A novel abuse liability assessment of e-cigarettes in young adults ii: Reinforcement enhancement and follow-up assessment.

A double-blind study was performed to test the abuse liability of electronic nicotine delivery systems (ENDS) in young adults; in particular, the influence of nicotine on reward sensitivity was assessed. A total of 53 healthy nonusers participated in experimental sessions during which they played a video game made available on a progressive ratio schedule of reinforcement and self-administered nicotine via ENDS. Participants were randomized into one of three groups. Two groups received either a dedicated concentration of nicotine (6 and 12 mg) or a placebo, and whether they received the placebo or their dedicated nicotine dose was randomly determined on a session-by-session basis to mask the sequencing of drug administration. The third group received only a 0 mg (placebo) vaping device during all sessions. In comparison to all placebo conditions, nicotine-induced reward sensitization was evidenced on behavioral measures of video game reinforcement, but not subjective appraisals of the vaping experience. A 1-month follow-up survey provided evidence that reinforcement enhancement by nicotine predicts increased abuse liability of ENDS. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Data crowdsourcing on psychomotor and cognitive effects of cannabis via mobile app.

In an effort to educate consumers of cannabis, we created a downloadable application (app) for mobile phones that collects data on the neuropsychological effects related to cannabis use. In particular, the app assessed four domains, these being: (i) psychomotor compensation, (ii) time estimation, (iii) sustained attention, and (iv) response inhibition. These tests were presented as a sequence of video games to be completed in under 10 min. Included in the analysis were 213 users who indicated that they were intoxicated from cannabis at the moment of app use. The control group contained individuals who reported using the app while sober (n = 137). A machine learning model was applied to the data to determine whether a particular pattern of performance was predictive of intoxication, and these results were used to inform the creation of a composite score that reflected aggregate performance for all four (i-iv) video games. Relative to the control group, the largest performance decrements were discovered within the initial 120 min after self-administration. These deficits abated as the time-since-use lengthened, and this pattern was consistent with the time-course of subjectively reported intoxication. Although significant limitations in interpretation exist due to the naturalistic and self-report data collection method, this proof-of-concept study points toward the potential utility of mobile app detection of cannabis effect. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Dopamine sensitization by methamphetamine treatment prior to instrumental training delays the transition into habit in female rats.

Early in instrumental learning, behavior is goal-directed and sensitive to changes in the value of the instrumental outcome. With sufficient repetition, responding becomes insensitive to changes in outcome value, or habitual. We have previously found that females transition into habit over a distinct range of training from 120 to 160 reinforced responses. This low level of instrumental training is markedly less than what has been shown to support habitual responding in male rats. To begin to investigate the early development of habit in females, we conducted a series of experiments in which we pretreated female rats with methamphetamine (METH) with the aim of sensitizing central dopamine, a major modulator of striatal function, prior to instrumental nose-poke training at the beginning and at the endpoint of the transition range in females. Following training, we tested for sensitivity to reinforcer devaluation (RD), which was conducted by repeatedly pairing reinforcers previously earned during training with lithium chloride (LiCl)-induced illness. As a counterpoint, a series of similar experiments was conducted separately in male rats. Additionally, in order to ascertain the validity of using nose-poke as an instrumental response, we compared sensitivity to devaluation between the Pavlovian approach towards the food magazine and the nose-poke response. In females, Vehicle groups responded in a habitual manner at both training levels (120 and 160 reinforced responses), whereas METH groups remained sensitive to devaluation. This suggests that increasing central dopamine delays habit formation in female rats. In male rats, Vehicle groups demonstrated goal-directed responding following training with 120 and 320 reinforced responses, and marginally goal-directed responding,with 160. METH-pretreated males were sensitive to devaluation at the 120 and 160 training levels, however, following more extended training to 320 reinforced responses, METH-pretreated males responded in a habitual manner, indicating that increasing central dopamine can advance habit formation in male rats. Overall, these results suggest that METH pretreatment maintains goal-directed responding in female rats when they are typically transitioning to habitual control of instrumental behavior and can advance habit formation in male rats given sufficient instrumental training. In addition, we found differential RD sensitivity of the nose-poke response used during instrumental training compared to Pavlovian approach towards the food magazine, confirming that there is a distinction between these two behaviors and that nose-poking is a valid instrumental response.

Reinforcement enhancement by nicotine: A novel abuse-liability assessment of e-cigarettes in young adults.

Nicotine can act as a primary positive reinforcer, and as negative reinforcer to relieve withdrawal; we tested whether it can also enhance the reinforcing efficacy of non-drug reinforcers. Young-adult never-users were delivered nicotine via e-cigarette, and a videogame reinforcer was used to test nicotine enhancement. Three dose groups were tested (placebo-only, 6 or 12-mg nicotine), and participants returned to the lab for several sessions over the course of 1 month. Those in the two nicotine-dose groups received placebo on some occasions and nicotine on others; nicotine enhancement of the videogame reinforcer was assessed in a within-subjects fashion by comparing each of the two nicotine groups' dedicated nicotine dose to placebo. In the placebo-only group, progressive-ratio (PR) schedule breakpoints did not alter as a function of videogame exposure, suggesting that the videogame retained its basic-reinforcing properties throughout the study. For the two groups that received nicotine, both doses of nicotine increased PR-schedule breakpoints for the videogame reinforcer relative to the placebo condition. Although nicotine was associated with greater subjective evaluation of the enjoyment of the videogame, it was unrelated to the enjoyment of the e-cigarette device. No evidence was found that nicotine elevated either anhedonia or withdrawal symptoms in the timeframe of the study. The results provide initial evidence that nicotine enhancement, via electronic cigarettes, occurs in non-frequent users of nicotine products and may be a reason they can develop nicotine dependence in the absence of withdrawal and direct effects of nicotine. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Startle, pre-pulse sensitization, and habituation in zebrafish.

BACKGROUND: The startle response, pre-pulse presentation of startle, and habituation in adult zebrafish (danio rerio) have not been formerly characterized using the same motion detection equipment within an integrated procedure. NEW METHOD: The methods presented in this manuscript describe the use of a video tracking software used previously in the detection of conditioned immobility in rodents, but adapted for the purposes of tracking zebrafish movement. RESULTS: The results from a series of investigations demonstrate an effective tracking and quantification of the startle response, as well as evidence that stimulus-experience history alters the startle response in adult zebrafish. COMPARISON WITH EXISTING METHODS: This method of tracking zebrafish allows for the quantification on movement of a single subject, and the delivery of the startle stimulus can be synchronized with the motion-detection software to obtain a high temporal resolution that is not provided by other means of motion-detection tracking. CONCLUSION: Objective techniques for evaluating these basic modifications of the startle response (pre-pulse and habituation) may be helpful in future behavioral analysis as this species is rapidly becoming among the most commonly utilized in preclinical pharmacological assessment.

Nicotine enhancement and reinforcer devaluation: Interaction with opioid receptors.

In rats, nicotine enhances responding maintained by non-pharmacological reinforcers, and discontinuation of nicotine devalues those same reinforcers. The goal of this study was to assess the interaction of nicotine and opioid receptors and to evaluate the degree to which nicotine enhancement and nicotine-induced devaluation are related to opioid activation. Nicotine (0.4mg/kg), or nicotine plus naloxone (0.3 or 3.0mg/kg), was delivered to rats prior to progressive ratio (PR) schedule sessions in which sucrose was used as a reinforcer. PR-schedule responding was assessed during ten daily sessions of drug delivery, and for three post-dosing days/sessions. Control groups for this investigation included a saline-only condition, and naloxone-only (0.3 or 3.0mg/kg) conditions. When administered in conjunction with nicotine, both naloxone doses attenuated nicotine enhancement of the sucrose reinforcer, and the combination of the larger dose of naloxone (3.0mg/kg) with nicotine produced significant impairments in sucrose reinforced responding. When administered alone, neither dose of naloxone (0.3 & 3.0mg/kg) significantly altered responding in comparison to saline. Furthermore, when dosing was discontinued after ten once-daily doses, all nicotine groups (nicotine-only and nicotine+naloxone combination) demonstrated significant decreases in sucrose reinforcement compared to the saline group. Although opioid antagonism attenuated reinforcement enhancement by nicotine, it did not prevent reinforcer devaluation upon discontinuation of nicotine dosing, and the higher dose of naloxone (3.0mg/kg) produced decrements upon discontinuation on its own in the absence of nicotine.

17ß-estradiol replacement in ovariectomized female rats slows set 1 dorsolateral striatial-dependent learning and enhances learning of set 2 in an extradimensional set-shifting paradigm.

The role of estrogen in extradimensional set-shifting was evaluated with replacement of 17ß-estradiol (E2) in ovariectomized (OVX) female rats. Rats were reinforced with food when they entered an arm of a plus-maze that was distinguished by visual and/or tactile cues (Set 1). In Set 2, reinforcement was shifted to construct a new association between food and visual/tactile cues that were different from Set 1. The purpose of using this extradimensional set-shifting task was to differentiate the effect of acute or continuous E2 on the dorsolateral (DLS) versus dorsomedial (DMS) striatum and medial prefrontal cortex (mPFC), because Set 1 and 2 learning, respectively, are associated with these particular brain regions. Results showed that compared to controls, acute E2-replaced female rats required more training trials to reach criterion in Set 1. Moreover, E2-replaced females showed a significant delay in the rate of acquisition of Set 1 learning compared to controls. In Set 2 there were no group differences in perseverative errors, which are reduced by mPFC activation, or when learning took place in a previously reinforced arm, a DMS-mediated effect. Despite this, control females required more training trials to learn Set 2 compared to Set 1, suggesting that prior learning in Set 1 interfered with Set 2 performance in non-E-replaced rats. In contrast, E2 groups learned Set 2 in fewer training trials than Set 1. These data suggest that E2 facilitates set shifting, apart from any apparent enhancement of DMS or mPFC function, perhaps by interfering with DLS-mediated Set 1 learning.

Reinforcer devaluation as a consequence of acute nicotine exposure and withdrawal.

RATIONALE: Nicotine discontinuation produces behaviors in rats that are congruent with anhedonia, and these symptoms may be related to the devaluation of non-nicotine reinforcers. OBJECTIVE: Four separate experiments were performed to explore the parameters surrounding nicotine-induced reinforcer devaluation. METHODS: In Experiments 1 and 2, nicotine (0.1 or 0.3 mg/kg) or 0.3 mg/kg nicotine plus 1.0 mg/kg mecamylamine was delivered to rats prior to progressive ratio (PR) schedule sessions in which sucrose was used as a reinforcer. In order to evaluate (a) reinforcer enhancement by nicotine and (b) reinforcer devaluation in the absence of nicotine, all rats experienced two PR schedule sessions per day for 10 days. Experiment 3 involved nicotine (0.3 mg/kg) and a visual stimulus in place of sucrose reinforcement. In Experiment 4, rats received nicotine (0.3 mg/kg) either before or after a single PR schedule session for 10 days. RESULTS: Experiments 1 and 2 demonstrate that reinforcer devaluation is related to the occupation of nicotinic-acetylcholine receptors. Results from Experiment 3 provide some evidence that devaluation occurs with either sucrose or visual-stimulus reinforcement. Experiment 4 demonstrates that a necessary condition for reinforcer devaluation to occur is the concurrent exposure to the reinforcer and nicotine. CONCLUSIONS: Reinforcer devaluation in rats emerges rapidly in a progressive, orderly fashion that coincides with accumulated exposure to nicotine. These results suggest that reinforcer devaluation may be a feature of nicotine that contributes to the abuse liability of tobacco products.

Nicotine-induced impulsive action: sensitization and attenuation by mecamylamine.

A conjunctive variable-interval differential-reinforcement-of-low-rate (VI-DRL, n=18) responding schedule and a stop-signal task (n=18) were used to evaluate the disinhibiting effects of nicotine on response withholding in rats. Sucrose solution was used to reinforce responding, and after a stable baseline was achieved under saline-administration conditions, 0.3 mg/kg nicotine was delivered before each session. Experiment 1 showed that repeated, but not the initial, administration of nicotine decreased performance on both tasks, and the effect of sensitization followed a similar timeline; 10 consecutive doses resulted in poorer proportion-correct VI-DRL trials and percent correct stop trials than the initial dose of nicotine. Furthermore, sensitization to 0.3 mg/kg nicotine decreased performance regardless of whether a spaced or consecutive-dosing regimen was followed. Experiment 2 was designed to test whether mecamylamine hydrochloride (0.1-1.0 mg/kg) could attenuate the effects of repeated 0.3 mg/kg nicotine administration, and the degree to which mecamylamine attenuation of the effect of nicotine to produce impulsive action was relative to dose. Results from experiment 2 showed that response disinhibition, as evaluated using the VI-DRL and stop-signal tasks, is related in a systematic manner to nicotinic-acetylcholine receptor activation.

Response disinhibition evoked by the administration of nicotine and nicotine-associated contextual cues.

Nicotine causes dose-dependent alterations in accuracy on the differential-reinforcement of low-rate responding (DRL) 29.5-s schedule in rats. The current investigation evaluated whether nicotine-associated contextual cues can produce nicotine-like perturbations in DRL-schedule performance in the absence of nicotine. Nicotine and saline administrations occurred just prior to DRL 29.5-s schedule responding for sucrose solution, and two different experimental contexts (differentiated by visual, olfactory, and tactile cues) were utilized. All subjects (N=16) experienced two consecutive sessions of DRL-schedule responding per day. The experimental group (n=8) was exposed to saline immediately prior to the first session and 0.3mg/kg nicotine before the second session, and the context was changed between sessions. This sequence of saline and then nicotine administration, paired with two reliable contexts, persisted for 12 consecutive days and successive nicotine administrations corresponded with increasingly poorer performance on the DRL 29.5-s schedule. No nicotine was administered for days 13-20 during context testing, and the nicotine-associated context produced response disinhibition on the DRL schedule. Two control groups were included in the design; subjects in one control group (n=4) received saline in each context to verify that the contexts themselves were not exerting control over operant responding. To assess how explicit and non-explicit pairings of nicotine and contextual cues influenced DRL behavior, subjects in a second control group (n=4) were given nicotine prior to the second session, but the contexts were not altered between sessions. The results from this experiment suggest that environmental stimuli associated with nicotine exposure can come to elicit nicotine-induced performance decrements on a DRL 29.5-s schedule.

A quantitative review of the ubiquitous relapse curve.

The primary goal of this study is to ascertain whether relapse to drug dependence, in terms of continuous abstinence assessment, exhibits a typical pattern that can be characterized by a common quantitative function. If the relapse curve is indeed ubiquitous, then some underlying mechanism must be operating to shape the curve that transcends variables such as drug class, population, or treatment type. Survival analyses are performed on 20 alcohol and tobacco treatment studies using the proportions of individuals remaining abstinent after a period of initial abstinence. Several parametric models of relapse are compared, and the results demonstrate that a log-logistic distribution is the most accurate reflection of the available data and the basic shape of the relapse curve is uniform. In most reports examined, the rate of relapse decelerates after initial abstinence has been achieved, and therefore, the amount of accumulated time abstinent may be the transcending variable that operates to shape the relapse curve.

Differential-reinforcement-of-low-rate-schedule performance and nicotine administration: a systematic investigation of dose, dose-regimen, and schedule requirement.

Differential-reinforcement-of-low-rate (DRL) schedules have been used to evaluate the effects of a wide variety of drugs, including amphetamines, cannabinoids, and antidepressant medication. To earn a reinforcer, organisms operating under a DRL schedule are required to withhold a response for a predetermined amount of time before responding, and therefore this schedule maintains a low rate of responding and can be viewed as a response-inhibition task. In experiment 1, three different DRL schedules (4.5, 9.5, and 29.5 s) were used to evaluate systematically a range of nicotine doses (0.0, 0.1, 0.3, and 0.5 mg/kg). The dose-response effect of nicotine then was compared with the effects of increased reinforcer magnitude on responding. Both the administration of nicotine and increased reinforcer magnitude engendered less accurate DRL-schedule performance compared with baseline conditions, and the dose and magnitude-dependent shifts were most evident on the DRL 29.5-s schedule. Experiment 2 compared the differences between acute and chronic dosing regimens (0.3 mg/kg nicotine) on DRL 29.5-s schedule responding. After 20 consecutive sessions of nicotine dosing, accuracy deteriorated significantly, demonstrating that chronic nicotine dosing leads to a behavioral sensitization apparent on the DRL 29.5-s schedule. The results from both experiments suggest that responding on the DRL 29.5-s schedule is sensitive to both dose-response and regimen-dependent effects of nicotine.

Simulated opioid withdrawal engenders risk-prone choice: a comparison of intravenous and intranasal-using populations.

Risk-sensitive foraging theory refers to a group of different models that predict the occurrence of risk-prone behavior; therefore, these models may help to characterize the risky behavior that is a hallmark of opioid dependence. The daily energy budget (DEB) rule, one model of risk-sensitivity, suggests that foragers will prefer highly variable food sources over less variable ones when all current options provide means that are insufficient to meet metabolic requirements. The tenets of the DEB rule were tested in the context of opioid dependence, the primary hypothesis being that opioid withdrawal may foster risky choice. Intravenous and intranasal-using opioid-dependent patients enrolled in a buprenorphine treatment program read scripts simulating opioid-agonist and -antagonist symptoms, and then made a series of decisions between two different opioid dealers. One dealer provided a constant source of heroin, and the other, a variable source. Separate measures were utilized to expose participants to either variability in delay of opioids or quantity of opioids. Participants were also required to complete a money questionnaire in which two hypothetical slot machines differed in respect to payoff amounts and probabilities. Results demonstrate that preference for the risky option was mediated by hypothetical drug deprivation in all circumstances, but this effect was more considerable in opioid-dependent participants who used intravenously. The current findings suggest that intravenous delivery places greater metabolic constraints on the user and therefore engenders greater risk-taking during withdrawal. The DEB rule is applicable to opioid dependence and provides a useful framework from which to examine the behaviors associated with opioid withdrawal.

Substitutes for tobacco smoking: a behavioral economic analysis of nicotine gum, denicotinized cigarettes, and nicotine-containing cigarettes.

Both pharmacological and nonpharmacological stimuli may be responsible for the reinforcement and maintenance of tobacco smoking. The present study examined the self-administration of nicotine gum, denicotinized cigarettes, and nicotine-containing cigarettes utilizing a behavioral economic design in order to investigate the pharmacological and nonpharmacological aspects of cigarette smoking. Cigarette-deprived, dependent smokers worked for cigarette puffs and nicotine gum in daily operant sessions. In one phase, nicotine-containing cigarettes were available at increasing unit prices across sessions. Three phases replicated these sessions with nicotine gum, denicotinized cigarettes, or both, concurrently available at a constant unit price. As nicotine-containing cigarette unit price increased, consumption decreased. However, as nicotine-containing cigarette unit price increased, nicotine gum and denicotinized cigarette consumption increased. Consumption of nicotine gum, but not denicotinized cigarettes, diminished when all three reinforcers were concurrently available. Concurrently available denicotinized cigarettes, but not nicotine gum, caused a statistically significant reduction in nicotine-containing cigarette consumption. In another phase, denicotinized cigarettes were available at increasing unit prices across sessions while nicotine gum was concurrently available at a constant unit price. This phase demonstrated that nicotine content had no reliable effect on cigarette or nicotine gum consumption. These results suggest that denicotinized cigarettes are a more effective alternative reinforcer than nicotine gum, indicating that nonpharmacological stimuli of smoking merit attention in smoking cessation treatment. Furthermore, these findings indicate that alternative reinforcement would be most effective in smoking cessation treatment when combined with high prices for cigarettes.

Increased effort requirements and risk sensitivity: a comparison of delay and magnitude manipulations.

Reward magnitude and delay to reward were independently manipulated in two separate experiments examining risk-sensitive choice in rats. A dual-running wheel apparatus was used and the tangential force resistance required to displace both wheels was low (50g) for half of the subjects, and high (120g) for the remaining subjects. Concurrent FI30-s and FI60-s schedules delivered equivalent amounts of food reward per unit time (i.e. 5 and 10 pellets of food, respectively), and these conditions served as the baseline treatment for all subjects. Variability, either in reward magnitude or delay, was introduced on the long-delay (60s) schedule during the second phase. All subjects were returned to the baseline condition in the third phase, and variability was introduced on the short-delay (30s) interval schedule during phase four. The subjects were again returned to the baseline condition in the fifth and final phase, ultimately yielding a five-phase ABACA design. Original baseline performance was characterized by a slight short-delay interval preference, and this pattern of performance was recovered with each subsequent presentation of the baseline condition. Overall, the data obtained from the reward magnitude and delay-to-reward manipulations were indistinguishable; subjects experiencing low-response effort requirement behaved in a risk-indifferent manner and subjects experiencing high-response effort requirement preferred the variable schedule. Implications for the daily energy budget rule on risk-sensitive foraging are discussed in light of these findings.