RESUMEN

Background: ß-Nicotyrine (ß-Nic) is a unique minor alkaloid constituent in electronic nicotine delivery systems (ENDS) that is derived from nicotine (Nic) degradation and can reach 25% of Nic concentrations in ENDS aerosol. ß-Nic slows Nic metabolism and prolongs systemic Nic exposure, which may alter the discriminability of Nic. The present study sought to examine ß-Nic has interoceptive effects itself, and if it alters the subjective effects ENDS products within a drug-discrimination paradigm. Methods: The pharmacodynamics of ß-Nic were examined in vitro, and a nicotine discrimination paradigm was used to determine if ß-Nic (0 - 5.0 mg/kg) shares discriminative stimulus properties with Nic (0.2 mg/kg) in male (n = 13) and female (n = 14) rats after 10- & 60-min ß-Nic pretreatment delays. A second group of rats was trained to discriminate ß-Nic and Nornicotine (Nornic) from saline to determine if ß-Nic alone has interoceptive properties and whether they are similar to Nornic. Results: ß-Nic had similar binding affinity and efficacy at the α4ß2 nicotinic receptor subtype as Nornic, ~50% of Nic efficacy. However, ß-Nic only weakly substituted for Nic during substitution testing in female rats, but not males, whereas Nornic fully substituted for Nic. Combination testing at the 10 and 60-min pretreatment intervals showed that ß-Nic dose-dependently increased the duration of nicotine's discriminative stimulus effects, especially at the 60-min delay. Drug naïve rats could reliably discriminate Nornic, but not ß-Nic, from Sal. Conclusion: ß-Nic increased and prolonged the interoceptive stimulus properties of Nic, suggesting it may alter to the abuse liability of ENDS through its ability to slow Nic metabolism.

RESUMEN

BACKGROUND: The rise in heroin addiction has heightened the need for novel and effective treatments. Physical exercise has been shown as an effective treatment for stimulant abuse in clinical and pre-clinical research. However, this treatment has not yet been tested on opioid addiction. This study examined the effects of physical activity (wheel running) on heroin-seeking in rats within a reinstatement paradigm (i.e., heroin relapse model). METHODS: Female and male rats were trained to self-administer intravenous heroin (0.015 mg/kg). Once trained, rats were placed into extinction (i.e., heroin abstinence) for 21 days with continuous access to a locked or unlocked running wheel. After extinction, rats were tested for drug- (heroin, caffeine, and yohimbine) and cue-primed reinstatement of heroin-seeking. RESULTS: Females completed more wheel revolutions than males across all study phases. Access to an unlocked running wheel reduced extinction and reinstatement of heroin-seeking, with greater reductions in females than males across several reinstatement conditions. In the locked wheel group, female rats showed greater reinstatement of heroin-seeking than males across several priming conditions. CONCLUSIONS: Wheel running reduced heroin-seeking in male and female rats, with females showing a more robust effect during reinstatement. The locked wheel group allowed an examination of sex differences in heroin reinstatement, which revealed that females showed greater vulnerability to heroin reinstatement than males, but with no other sex differences observed in maintenance or extinction. Overall, the results indicate that voluntary physical exercise may be an effective treatment for heroin dependence in humans.

Asunto(s)

RESUMEN

The FDA recently extended their regulatory authority to electronic cigarettes (ECs). Because the abuse liability of ECs is a leading concern of the FDA, animal models are urgently needed to identify factors that influence the relative abuse liability of these products. The ability of tobacco products to induce nicotine dependence, defined by the emergence of anhedonia and other symptoms of nicotine withdrawal following cessation of their use, contributes to tobacco abuse liability. The present study compared the severity of precipitated withdrawal during chronic infusion of nicotine alone or nicotine-dose equivalent concentrations of three different EC refill liquids in rats, as indicated by elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior). Because these EC liquids contain constituents that may enhance their abuse liability (e.g., minor alkaloids), we hypothesized that they would be associated with greater withdrawal effects than nicotine alone. Results indicated that the nicotinic acetylcholine receptor antagonist mecamylamine precipitated elevations in ICSS thresholds in rats receiving a chronic infusion of nicotine alone or EC liquids (3.2mg/kg/day, via osmotic pump). Magnitude of this effect did not differ between formulations. Our findings indicate that nicotine alone is the primary CNS determinant of the ability of ECs to engender dependence. Combined with our previous findings that nicotine alone and these EC liquids do not differ in other preclinical addiction models, these data suggest that product standards set by the FDA to reduce EC abuse liability should primarily target nicotine, other constituents with peripheral sensory effects (e.g. flavorants), and factors that influence product appeal (e.g., marketing).

Asunto(s)

RESUMEN

BACKGROUND: The popularity of electronic cigarettes (ECs) has increased dramatically despite their unknown health consequences. Because the abuse liability of ECs is one of the leading concerns of the Food and Drug Administration (FDA), models to assess it are urgently needed to inform FDA regulatory decisions regarding these products. The purpose of this study was to assess the relative abuse liability of an EC liquid compared to nicotine alone in rats. Because this EC liquid contains non-nicotine constituents that may enhance its abuse liability, we hypothesized that it would have greater abuse liability than nicotine alone. METHODS: Nicotine alone and nicotine dose-equivalent concentrations of EC liquid were compared in terms of their acute effects on intracranial self-stimulation (ICSS) thresholds, acquisition of self-administration, reinforcing efficacy (i.e., elasticity of demand), blockade of these behavioral effects by mecamylamine, nicotine pharmacokinetics and nicotinic acetylcholine receptor binding and activation. RESULTS: There were no significant differences between formulations on any measure, except that EC liquid produced less of an elevation in ICSS thresholds at high nicotine doses. CONCLUSIONS: Collectively, these findings suggest that the relative abuse liability of this EC liquid is similar to that of nicotine alone in terms of its reinforcing and reinforcement-enhancing effects, but that it may have less aversive/anhedonic effects at high doses. The present methods may be useful for assessing the abuse liability of other ECs to inform potential FDA regulation of those products.

Asunto(s)

RESUMEN

BACKGROUND: Previous research has found that rats behaviorally screened for high (vs. low) wheel running were more vulnerable to cocaine abuse. To assess the extent to which a genetic component is involved in this drug-abuse vulnerability, rats selectively bred for high or low voluntary running (HVR or LVR, respectively) were examined for differences in cocaine seeking in the present study. METHODS: Female rats were trained to lever press for food and then were assessed for differences in acquisition of cocaine (0.4mg/kg; i.v.) self-administration across 10 sessions. Once acquired, rats self-administered cocaine for a 14-day maintenance phase, followed by a 14-day extinction phase when cocaine was no longer available. Subsequently, reinstatement of cocaine seeking was examined with priming injections of cocaine (5, 10 & 15mg/kg), caffeine (30mg/kg), yohimbine (2.5mg/kg) and cocaine-paired cues. RESULTS: A greater percentage of LVR rats met the acquisition criteria for cocaine self-administration and in fewer sessions than HVR rats. No differences in responding for cocaine were observed between phenotypes during maintenance. However, during extinction LVR rats initially responded at higher rates and persisted in cocaine seeking for a greater number of sessions. No phenotype differences were observed following drug and cue-primed reinstatement of cocaine seeking. CONCLUSIONS: In general, LVR rats were more sensitive to the reinforcing effects of cocaine than HVR rats during periods of transition into and out of cocaine self-administration. Thus, LVR rats sometimes showed a greater vulnerability cocaine seeking than HVR rats.

Asunto(s)