on saline sessions. Experiment 1 examined substitution for nicotine by ABT-418, nornicotine, epibatidine, varenicline, or cytisine in 4-min extinction tests. Experiments 2-5 [low-dose nicotine (0.05 mg/kg), ABT-418, nornicotine, or varenicline, respectively] examined whether substitution for nicotine would persist if extinction tests were increased to 20 min and repeated daily for 6 days. Finally, generalization of this extinction back to the nicotine training stimulus was assessed. Full substitution in brief 4-min extinction tests was seen for ABT-418, nornicotine, epibatidine, varenicline, and cytisine. Low-dose nicotine, ABT-418, nornicotine, and varenicline, evoked only a partial 'nicotine-like' response in the first 20-min extinction test. With repeated extinction, only low-dose nicotine, nornicotine, and varenicline continued to substitute. Extinction with nornicotine and varenicline transferred back to nicotine as indicated by a partial conditioned response to the training stimulus. Interpretations regarding 'nicotine-like' effects of a ligand depend on the nature of the test. Understanding the processes mediating transfer of extinction learning with potential pharmacotherapies may reveal new treatment targets.

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    • "With that said, the variance in the var→var group is quite large, indicating that responding is partially attenuated in some rats. These findings extend those of Reichel et al. (2010) that also found only partial varenicline generalization to the 0.4 mg/kg training dose in transfer of extinction. The pattern of responding found in the present study suggests that the varenicline stimulus may be more similar to the lower nicotine doses and, that the stimulus elements that compose the 0.4 mg/kg training dose of nicotine differ somewhat from those lower doses in at least a subset of rats. "
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    ABSTRACT: Rationale: Pharmacotherapies are often utilized to aid in smoking cessation, and switching medication when treating nicotine dependence has become more commonplace. Although common, little is known about the impact of the initial therapy on the effects of the subsequent therapy. Objectives: To begin to fill this gap in our understanding, this project determined how switching compounds that share stimulus elements with nicotine during extinction altered extinction responding and generalization of this extinction back to nicotine. Methods: Rats were trained in a discriminated goal-tracking task where nicotine administration was followed by intermittent sucrose access; sucrose was withheld following saline administration. In experiment 1, nornicotine supplanted nicotine in extinction sessions 1-3 and then a switch to varenicline on extinction sessions 4-6 was examined. In experiment 2, the reverse was investigated; varenicline to start extinction and then a switch to nornicotine. Generalization of extinction back to the nicotine stimulus was then assessed by generating a cumulative dose-effect curve. Results: Generalization of extinction back to the training nicotine stimulus was greater if nornicotine had been received at any point in extinction compared to only receiving varenicline. Whereas, extinction with varenicline alone showed more generalization to lower doses of nicotine. Conclusions: A switch in cessation pharmacotherapy during extinction did not impede or enhance generalization back to the nicotine-training stimulus. The nornicotine stimulus appears to share more stimulus overlap with the 0.4 mg/kg nicotine stimulus and varenicline may share more overlap with lower nicotine doses.
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    • "The a 4 b 2 -containing receptors seem to be of particular importance. For example, the a 4 b 2 partial receptor agonist varenicline and the a 4 b 2 agonists ABT-418 fully substitute for the nicotine stimulus in the DGT task (Reichel et al., 2010). Further, the a 4 b 2 antagonist dihydrob-erythroidine blocks conditioned responding evoked by the nicotine stimulus (Struthers et al., 2009). "

    Full-text · Article · Apr 2015 · Neuropharmacology
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    • "This suggestion is consistent with previous research using this approach (Polewan et al., 2013; Reichel et al., 2010). For example, using the brief 4- min testing protocol, the a 4 b 2 nicotinic acetylcholine receptor agonist ABT-418 (0.6 mg/kg) evoked goal-tracking comparable to nicotine (Reichel et al., 2010). However, in repeated extinction sessions, like those used here, ABT-418 only evoked a partial conditioned response in the first session, and no substitution in the subsequent 5 extinction session. "
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    ABSTRACT: Bupropion is an atypical antidepressant that increases long-term quit rates of tobacco smokers. A better understanding of the relation between nicotine and this first-line medication may provide insight into improving treatment. For all experiments, rats first had nicotine (0.4 mg base/kg) and saline session intermixed; intermittent access to sucrose only occurred on nicotine session. Nicotine in this protocol comes to differentially control "anticipatory" dipper entries. To more closely examine the overlap in the interoceptive stimulus effects of nicotine and bupropion, we assessed whether subsequent prolonged and repeated non-reinforced (extinction) sessions with the bupropion stimulus could weaken responding to nicotine (i.e., transfer of extinction). We also examined whether retraining the discrimination after initial extinction and then conducting extinction again (i.e., re-extinction) with bupropion would affect responding. We found that bupropion (20 and 30 mg/kg) fully substituted for the nicotine stimulus in repeated 20-min extinction sessions. The extent of substitution in extinction did not necessarily predict performance in the transfer test (e.g., nicotine responding unchanged after extinction with 20 mg/kg bupropion). Generalization of extinction back to nicotine was not seen with 20 mg/kg bupropion even after increasing the number of extinction session from 6 to 24. Finally, there was evidence that learning in the initial extinction phase was retained in the re-extinction phase for nicotine and bupropion. These findings indicate that learning involving the nicotine stimuli are complex and that assessment approach for stimulus similarity changes conclusions regarding substitution by bupropion. Further research will be needed to identify whether such differences may be related to different facets of nicotine dependence and/or its treatment.
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