The effects of neonatal manganese exposure on impulsivity, unlearned motoric function, and reward

This study examined the effects of low to moderate doses of manganese (0, 250, or 750 _g per day from PD 1-21) on a comprehensive battery of behaviors in rats during the neonatal period, preweanling period, and in adulthood

Forced Abstinence Model of Relapse to Study Pharmacological Treatments of Substance Use Disorder

Understanding and preventing relapse to drug use is one of the most difficult challenges faced by clinicians and practitioners in the struggle to help people remain abstinent. In this paper, we review basic preclinical research on forced abstinence periods that identify the neural substrates involved and neural adaptations that occur after a drug-free period. Our attention focuses on forced abstinence after self-administration because of its promise for translational research in the development of candidate medications to reduce relapse. This model requires subjects (often rats) to initially acquire drug self-administration. However, rather than extinguishing behavior with daily drug-free sessions as in the reinstatement model of drug seeking, subjects are removed from the self-administration situation and do not receive any exposure to the drug. Notably, the integrity of the drug-taking behavior and the drug-associated cues in the drug-taking environment are preserved because they are not experienced in the absence of the drug. Research shows time dependent increases in drug-seeking following forced abstinence periods. More so, neural substrates and adaptations within the mesocorticolimbic system and the nigrostriatal system have been identified that contribute to increased drug seeking following abstinence. From a translational perspective, behavioral and pharmacological treatment of substance use disorder often starts during this initial abstinence period (either forced or voluntary). The forced abstinence model simulates some of the features of this treatment situation and thus allows for the study of potential treatments that alter relapse of drug-seeking behaviors along with the accompanying neurobiological changes

Competition Between the Conditioned Rewarding Effects of Cocaine and Novelty

Access to novelty might provide an alternative learning history that competes with conditioned drug reward. We tested this suggestion in rats using a place conditioning procedure with cocaine and novelty. In Experiment 1, rats were conditioned with cocaine to prefer one side of an apparatus. In a subsequent phase, cocaine exposure continued; however, on the unpaired side, separate group of rats had access to novel objects, cocaine injections, or saline with no objects. Pairings with novel objects or cocaine shifted a preference away from the cocaine-paired environment during drug-free and drug-challenge tests. Experiment 2 tested novelty’s impact when cocaine exposure was discontinued. The identical procedures were used, except drug exposure ceased on the cocaine-paired side during the second phase. Both groups expressed a preference for the cocaine compartment. This preference was maintained for rats that did not have novel objects; however, rats that experienced novelty spent similar amounts of time in both compartments during both tests. Overall, the conditioned rewarding effects of novelty competed with those of cocaine as evidenced by a change in choice behaviors motivated by drug reward

Forced Abstinence Model of Relapse to Study Pharmacological Treatments of Substance Use Disorder

Understanding and preventing relapse to drug use is one of the most difficult challenges faced by clinicians and practitioners in the struggle to help people remain abstinent. In this paper, we review basic preclinical research on forced abstinence periods that identify the neural substrates involved and neural adaptations that occur after a drug-free period. Our attention focuses on forced abstinence after self-administration because of its promise for translational research in the development of candidate medications to reduce relapse. This model requires subjects (often rats) to initially acquire drug self-administration. However, rather than extinguishing behavior with daily drug-free sessions as in the reinstatement model of drug seeking, subjects are removed from the self-administration situation and do not receive any exposure to the drug. Notably, the integrity of the drug-taking behavior and the drug-associated cues in the drug-taking environment are preserved because they are not experienced in the absence of the drug. Research shows time dependent increases in drug-seeking following forced abstinence periods. More so, neural substrates and adaptations within the mesocorticolimbic system and the nigrostriatal system have been identified that contribute to increased drug seeking following abstinence. From a translational perspective, behavioral and pharmacological treatment of substance use disorder often starts during this initial abstinence period (either forced or voluntary). The forced abstinence model simulates some of the features of this treatment situation and thus allows for the study of potential treatments that alter relapse of drug-seeking behaviors along with the accompanying neurobiological changes

Sign- vs. goal-tracking in a feature positive discrimination task with nicotine: Importance of spatial location of the conditional stimulus

We assessed whether sign-tracking developed along with goal-tracking in a Pavlovian drug discrimination task. Rats had nicotine sessions intermixed with saline sessions. For nicotine sessions, 15-sec illumination of a light near (Experiment 1) or far (Experiment 2) from the dipper receptacle was followed by sucrose. Saline sessions were similar except sucrose was withheld. Regardless of location, the light evoked goal-tracking only on nicotine sessions. Only rats with the light near the dipper developed sign-tracking

Bupropion differentially impacts acquisition of methamphetamine self-administration and sucrose-maintained behavior

Bupropion reduces the subjective effects and cue-induced craving for methamphetamine in humans. Given these effects of bupropion on methamphetamine in humans and its widespread clinical use, a preclinical model of drug-taking was used to determine if pretreatment with bupropion would alter the acquisition of methamphetamine self-administration. During acquisition, rats were given saline or bupropion (30 or 60 mg/kg, IP) 5 min before a 60-min session. For the first 8 days, each response on the active lever produced an infusion of methamphetamine (0.025 mg/kg). Responding on the inactive lever had no programmed consequence. This FR1 schedule was then increased to an FR3 for 4 more days. In a parallel study, the identical procedures were used to test the impact of bupropion on sucrose-maintained responding. Bupropion pretreatment decreased the number of methamphetamine infusions and sucrose deliveries earned on an FR1 and FR3. However, bupropion pretreatment only delayed discrimination between the active and inactive levers in the methamphetamine self-administration rats. Discrimination between active and inactive levers was acquired in all groups in the sucrose experiment regardless of pretreatment condition. Combined, these results suggest that bupropion has a more general effect within the appetitive/reward system of the brain rather than having complete specificity for methamphetamine

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 to no reward (saline). A modified variant of this task, “reference-conditioning” procedure, compares two potentially rewarding stimuli (high versus 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 alternating 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 sensitivity for measuring associatively-motivated choice behavior

Sign- vs. goal-tracking in a feature positive discrimination task with nicotine: Importance of spatial location of the conditional stimulus

We assessed whether sign-tracking developed along with goal-tracking in a Pavlovian drug discrimination task. Rats had nicotine sessions intermixed with saline sessions. For nicotine sessions, 15-sec illumination of a light near (Experiment 1) or far (Experiment 2) from the dipper receptacle was followed by sucrose. Saline sessions were similar except sucrose was withheld. Regardless of location, the light evoked goal-tracking only on nicotine sessions. Only rats with the light near the dipper developed sign-tracking

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

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 to 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

Bupropion Attenuates Methamphetamine Self-Administration in Adult Male Rats

Bupropion is a promising candidate medication for methamphetamine use disorder. As such, we used a preclinical model of drug-taking to determine the effects of bupropion on the reinforcing effects of methamphetamine (0.025, 0.05 or 0.1 mg/kg/infusion). Specificity was determined by investigating the effects of bupropion on responding maintained by sucrose. In the selfadministration study, rats were surgically prepared with indwelling jugular catheters and trained to self-administer methamphetamine under an FR5 schedule. A separate group of rats was trained to press a lever for sucrose. Once responding stabilized, rats were pretreated with bupropion (0, 10, 30 and 60 mg/kg IP) 5 min before chamber placement in a unique testing order. Following acute testing, rats were then repeatedly pretreated with 30 and 60 mg/kg bupropion. Acute treatments of bupropion dose dependently reduced drug intake for 0.025 to 0.1 mg/kg methamphetamine; sucrose deliveries were only reduced with the high bupropion dose. Repeated exposure to 60 mg/ kg bupropion before the session resulted in a consistent decrease in methamphetamine intake (0.05 and 0.1 mg/kg) and sucrose deliveries. Considered together, this pattern of findings demonstrates that bupropion decreases responding for methamphetamine, but the effects are only somewhat specific