Human laboratory models of reward in substance use disorder.

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.

Treatment with dextroamphetamine decreases the reacquisition of cocaine self-administration: Consistency across social contexts.

RATIONALE: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: These data support previous studies reporting that d-amphetamine decreases cocaine intake and demonstrate its efficacy across social contexts.

"Tranq-dope" overdose and mortality: lethality induced by fentanyl and xylazine.

Introduction: 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. Methods: 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. Results: 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 LD50 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. Discussion: 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.

"Tranq-Dope" Overdose and Mortality: Lethality Induced by Fentanyl and Xylazine.

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 30, 60, 90, 120, and 1440 min (24 hr) 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 LD50 for fentanyl. 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.

Response-contingent cocaine increases the reinforcing effectiveness of social contact.

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. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Interactions Between Opioids and Dextroamphetamine on Locomotor Activity: Influence of an Opioid's Relative Efficacy at the Mu Receptor.

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(d-)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 d-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 d-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 d-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 d-amphetamine.