Human laboratory models in substance use disorder provide a key intermediary step between highly controlled and mechanistically informative non-human preclinical methods and clinical trials conducted ...in human populations. Much like preclinical models, the variety of human laboratory methods provide insights into specific features of substance use disorder rather than modelling the diverse causes and consequences simultaneously in a single model. This narrative review provides a discussion of popular models of reward used in human laboratory research on substance use disorder with a focus on the specific contributions that each model has towards informing clinical outcomes (forward translation) and analogs within preclinical models (backward translation). Four core areas of human laboratory research are discussed: drug self-administration, subjective effects, behavioral economics, and cognitive and executive function. Discussion of common measures and models used, the features of substance use disorder that these methods are purported to evaluate, unique issues for measure validity and application, and translational links to preclinical models and special considerations for studies wishing to evaluate homology across species is provided.
•This review overviews popular models of reward used in substance use research.•Unique issues for measure validity and application are discussed.•Translational links to preclinical models and homology are considered.•Directions to improve human laboratory models of reward are provided.
The reinforcing efficacy, or behavior-strengthening effect, of a substance is a critical determinant of substance use typically quantified by measuring behavioral allocation to the substance under ...schedules of reinforcement with escalating response requirements. Although responses on these tasks are often used to indicate stable reinforcing effects or trait-level abuse potential for an individual, task designs often demonstrate within-person variability across varying degrees of a constraint within experimental procedures. As a result, quantifying behavioral allocation is an effective approach for measuring the impact of contextual and psychosocial factors on substance reward. We review studies using laboratory self-administration, behavioral economic purchase tasks, and ambulatory assessments to quantify the impact of various contextual and psychosocial factors on behavioral allocation toward consumption of a substance. We selected these assessment approaches because they cover the translational spectrum from experimental control to ecological relevance, with consistent support across these approaches representing greater confidence in the effect. Conceptually, we organized factors that influence substance value into two broad categories: factors that influence the cost/benefit ratio of the substance (social context, stress and affect, cue exposure), and factors that influence the cost/benefit ratio of an alternative (alternative non-drug reinforcers, alternative drug reinforcers, and opportunity costs). We conclude with an overview of future research directions and considerations for clinical application.
•Drug reward can be quantified as behavioral allocation toward substances.•Drug reward fluctuates across context and with the introduction of alternatives.•Presence of peers, affect, stress, and cues increases drug value.•Drug and non-drug alternatives and opportunity costs decrease drug value.•Treatments may be enhanced by targeting both drug and non-drug reward.
The recreational use of fentanyl in combination with xylazine (i.e., "tranq-dope") represents a rapidly emerging public health threat characterized by significant toxicity and mortality. This study ...quantified the interactions between these drugs on lethality and examined the effectiveness of potential rescue medications to prevent a lethal overdose.
Male and female mice were administered acute doses of fentanyl, xylazine, or their combination via intraperitoneal injection, and lethality was determined 0.5, 1.0, 1.5, 2.0, and 24 h after administration. Both fentanyl and xylazine produced dose-dependent increases in lethality when administered alone.
A nonlethal dose of fentanyl (56 mg/kg) produced an approximately 5-fold decrease in the estimated LD50 for xylazine (i.e., the dose estimated to produce lethality in 50% of the population). Notably, a nonlethal dose of xylazine (100 mg/kg) produced an approximately 100-fold decrease in the estimated LD
for fentanyl. Both drug combinations produced a synergistic interaction as determined via isobolographic analysis. The opioid receptor antagonist, naloxone (3 mg/kg), but not the alpha-2 adrenergic receptor antagonist, yohimbine (3 mg/kg), significantly decreased the lethality of a fentanyl-xylazine combination. Lethality was rapid, with death occurring within 10 min after a high dose combination and generally within 30 min at lower dose combinations. Males were more sensitive to the lethal effects of fentanyl-xylazine combinations under some conditions suggesting biologically relevant sex differences in sensitivity to fentanyl-xylazine lethality.
These data provide the first quantification of the lethal effects of "tranq-dope" and suggest that rapid administration of naloxone may be effective at preventing death following overdose.
Epidemiological studies report a high concordance rate of drug use within groups, suggesting an interplay between drug reinforcement and social cohesion. Preclinical studies reveal that (a) ...contingent access to a social partner increases cocaine intake and (b) experimenter-delivered cocaine increases the reinforcing effects of social contact. The purpose of this study was to determine if response-contingent cocaine increases the reinforcing effectiveness of social contact. Male rats were implanted with intravenous catheters and trained on a fixed ratio (FR1) schedule for 30-s access to a social partner. The reinforcing effectiveness of social contact was then determined using a progressive ratio (PR) schedule. After the PR test, rats were divided into two groups in which each response on an FR1 schedule produced social access and either response-contingent cocaine (0.5 mg/kg/infusion) or saline. After 9 days, the reinforcing effectiveness of social contact in the absence of infusions was determined again on the PR schedule. The cocaine and saline reinforcers were then switched between groups and the latter procedures were repeated. Recent exposure to response-contingent cocaine increased the reinforcing effectiveness of social contact on the PR schedule. This effect was transient, and the reinforcing effectiveness of social contact returned to baseline levels once response-contingent cocaine was replaced with saline. These data indicate that recent exposure to response-contingent cocaine transiently increases the reinforcing effectiveness of social contact and suggest that cocaine use may strengthen social cohesion by increasing the reinforcing effects of social contact with other individuals.
Public Health Significance
One of the most reliable predictors of drug use is whether an individual's peers use drugs. This study examined whether response-dependent cocaine increases the motivation for social contact. We report that response-dependent cocaine transiently increases the motivation for social contact, suggesting that cocaine use may increase social cohesion under some conditions.
A return to cocaine use following abstinence frequently occurs in a social context, and the presence of other individuals using cocaine may contribute to the likelihood of use. Previous studies have ...reported that chronic d-amphetamine treatment decreases cocaine self-administration in laboratory animals and reduces a return to cocaine use following abstinence in humans.
The purpose of this study was to examine the effects of chronic d-amphetamine treatment on the reacquisition of cocaine use in rats self-administering cocaine in different social contexts.
Male and female rats were implanted with intravenous catheters and trained to self-administer cocaine during daily 6-hr sessions. After 14 days, cocaine self-administration was extinguished by substituting saline for the cocaine stimulus. At this time, rats were randomized to receive chronic treatment with either d-amphetamine or saline. After 9 days of extinction, cocaine was again made available during daily 6-hr sessions. At this time, rats were further randomized into three social conditions: (1) rats continued self-administering cocaine in isolation, (2) rats self-administered cocaine in the presence of a same-sex partner that also self-administered cocaine, or (3) rats self-administered cocaine in the presence of a same-sex partner that did not have access to cocaine. Daily treatment with d-amphetamine or saline continued for the duration of reacquisition testing.
Chronic treatment with d-amphetamine decreased cocaine intake during reacquisition, but these effects were not influenced by the social context. No sex differences were observed.
These data support previous studies reporting that d-amphetamine decreases cocaine intake and demonstrate its efficacy across social contexts.
•D-amphetamine and social context were examined on cocaine self-administration.•Cocaine self-administration was established prior to extinction and reacquisition.•Chronic d-amphetamine decreased the reacquisition of cocaine self-administration.•The effects of d-amphetamine were independent of social context.
Opioids and stimulants are often used in combination for both recreational and non-recreational purposes. High-efficacy mu opioid agonists generally increase the behavioral effects of stimulants, ...whereas opioid receptor antagonists generally attenuate the behavioral effects of stimulants; however, less is known regarding the interactions between stimulants and opioids possessing low to intermediate efficacy at the mu receptor. The purpose of this study was to examine the role of an opioid's relative efficacy at the mu receptor in altering the behavioral effects of dextro(
-)amphetamine. To this end, opioids possessing a range of relative efficacy at the mu receptor were examined alone and in combination with cumulative doses of
-amphetamine on a test of open-field, locomotor activity in male rats. Levorphanol, buprenorphine, butorphanol, nalbuphine, (-)-pentazocine, (-)-metazocine, (-)-cyclazocine, (-)-NANM, and nalorphine increased the locomotor effects of
-amphetamine in either an additive or greater-than-additive manner according to an effect-additive model. Only the selective, high-efficacy kappa agonist, spiradoline, and the non-selective opioid receptor antagonist, naloxone, failed to increase the effects of
-amphetamine under the conditions examined. These data indicate that opioids possessing a large range of relative efficacy at the mu receptor, including those possessing very low relative efficacy, significantly increase the locomotor effects of
-amphetamine.
Background
Nivolumab plus ipilimumab (NIVO + IPI) has demonstrated long‐term efficacy and safety in patients with previously untreated, advanced renal cell carcinoma (aRCC). Although most phase 3 ...clinical trials exclude patients with brain metastases, the ongoing, multicohort phase 3b/4 CheckMate 920 trial (ClincalTrials.gov identifier NCT02982954) evaluated the safety and efficacy of NIVO + IPI in a cohort that included patients with aRCC and brain metastases, as reported here.
Methods
Patients with previously untreated aRCC and asymptomatic brain metastases received NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks × 4 followed by NIVO 480 mg every 4 weeks. The primary end point was the incidence of grade ≥3 immune‐mediated adverse events (imAEs) within 100 days of the last dose of study drug. Key secondary end points were progression‐free survival and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (both determined by the investigator). Exploratory end points included overall survival, among others.
Results
After a minimum follow‐up of 24.5 months (N = 28), no grade 5 imAEs occurred. The most common grade 3 and 4 imAEs were diarrhea/colitis (n = 2; 7%) and hypophysitis, rash, hepatitis, and diabetes mellitus (n = 1 each; 4%). The objective response rate was 32% (95% CI, 14.9%‐53.5%) with a median duration of response of 24.0 months; 4 of 8 responders remained without reported progression. Seven patients (25%) had intracranial progression. The median progression‐free survival was 9.0 months (95% CI, 2.9‐12.0 months), and the median overall survival was not reached (95% CI, 14.1 months to not estimable).
Conclusions
In patients who had previously untreated aRCC and brain metastases—a population with a high unmet medical need that often is underrepresented in clinical trials—the approved regimen of NIVO + IPI followed by NIVO showed encouraging antitumor activity and no new safety signals.
CheckMate 920 is the first prospective, multicohort study of nivolumab plus ipilimumab as first‐line therapy for advanced renal cell carcinoma in patients who have a poor prognosis and a high unmet medical need. In cohort 3 (advanced renal cell carcinoma and brain metastases), nivolumab plus ipilimumab has a safety profile consistent with previous reports of this dosing regimen with encouraging antitumor activity.
Selective serotonin reuptake inhibitors (SSRIs) are widely used for treating neuropsychiatric disorders. However, the exact mechanism of action and why effects can take several weeks to manifest is ...not clear. The hypothesis of neuroplasticity is supported by preclinical studies, but the evidence in humans is limited. Here, we investigate the effects of the SSRI escitalopram on presynaptic density as a proxy for synaptic plasticity. In a double-blind placebo-controlled study (NCT04239339), 32 healthy participants with no history of psychiatric or cognitive disorders were randomized to receive daily oral dosing of either 20 mg escitalopram (n = 17) or a placebo (n = 15). After an intervention period of 3-5 weeks, participants underwent a
CUCB-J PET scan (29 with full arterial input function) to quantify synaptic vesicle glycoprotein 2A (SV2A) density in the hippocampus and the neocortex. Whereas we find no statistically significant group difference in SV2A binding after an average of 29 (range: 24-38) days of intervention, our secondary analyses show a time-dependent effect of escitalopram on cerebral SV2A binding with positive associations between
CUCB-J binding and duration of escitalopram intervention. Our findings suggest that brain synaptic plasticity evolves over 3-5 weeks in healthy humans following daily intake of escitalopram. This is the first in vivo evidence to support the hypothesis of neuroplasticity as a mechanism of action for SSRIs in humans and it offers a plausible biological explanation for the delayed treatment response commonly observed in patients treated with SSRIs. While replication is warranted, these results have important implications for the design of future clinical studies investigating the neurobiological effects of SSRIs.
Data on safety and effectiveness of RPV from the real-world setting as well as comparisons with other NNRTIs such as efavirenz (EFV) remain scarce.
Participants of EuroSIDA were included if they had ...started a RPV- or an EFV-containing regimen over November 2011-December 2017. Statistical testing was conducted using non-parametric Mann-Whitney U test and Chi-square test. A logistic regression model was used to compare participants' characteristics by treatment group. Kaplan-Meier analysis was used to estimate the cumulative risk of virological failure (VF, two consecutive values > 50 copies/mL).
1,355 PLWH who started a RPV-based regimen (11% ART-naïve), as well as 333 initiating an EFV-containing regimen were included. Participants who started RPV differed from those starting EFV for demographics (age, geographical region) and immune-virological profiles (CD4 count, HIV RNA). The cumulative risk of VF for the RPV-based group was 4.5% (95% CI 3.3-5.7%) by 2 years from starting treatment (71 total VF events). Five out of 15 (33%) with resistance data available in the RPV group showed resistance-associated mutations vs. 3/13 (23%) among those in the EFV group. Discontinuations due to intolerance/toxicity were reported for 73 (15%) of RPV- vs. 45 (30%) of EFV-treated participants (p = 0.0001). The main difference was for toxicity of central nervous system (CNS, 3% vs. 22%, p < 0.001).
Our estimates of VF > 50 copies/mL and resistance in participants treated with RPV were similar to those reported by other studies. RPV safety profile was favourable with less frequent discontinuation due to toxicity than EFV (especially for CNS).
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