Jamie L. Wilkinson

Intravenous nicotine conditions a place preference in rats using an unbiased design.

The rewarding effects of nicotine contribute to the chronic use of tobacco products. The place conditioning task, a widely used pre-clinical model to study drug reward, has lead to mixed results in rats when nicotine was administered subcutaneously or intraperitoneally; intravenously administered nicotine has not been examined. Further, much of the research demonstrating a nicotine-conditioned place preference in rats has used a biased design making these results susceptible to non-reward interpretations. The present study assessed whether intravenous (IV) nicotine would condition a place preference in an unbiased design and evaluated important behavioral parameters: nicotine dose, number of conditioning trials, and infusion-to-placement interval. In adult male Sprague Dawley rats, IV nicotine (0.03 mg/kg) conditioned a place preference after 8 conditioning trials. This conditioned preference was observed whether nicotine was infused 10 min before or immediately after placement in the paired environment for 10 min; infusing nicotine immediately after removal from the paired environment did not condition a preference after 4 or 8 conditioning trials. Four conditioning trials were not sufficient to condition a preference regardless of the temporal relation between the paired environment and 0.03 mg/kg nicotine. A 0.01 mg/kg dose of nicotine did not condition a place preference after 4 or 8 trials when infused immediately upon placement in the paired environment. Intravenous nicotine (0.03 mg/kg) has rewarding effects in an unbiased design suggesting that the place conditioning protocol used in the present study might be an especially useful model for studying the processes underlying the conditioned rewarding effects of nicotine.

Stimulus Properties of Nicotine, Amphetamine, and Chlordiazepoxide as Positive Features in a Pavlovian Appetitive Discrimination Task in Rats

Recent experiments from our laboratory have demonstrated that drug states can signal when environmental cues will be followed by rewarding outcomes (ie Pavlovian conditioning). However, little is known about the generality of this approach and whether it can be used for studying the pharmacological properties of drug states. Accordingly, the present experiments tested the pharmacological specificity of nicotine (0.4 mg/kg), amphetamine (1 mg/kg), and chlordiazepoxide (CDP, 5 mg/kg) in this Pavlovian drug discrimination procedure. Following drug administration, presentation of a conditional stimulus (CS) was followed by brief access to sucrose. When saline was administered, the same CS was presented but sucrose was withheld. In substitution tests, rats in each condition received varying doses of all training drugs and caffeine. Anticipatory food seeking developed during the CS on drug sessions but not on saline sessions for all drug features (ie drug state-specific conditional response (CR)). In generalization tests, this CR decreased as a function of decreases in the training dose. Median effective doses (ED50s) were calculated for nicotine (0.054 mg/kg), amphetamine (0.26 mg/kg), and CDP (2.48 mg/kg). No compound tested substituted for the CDP training drug. Partial substitution was evident between nicotine and amphetamine; CDP did not substitute for either of these drug features. Caffeine fully substituted for nicotine (ED50=15.45 mg/kg) and amphetamine (ED50=3.70 mg/kg), but not for CDP. These results are consistent with the hypothesis that drug states can occasion appetitive Pavlovian CRs in a pharmacologically specific manner.

Vaccines to combat smoking

Background: Current US FDA-approved biological therapies for treating smoking target central nervous system processes. Although these therapies have had some success, relapse within a year is still high. Clearly additional strategies are needed to aid individuals in maintaining abstinence. Objective/methods: We briefly discuss promising research using vaccines to combat smoking and then identify some potentially important directions for future research. Results/conclusions: Immunization with a nicotine vaccine generates drug-specific antibodies that sequester some of the nicotine in the peripheral circulation preventing it from entering the brain, thus decreasing its addictive effects. Albeit promising, much more research is necessary to identify more efficacious vaccine designs and formulations, as well as optimal immunization regimens. A further understanding of the factors contributing to the substantial individual differences in immunogenicity to these vaccines and how to best use vaccines in combination with other treatment strategies will increase the success of intervention efforts.

Methamphetamine functions as a positive and negative drug feature in a Pavlovian appetitive discrimination task.

This research determined the ability of methamphetamine to serve as a positive or negative feature, and assessed the ability of bupropion, cocaine, and naloxone to substitute for the methamphetamine features. Rats received methamphetamine (0.5 mg/kg, intraperitoneally) or saline 15 min before a conditioning session. For the feature positive (FP) group, offset of 15-s cue lights was followed by access to sucrose on methamphetamine sessions; sucrose was withheld during saline sessions. For the feature negative (FN) group, the light offset was followed by sucrose on saline sessions; sucrose was withheld during methamphetamine sessions. During acquisition, the FP group had higher responding on methamphetamine sessions than on saline sessions. For the FN group, responding was higher on saline sessions than on methamphetamine sessions. Conditioned responding was sensitive to methamphetamine dose. For the FP group, bupropion and cocaine fully and partially substituted for methamphetamine, respectively. In contrast, both drugs fully substituted for methamphetamine in the FN group. Naloxone did not substitute in either set of rats. FP-trained rats were more sensitive to the locomotor stimulating effects of the test drugs than FN-trained rats. This research demonstrates that the pharmacological effects of methamphetamine function as a FP or FN in this Pavlovian discrimination task and that training history can affect conditioned responding and locomotor effects evoked by a drug.

Bupropion hydrochloride produces conditioned hyperactivity in rats

Bupropion is marketed as an antidepressant, Wellbutrin and smoking cessation aid, Zyban. Although the therapeutic neurological mechanisms of bupropion have not been fully elucidated, bupropion shares some behavioral similarities with classic psychomotor stimulants. The present study sought to further investigate these psychomotor stimulant effects of bupropion by assessing whether repeated administration of bupropion in a distinct environment produced conditioned hyperactivity. Paired rats received 10 daily i.p. injections of bupropion (2.5-30 mg/kg) before placement in locomotor chambers for 30 min. Bupropion (10-30 mg/kg) produced acute locomotor hyperactivity compared to Unpaired controls. After repeated administration, there was no progressive increase or decrease in bupropion-induced activity. In a subsequent drug-free session conditioned hyperactivity was observed at 5-30 mg/kg doses. In a follow-up experiment, we examined whether responsiveness to novelty predicted the subsequent unconditioned and conditioned locomotor effect of bupropion. Reactivity to inescapable novelty, novel environment approach, and novel-object interaction were measured before locomotor conditioning with 30 mg/kg bupropion. We replicated the previous experiment, but scores on the novelty screens did not predict locomotor response to bupropion. This study extends the literature by demonstrating that environmental cues repeatedly paired with the stimulant effects of bupropion come to evoke elevated activity in the absence of drug (i.e., conditioned hyperactivity). This finding is consistent with the literature suggesting that bupropion shares many behavioral similarities with other psychomotor stimulants which also produce conditioned hyperactivity. However, a predictive relation between reactivity to forced novelty and the subsequent locomotor effect of bupropion may not be one of these similarities.

Preexposure to nicotine alters the subsequent locomotor stimulant effects of bupropion in rats.

Little is known about the interaction between nicotine and bupropion (Zyban), but many studies suggest they have neurological and behavioral similarities. One feature of drugs with common profiles is the ability to cross-sensitize possibly through neurological changes in the reward pathway. Activation of this pathway might explain the effectiveness of bupropion as a smoking cessation aid. The present research investigated whether repeated nicotine administration altered the subsequent locomotor effects of bupropion. In experiment 1, rats were preexposed to nicotine (0.4 mg/kg subcutaneously) or saline on eight separate occasions in the home cage and then tested with bupropion (0, 20, or 30 mg/kg) in locomotor chambers. The acute stimulant effect of 30 mg/kg of bupropion was potentiated by nicotine preexposure. In experiment 2, rats received nicotine repeatedly paired with the locomotor chambers or home cages. An additive effect was observed between acute bupropion and nicotine-conditioned hyperactivity in the chamber-paired group. This enhancement of the acute locomotor effects of bupropion might reflect alterations in common dopaminergic processes.

An investigation of bupropion substitution for the interoceptive stimulus effects of nicotine

Although the exact mechanism that makes bupropion hydrochloride (Zyban®) effective as a smoking cessation aid has not been fully elucidated, studies have found that bupropion and nicotine share behavioural and neurophysiological properties suggesting that bupropion might serve as a substitute for nicotine. In fact, bupropion prompts nicotine-appropriate responding in operant and Pavlovian drug discrimination studies with rats. A majority of the literature examining this substitution pattern has been done with an operant paradigm. The present research extended this literature by further characterising the behavioural and neuropharmacological properties underlying the substitution for a nicotine conditioned stimulus (CS). Examination of the dose—effect function and temporal dynamics of this substitution pattern showed that bupropion (20 mg/kg) produced conditioned responding similar to nicotine (0.4 mg base/kg) (ED50 = 9.9 mg/kg) at 15 and 30 min after injection and partially substituted 5 and 60 min post-injection. Bupropion produced a pattern of conditioned responding similar to nicotine during a 60-min extinction test. Additionally, it has been hypothesised that bupropion and nicotine have an overlapping dopaminergic mechanism. We tested the effects of bupropion pretreatment, the nicotine dose—effect function and the ability of dopamine antagonist to block the substitution of bupropion for nicotine. Pretreatment with doses of bupropion that did not substitute for the nicotine stimulus (5 and 10 mg/kg) did not affect nicotine-conditioned responding; pretreatment with 20 mg/kg attenuated nicotine-evoked responding. Pretreatment with the dopamine antagonists SCH-23390 and eticlopride blocked the substitution. Finally, S,S-hydroxybupropion, the major metabolite of bupropion in humans, did not substitute for the nicotine CS.

Pavlovian drug discrimination with bupropion as a feature positive occasion setter: Substitution by methamphetamine and nicotine, but not cocaine

Bupropion can serve as a discriminative stimulus (SD) in an operant drug discrimination task, and a variety of stimulants substitute for the bupropion SD. There are no reports, however, of bupropion functioning as a Pavlovian occasion setter (i.e. feature positive modulator). The present experiment seeks to fill this gap in the literature by training bupropion in rats as a feature positive modulator that disambiguates when a light will be paired with sucrose. Specifically, on bupropion (10 mg/kg intraperitoneal) sessions, offset of 15‐second cue lights were followed by brief delivery of liquid sucrose; saline sessions were similar except no sucrose was available. Rats readily acquired the discrimination with more conditioned responding to the light on bupropion sessions. Bupropion is approved for use as a smoking cessation aid, and more recently has drawn attention as a potential pharmacotherapy for cocaine and methamphetamine abuse. Accordingly, after discrimination training, we tested the ability of cocaine (1–10 mg/kg), methamphetamine (0.1 to 1 mg/kg) and nicotine (0.00625 to 0.2 mg/kg) to substitute for the bupropion feature. Nicotine (0.05 mg/kg) and methamphetamine (0.3 mg/kg) substituted fully for bupropion; cocaine did not substitute. These results extend previous research on shared stimulus properties between bupropion and other stimulants to a Pavlovian occasion setting function. Further, this is the first report of nicotine and methamphetamine substitution for bupropion. The overlap in stimulus properties might explain the effectiveness of bupropion as a smoking cessation aid and highlight the possible utility of bupropion for treatment of stimulant use disorder.

Reference place conditioning procedure with cocaine: increased sensitivity for measuring associatively motivated choice behavior in rats.

Place conditioning is widely used to study the conditioned rewarding effects of drugs. In the standard version, one reward (cocaine) is compared with no reward (saline). A modified variant of this task, ‘reference-conditioning’ procedure, compares two potentially rewarding stimuli (high vs. low cocaine dose). There has been little research on the utility of this procedure. Experiment 1 used the standard protocol with saline administered before confinement to the reference compartment of a place conditioning chamber. On alternate days, saline, 2.5, 5, 7.5, 10, or 20 mg/kg cocaine was administered before confinement to the opposite compartment. In experiments 2 and 3, reference-compartment saline was replaced with 5 and 7.5 mg/kg cocaine, respectively. Relative to saline, 7.5–20 mg/kg cocaine had comparable conditioned rewarding effects (i.e. similar increase in time in paired compartment). When cocaine replaced saline, there was competition at doses lower than 7.5 mg/kg. Rats that received 7.5 versus 2.5 mg/kg spent similar time in each compartment, indicating competition. Competition was not seen with 5 versus 20 mg/kg; preference was for the 20 mg/kg compartment. Experiment 4 showed that the competition at 2.5 mg/kg was not due to reward sensitization. The reference-conditioning procedure has increased the sensitivity for measuring associatively motivated choice behavior.