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AIMS: Opioid use disorder (OUD) remains a serious public health problem. Opioid maintenance treatment is effective but under-utilized, hard to access under existing federal regulations, and, once patients achieve OUD stability, challenging to discontinue. Fewer than 2% of persons with OUD stop using opioids completely. There have been calls from public advocacy groups, governmental agencies, and public health officials for new treatments for OUD. Dezocine, a non-scheduled opioid previously used in the United States and currently widely prescribed in China for pain management, could be a candidate for a novel OUD treatment medication in the U.S. Nonetheless, to date, there have been no reviews of the clinical and preclinical literature detailing dezocine's abuse potential, a key consideration in assessing its clinical utility. DISCUSSION: There are no English language reports of human abuse, dependence, or overdose of dezocine, despite years of extensive clinical use. There are a few case reports of dezocine abuse in the Chinese literature, but there are no reports of overdose deaths. Dezocine is perceived as an opioid and is "liked" by opioid-experienced human and non-human primates, properties that are not dose-dependent and are mitigated by ceiling effects-higher doses do not result in more "liking." There is little withdrawal, spontaneous or precipitated, in humans, monkeys, rats, or mice treated chronically with dezocine alone. However, at some doses, dezocine can precipitate withdrawal in humans and monkeys dependent on other opioids. In rodents, dezocine reduces the severity of morphine withdrawal and the rewarding properties of other opioids. CONCLUSIONS: Although dezocine is reinforcing in humans and monkeys with prior or concurrent opioid use within a restricted dose range, there are only a few anecdotal reports of dezocine abuse despite of the long history of use in humans. Given the evidence of dezocine's limited abuse potential, it could be useful both as a treatment for OUD. However, in-depth studies would be required for dezocine to be re-considered for clinical use.

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Drug discrimination research has generated rich evidence for the capacity of interoceptive drug stimuli to control behavior by serving as discriminative cues. Owing to its neuropharmacological specificity, drug discrimination learning has been widely used to characterize the stimulus effects and neuropharmacological underpinning of drugs. Apart from such utility, discriminative drug stimuli may help regulate drug use by disambiguating conditioned associations and post-intake outcomes. First, this review summarizes the evidence supporting interoceptive regulation of drug intake from the literature of exteroceptive discriminative control of drug-related behavior, effects of drug priming, and self-titration of drug intake. Second, an overview of interoceptive control of reward-seeking and the animal model of discriminated goal-tracking is provided to illustrate interoceptive stimulus control of the initiation and patterning of drug intake. Third, we highlight the importance of interoceptive control of aversion-avoidance in the termination of drug-use episodes and describe the animal model of discriminated taste avoidance that supports such a position. In bridging these discriminative functions of drug stimuli, we propose that interoceptive drug stimuli help regulate intake by disambiguating whether intake will be rewarding, nonrewarding, or aversive. The reflection and discussion on current theoretical formulations of interoceptive control of drug intake may further scientific advances to improve animal models to study the mechanisms by which interoceptive stimuli regulate drug intake, as well as how alterations of interoceptive processes may contribute to the transition to dysregulated drug use.

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RATIONALE: Isobutyryl-carfentanyl is the most recently discovered fentanyl analogue with a chemical structure that is similar to that of carfentanyl. Its analogue, carfentanyl, is regarded as one of the most lethal drugs in the world, with a potency of 10,000 times that of morphine. Therefore, isobutyryl-carfentanyl may possess a comparably high potency and its harmful effects cannot be ignored. OBJECTIVES: This study was designed to assess the analgesic effect of isobutyryl-carfentanyl and the potential risks associated with its misuse. METHODS: In this study, we assessed the acute toxicity of isobutyryl-carfentanyl by up-and-down-procedure, the analgesic efficacy by hot-plate test, the abuse potential by conditioned place preference (CPP), drug self-administration, and drug discrimination tests, and compared it with fentanyl and carfentanyl. RESULTS: The estimated median lethal dose (LD50) of isobutyryl-carfentanyl administered were 175 mg/kg (intragastric administration, IG), 15.84 mg/kg (intraperitoneal injection, IP), 15.84 mg/kg (subcutaneous injection, SC), and 1.6 mg/kg (intravenous injection, IV), respectively. The 50% maximal analgesic effect (ED50) of isobutyryl-carfentanyl was determined to be 0.00319 mg/kg, with an analgesic potency 14 times that of fentanyl and 0.82 times that of carfentanyl. Isobutyryl-carfentanyl exhibited a significant positional preference at a minimum dose of 0.1 mg/kg, while fentanyl exhibited a significant positional preference at a minimum dose of 0.3 mg/kg. In the heroin (0.05 mg/kg/infusion) self-administration substitution experiment, isobutyryl-carfentanyl showed significant self-administration behaviour at doses of 0.0005-0.001 mg/kg/infusion, with the maximum number of infusions observed at a dose of 0.001 mg/kg. In the heroin (1 mg/kg) drug discrimination experiment, fentanyl (0.005-0.02 mg/kg), carfentanyl (0.0005-0.002 mg/kg), and isobutyryl-carfentanyl (0.001-0.005 mg/kg) were tested in the dose-effect curves. The results showed that all three drugs exhibit dose-dependent increase in the number of drug-associated nose pokes responses and reduction in the rate of nose pokes. The subjective effect potency of isobutyryl-carfentanyl was found to be 4.4 times that of fentanyl and 0.5 times that of carfentanyl. CONCLUSIONS: In summary, isobutyryl-carfentanyl has high acute toxicity and analgesic effect, with strong psychological dependence approximately 5 times that of fentanyl and 0.5 times that of carfentanyl, and has extremely high abuse potency.

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Despite a significant decrease in the number of prescriptions for opioids, the opioid crisis continues, fueled in large part by the availability of the phenylpiperadine mu opioid receptor (MOR) agonist fentanyl. In contrast, the number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically with gabapentinoids commonly detected in opioid overdose victims. Although gabapentinoids can decrease the potency of the opioid receptor antagonist naloxone to reverse heroin-induced hypoventilation in male rats, the specificity and nature of interaction between gabapentinoids and MOR agonists and any potential sex difference in those interactions are not well characterized. Gabapentinoids were studied in female and male rats discriminating fentanyl (0.0032 mg/kg, i.p.) or cocaine (3.2 mg/kg, i.p.). Alone, neither gabapentin nor pregabalin significantly increased fentanyl- or cocaine-appropriate responding. In rats discriminating fentanyl, each gabapentinoid dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the left whereas naloxone dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the right. Each gabapentinoid (100 mg/kg) significantly decreased the potency of naloxone to antagonize the discriminative stimulus effect of fentanyl or heroin. In contrast, each gabapentinoid dose-dependently shifted the cocaine discrimination dose-effect function to the right. There were no significant sex differences in this study. These results suggest that gabapentinoids impact the misuse of opioids, the co-use of opioids and stimulant drugs, and the increasing number of overdose deaths in individuals using opioids, stimulant drugs, and gabapentinoids in mixtures. Significance Statement The number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically with gabapentinoids commonly detected in opioid overdose victims. This study reports that in rats gabapentinoids increase the potency of fentanyl and heroin to produce discriminative stimulus effects while decreasing the potency of naloxone to antagonize those effects of fentanyl and heroin. These results can help guide policies for regulating gabapentinoids and treating opioid misuse and overdose.

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Previous studies demonstrated that sigma-receptor (σR) antagonists alone fail to alter cocaine self-administration despite blocking various other effects of cocaine. However, σR antagonists when combined with dopamine transporter (DAT) inhibitors substantially decrease cocaine self-administration. To better understand the effects of this combination, the present study examined the effects of σR antagonist and DAT inhibitor combinations in male rats discriminating cocaine (10 mg/kg, i.p.) from saline injections. The DAT inhibitors alone (WIN 35,428 and methylphenidate) at low (0.1 mg/kg) doses that were minimally active, failed to shift the dose-effect function for discriminative-stimulus effects of cocaine to the left more than two-fold. At 0.32 mg/kg the DAT inhibitors alone shifted the cocaine dose-effect function leftward 24- or 6.6-fold, respectively. The σR antagonists (BD1008, BD1047, and BD1063) failed to fully substitute for cocaine, though BD1008 and BD1047 substituted partially. At 10 mg/kg, BD1008, BD1047, or BD1063 alone shifted the cocaine dose-effect function leftward less than 6.0-fold. In combination with 0.1 mg/kg WIN 35,428, the 10 mg/kg doses of σR antagonists shifted the cocaine dose-effect function from 12.3 to 36.7-fold leftward, and with 0.32 mg/kg WIN 35,428 from 14.3 to 440-fold leftward. In combination with 0.1 mg/kg methylphenidate, those σR antagonist doses shifted the cocaine dose-effect function from 5.5 to 55.0-fold leftward and with 0.32 mg/kg methylphenidate from 10.5 to 48.1-fold leftward. The present results suggest that dual DAT/σR inhibition produces agonist-like subjective effects that may promote decreases in self-administration obtained in previous studies. Significance Statement There is currently no approved medication for treating stimulant abuse, though dopamine-uptake inhibitors in combination with sigma-receptor (σR) antagonists decrease cocaine self-administration in laboratory animals. The present study assessed how this combination alters the discriminative-stimulus effects of cocaine in male rats. Results suggest that concurrent dopamine uptake inhibition and σR antagonism together may promote decreases in self-administration possibly by mimicking the subjective effects extant when subjects cease continued cocaine self-administration.

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Recently, the abuse of synthetic cathinones is increasing among young people. α-Pyrrolidinobutiothiophenone (α-PBT), a synthetic cathinone, is a designer drug that is freely traded online with no legal restrictions. Moreover, there is currently no scientific basis for legal regulation. Here, we examined the addictive properties of α-PBT using a drug discrimination (DD) task. We also investigated the role of α-PBT in brain stimulation reward (BSR) using an intracranial self-stimulation (ICSS) paradigm in rats. Initially, the rats were trained to discriminate between cocaine and saline. After the discrimination training criteria were met, we determined the dose-effect curves of cocaine and conducted generalization tests with α-PBT and α-pyrrolidinopentiothiophenone (α-PVT) using a cumulative dosing protocol. In a separate set of studies, we examined the dopaminergic mechanisms underlying the function of α-PBT as an interoceptive stimulus (17.8 mg/kg) by intraperitoneally injecting either the dopamine (DA) D1 antagonist SCH23390 (0.06 and 0.12 mg/kg) or the D2 antagonist eticlopride (0.05 and 0.1 mg/kg) 15 min before DD testing. Brain reward function was measured using an ICSS procedure to examine the effects of α-PBT on ICSS threshold under the frequency-rate procedure. Our results showed that α-PBT functioned as a discriminative cue similar to cocaine in rats. More importantly, SCH23390 abolished the effects of α-PBT as an interoceptive stimulus in a dose-dependent manner in rats trained to press a lever to receive cocaine. Similarly, eticlopride dose-dependently attenuated the effect of α-PBT used as a discriminative cue. Additionally, cumulative α-PBT administration dose-dependently lowered ICSS thresholds compared with those in saline-treated rats. Furthermore, α-PBT-induced potentiation of BSR was abolished by pretreatment with both SCH23390 and eticlopride. Taken together, our results suggest that α-PBT can function as a cocaine-like discriminative cue via the activation of D1 and D2 receptors. α-PBT also appears to influence BSR by reducing the brain reward threshold via changes in D1 and D2 receptors. The present study suggests that α-PBT could have addictive properties through DA D1 and D2 receptors and thus poses a threat to humans.

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INTRODUCTION: Interoceptive stimuli elicited by drug administration acquire conditioned modulatory properties of the induction of conditioned appetitive behaviours by exteroceptive cues. This effect may be modeled using a drug discrimination task in which the drug stimulus is trained as a positive-feature (FP) occasion setter (OS) that disambiguates the relation between an exteroceptive light conditioned stimulus (CS) and a sucrose unconditioned stimulus (US). We previously reported that females are less sensitive to generalization of a FP morphine OS than males, so we investigated the role of endogenous ovarian hormones in this difference. METHODS: Male and female rats received intermixed injections of 3.2 mg/kg morphine or saline before each daily training session. Training consisted of 8 presentations of the CS, each followed by access to sucrose on morphine, but not saline sessions. Following acquisiton, rats were tested for generalization of the morphine stimulus to 0, 1.0, 3.2, and 5.4 mg/kg morphine. Female rats were monitored for estrous cyclicity using vaginal cytology throughout the study. RESULTS: Both sexes acquired stable drug discrimination. A gradient of generalization was measured across morphine doses and this behaviour did not differ by sex, nor did it differ across the estrous cycle in females. CONCLUSIONS: Morphine generalization is independent of fluctuations in levels of sex and endogenous gonadal hormones in females under these experimental conditions.

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RATIONALE: Internally perceived stimuli evoked by morphine administration can form Pavlovian associations such that they can function as occasion setters (OSs) for externally perceived reward cues in rats, coming to modulate reward-seeking behaviour. Though much research has investigated mechanisms underlying opioid-related reinforcement and analgesia, neurotransmitter systems involved in the functioning of opioids as Pavlovian interoceptive discriminative stimuli remain to be disentangled despite documented differences in the development of tolerance to analgesic versus discriminative stimulus effects. OBJECTIVES: Dopamine has been implicated in many opioid-related behaviours, so we aimed to investigate the role of this neurotransmitter in expression of morphine occasion setting. METHODS: Male and female rats were assigned to positive- (FP) or negative-feature (FN) groups and received an injection of morphine or saline before each training session. A 15-s white noise conditioned stimulus (CS) was presented 8 times during every training session; offset of this stimulus was followed by 4-s access to liquid sucrose on morphine, but not saline, sessions for FP rats. FN rats learned the reverse contingency. Following stable discrimination, rats began generalization testing for expression of morphine-guided sucrose seeking after systemic pretreatment with different doses of the non-selective dopamine receptor antagonist, flupenthixol, and the non-selective dopamine receptor agonist, apomorphine, combined with training doses of morphine or saline in a Latin-square design. RESULTS: The morphine discrimination was acquired under both FP and FN contingencies by males and females. Neither flupenthixol nor apomorphine at any dose substituted for morphine, but both apomorphine and flupenthixol disrupted expression of the morphine OS. This inhibition was specific to sucrose seeking during CS presentations rather than during the period before CS onset and, in the case of apomorphine more so than flupenthixol, to trials on which access to sucrose was anticipated. CONCLUSIONS: Our findings lend support to a mechanism of occasion setting involving gating of CS-induced dopamine release rather than by direct dopaminergic modulation by the morphine stimulus.

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Synthetic cannabinoid receptor agonists (SCRAs) remain one the largest classes of new psychoactive substances, and are increasingly associated with severe adverse effects and death compared to the phytocannabinoid Δ9-tetrahydrocannabinol (THC). In the attempt to circumvent the rapid emergence of novel SCRAs, several nations have implemented 'generic' legislations, or 'class-wide' bans based on common structural scaffolds. However, this has only encouraged the incorporation of new chemical entities, including distinct core and linker structures, for which there is a dearth of pharmacological data. The current study evaluated five emergent OXIZID SCRAs for affinity and functional activity at the cannabinoid CB1 receptor (CB1) in HEK 293 cells, as well as pharmacological equivalence with THC in drug discrimination in mice. All OXIZID compounds behaved as agonists in Gαi protein activation and ß-arrestin 2 translocation assays, possessing low micromolar affinity at CB1. All ligands also substituted for THC in drug discrimination, where potencies broadly correlated with in vitro activity, with the methylcyclohexane analogue BZO-CHMOXIZID being the most potent. Notably, MDA-19 (BZO-HEXOXIZID) exhibited partial efficacy in vitro, generating an activity profile most similar to that of THC, and partial substitution in vivo. Overall, the examined OXIZIDs were comparatively less potent and efficacious than previous generations of SCRAs. Further toxicological data will elucidate whether the moderate cannabimimetic activity for this series of SCRAs will translate to severe adverse health effects as seen with previous generations of SCRAs.

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RATIONALE: The subjective effects of alcohol are associated with alcohol use disorder (AUD) vulnerability and treatment outcomes. The interoceptive effects of alcohol are part of these subjective effects and can be measured in animal models using drug discrimination procedures. The newly developed mGlu2 and mGlu3 negative allosteric modulators (NAMs) are potential therapeutics for AUD and may alter interoceptive sensitivity to alcohol. OBJECTIVES: To determine the effects of mGlu2 and mGlu3 NAMs on the interoceptive effects of alcohol in rats. METHODS: Long-Evans rats were trained to discriminate the interoceptive stimulus effects of alcohol (2.0 g/kg, i.g.) from water using both operant (males only) and Pavlovian (male and female) drug discrimination techniques. Following acquisition training, an alcohol dose-response (0, 0.5, 1.0, 2.0 g/kg) experiment was conducted to confirm stimulus control over behavior. Next, to test the involvement of mGlu2 and mGlu3, rats were pretreated with the mGlu2-NAM (VU6001966; 0, 3, 6, 12 mg/kg, i.p.) or the mGlu3-NAM (VU6010572; 0, 3, 6, 12 mg/kg, i.p.) before alcohol administration (2.0 g/kg, i.g.). RESULTS: In Pavlovian discrimination, male rats showed greater interoceptive sensitivity to 1.0 and 2.0 g/kg alcohol compared to female rats. Both mGlu2-NAM and mGlu3-NAM attenuated the interoceptive effects of alcohol in male and female rats using Pavlovian and operant discrimination. There may be a potential sex difference in response to the mGlu2-NAM at the highest dose tested. CONCLUSIONS: Male rats may be more sensitive to the interoceptive effects of the 2.0 g/kg alcohol training dose compared to female rats. Both mGlu2-and mGlu3-NAM attenuate the interoceptive effects of alcohol in male and female rats. These drugs may have potential for treatment of AUD in part by blunting the subjective effects of alcohol.

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RATIONALE: It is unclear if e-cigarettes have reduced abuse liability relative to traditional cigarettes, especially when considering advanced devices which deliver nicotine more efficiently. Translatable and predictive animal models are needed to addresses this question. OBJECTIVES: Our goal was to explore the subjective stimulus effects of e-cigarettes by training rats to discriminate puffs of nicotine aerosol from vehicle aerosol using an aerosol delivery system designed to model e-cigarette use patterns in humans. METHODS: Rats were trained to discriminate between ten, 10 s puffs of aerosol generated from 3 mg/ml nicotine e-liquid and nicotine-free e-liquid using a food-reinforced operant procedure. Following acquisition, tests were conducted to determine the specificity of the nicotine aerosol stimulus as well as the impact to the stimulus effects of nicotine resulting from the addition of menthol to e-liquid. RESULTS: Rats learned the nicotine aerosol puff vs vehicle puff discrimination in a mean of 25 training sessions. Injected nicotine fully substituted for the stimulus effects of nicotine aerosol. The stimulus effects of nicotine aerosol were blocked by the nicotinic receptor antagonist mecamylamine. The nicotinic receptor partial agonist, varenicline as well as the stimulant d-amphetamine substituted more robustly for nicotine aerosol puffs than did the NMDA antagonist, ketamine. Menthol enhanced the stimulus effects of nicotine aerosol without altering nicotine blood plasma levels. CONCLUSIONS: Nicotine aerosol puffs can function as a training stimulus in rats. The stimulus effects were CNS-mediated and receptor specific. Menthol appears to enhance the stimulus effects of nicotine aerosol through a pharmacodynamic rather than pharmacokinetic mechanism.

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BACKGROUND: The cannabis plant contains several cannabinoids, and many terpenoids that give cannabis its distinctive flavoring and aroma. Δ9-Tetrahydrocannabinol (Δ9-THC) is the plant's primary psychoactive constituent. Given the abuse liability of Δ9-THC, assessment of the psychoactive effects of minor cannabinoids and other plant constituents is important, especially for compounds that may be used medicinally. This study sought to evaluate select minor cannabinoids and terpenes for Δ9-THC-like psychoactivity in mouse Δ9-THC drug discrimination and determine their binding affinities at CB1 and CB2 receptors. METHODS: Δ9-THC, cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabichromenevarin (CBCV), Δ8-tetrahydrocannabinol (Δ8-THC), (6aR,9R)-Δ10-tetrahydrocannabinol [(6aR,9R)-Δ10-THC], Δ9-tetrahydrocannabinol varin (THCV), ß-caryophyllene (BC), and ß-caryophyllene oxide (BCO) were examined. RESULTS: All minor cannabinoids showed measurable cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor binding, with CBC, CBCV, and CBD, showing the weakest CB1 receptor binding affinity. BC and BCO exhibited negligible affinity for both CB1 and CB2 receptors. In drug discrimination, only Δ8-THC fully substituted for Δ9-THC, while CBN and (6aR,9R)-Δ10-THC partially substituted for Δ9-THC. THCV and BCO did not alter the discriminative stimulus effects of Δ9-THC. CONCLUSION: In summary, only some of myriad cannabinoids and other chemicals found in the cannabis plant bind potently to the identified cannabinoid receptors. Further, only four of the compounds tested herein [Δ9-THC, Δ8-THC, (6aR,9R)-Δ10-THC, and CBN] produced Δ9-THC-like discriminative stimulus effects, suggesting they may possess cannabimimetic subjective effects. Given that the medicinal properties of phytocannabinoids and terpenoids are being investigated scientifically, delineation of their potential adverse effects, including their ability to produce Δ9-THC-like intoxication, is crucial.

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The abuse potential of novel CNS-active drug candidates with low specificity for known receptors involved in abuse might be complex to test preclinically relative to an appropriate reference drug of abuse. Suvorexant, a Schedule IV dual orexin receptor antagonist was investigated for its potential use as a reference drug in Drug Discrimination Learning (DDL) studies. Firstly, toxicokinetic properties of suvorexant were determined in male and female rats after single oral doses of 160 and 325 mg/kg in MC and PEG400. Thereafter the subjective effects of suvorexant at 325 mg/kg versus vehicle were evaluated in a DDL paradigm and plasma exposures were measured. Mean maximum plasma exposures in male rats after a single dose of 325 mg/kg suvorexant were 2.5- (MC) to 10.5-fold (PEG400) the human exposure at supratherapeutic doses of 40 mg q.d. (Cmax:1.1 µM), and 4.9- (MC) to 20.8-fold (PEG400) the approved maximum human efficacious dose (20 mg q.d.; 0.557 µM). Training male rats at 325 mg/kg in the DDL study however did not result in discriminative stimulus generalisation versus respective vehicles. Suvorexant, a Schedule IV dual orexin receptor antagonist failed to serve as a robust reference drug of abuse in the DDL paradigm in rats despite appropriate exposures.

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Diclazepam, a designer benzodiazepine, is a lesser-known novel anxiolytic substance and a structural analog of diazepam. Although several case studies have reported the adverse effects of diclazepam, their potential impacts remain unknown. Therefore, this study aimed to determine the effects of diclazepam in rodents using drug discrimination, locomotor activity, self-administration (SA), and conditioned place preference (CPP) tests. Sprague-Dawley rats (male, 8 weeks old, weighing 220-450 g, n = 12 per group) and C57BL/6 mice (male, 7 weeks old, weighing 20-25 g, n = 7-8 per group) were administered alprazolam, morphine, and diclazepam. Diclazepam fully elicited alprazolam-appropriate dose-dependent lever responses (>80 %) similar to those of alprazolam. In rats administered 0.5 mg/kg of morphine, a partial substitution (80 %-20 %) was observed. Mice receiving intraperitoneal injections of diclazepam (0.05, 0.2, and 2 mg/kg) showed decreased locomotor activity. In the SA experiment, mice that self-administered intravenous diclazepam (2 µg/kg/infusion) showed significantly higher infusion and active lever responses compared to the vehicle group. No statistically significant rewarding effects of diclazepam at the doses of 0.2 and 2 mg/kg evaluated using the CPP paradigm were found. In conclusion, diclazepam has reinforcing effects and shares the interoceptive effects of alprazolam. Therefore, legal restrictions on the use of diclazepam should be carefully considered.

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Introduction: Cannabidiol (CBD) has gained considerable public and scientific attention because of its known and potential medicinal properties, as well as its commercial success in a wide range of products. Although CBD lacks cannabimimetic intoxicating side effects in humans and fails to substitute for cannabinoid type-1 receptor (CB1R) agonists in laboratory animal models of drug discrimination paradigm, anecdotal reports describe it as producing a "pleasant" subjective effect in humans. Thus, we speculated that this phytocannabinoid may elicit distinct subjective effects. Accordingly, we investigated whether mice would learn to discriminate CBD from vehicle. Additionally, we examined whether CBD may act as a CB1R allosteric and whether it would elevate brain endocannabinoid concentrations. Materials and Methods: C57BL/6J mice underwent discrimination training of either CBD or the high-efficacy CB1R agonist CP55,940 from vehicle. Additionally, we examined whether CBD or the CB1R-positive allosteric modulator ZCZ011 would alter the CP55,940 discriminative cue. Finally, we tested whether an acute CBD injection would elevate endocannabinoid levels in brain, and also quantified blood and brain levels of CBD. Results: Mice failed to discriminate high doses of CBD from vehicle following 124 training days, though the same subjects subsequently acquired CP55,940 discrimination. In a second group of mice trained to discriminate CP55,940, CBD neither elicited substitution nor altered response rates. A single injection of 100 or 200 mg/kg CBD did not affect brain levels of endogenous cannabinoids and related lipids and resulted in high drug concentrations in blood and whole brain at 0.5 h and continued to increase at 3 h. Discussion: CBD did not engender an interoceptive stimulus, did not disrupt performance in a food-motivated operant task, and lacked apparent effectiveness in altering brain endocannabinoid levels or modulating the pharmacological effects of a CB1R agonist. These findings support the assertions that CBD lacks abuse liability and its acute administration does not appear to play a functional role in modulating key components of the endocannabinoid system in whole animals.

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RATIONALE: Increasing evidence shows that imidazoline I2 receptor agonists enhance opioid-induced analgesia, suggesting that the combination of I2 receptor agonists with opioids could be a favorable strategy for pain control. However, the effect of I2 receptor agonists on the abuse liability of opioids is unknown. This study examined the impact of the I2 receptor agonist 2-BFI on some abuse-related behavioral effects of the opioid morphine in rats. OBJECTIVES: The von Frey filament test was used to determine the antinociceptive effects of 2-BFI (intravenous, i.v.) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. IV self-administration was used to assess the reinforcing effects of 2-BFI alone and to assess the effects of non-contingent injections of 2-BFI (i.p.) on morphine self-administration. A two-lever drug discrimination paradigm in which rats were trained to discriminate 3.2 mg/kg morphine (i.p.) from saline was used to examine whether 2-BFI or another I2 receptor agonist 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride (BU224) affected the discriminative stimulus effects of morphine. RESULTS: 2-BFI could not maintain reliable self-administration behavior in rats with no pain or CFA-treated inflammatory pain. However, pretreatment with 2-BFI (i.p.) produced dose-dependent decreases in the dose-effect curve of morphine self-administration. Both 2-BFI and BU224 did not substitute for morphine but significantly attenuated the discriminative stimulus effects of morphine. CONCLUSIONS: These results suggest that I2 receptor agonists do not enhance, but in fact appear to decrease, the abuse liability of opioids, further supporting the potential utility of I2 receptor agonist-opioid combination therapy for pain control.

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Background: Route of administration is an important pharmacokinetic variable in development of translationally relevant preclinical models. Humans primarily administer cannabis through smoking, vaping, and edibles. In contrast, preclinical research has historically utilized injected Δ9-tetrahydrocannabinol (THC). The present study sought to examine how route of administration affected the potency and time course of THC's discriminative stimulus properties. Methods: Adult female and male C57BL/6 mice were trained to discriminate intraperitoneal (i.p.) THC from vehicle in a drug discrimination procedure. After discrimination was acquired, a dose-effect curve was determined for i.p., oral (p.o.), subcutaneous (s.c.), and aerosolized THC. Subsequently, the time course of effects of each route of administration was determined. Results: THC administered i.p., p.o., s.c., or via aerosolization fully substituted for i.p. THC. The potency of THC's psychoactive effects was similar for i.p., p.o., and s.c., except that THC was more potent when administered s.c. vs p.o. in females. All routes of administration had a similar potency in both sexes. The duration of THC's psychoactive effects was similar across i.p., s.c., and p.o. routes of administration, whereas aerosolized THC produced a faster onset and shorter duration of effects compared to the other routes. Conclusion: THC administered via multiple routes of administration, including those commonly used in preclinical research (i.p. and s.c.) and more translationally relevant routes (aerosol and p.o.), produced THC-like discriminative stimulus effects in mice trained to discriminate i.p. THC. More precise predictions of THC's effects in humans may result from use of these translationally relevant routes of administration.

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BACKGROUND: Drugs that act on the central nervous system (CNS) and have sedative effects can lead to abuse in humans. New CNS-active drugs often require evaluation of their abuse potential in dedicated animal models before marketing approval. Daridorexant is a new dual orexin receptor antagonist (DORA) with sleep-promoting properties in animals and humans. It was approved in 2022 in the United States and Europe for the treatment of insomnia disorder. AIMS: Nonclinical evaluation of abuse potential of daridorexant using three specific rat models assessing reinforcement, interoception, and withdrawal. METHODS: Reinforcing effects of daridorexant were assessed in an operant rat model of intravenous drug self-administration. Similarity of interoceptive effects to those of the commonly used sleep medication zolpidem was tested in an operant drug discrimination task. Withdrawal signs indicative of physical dependence were evaluated upon sudden termination of chronic daridorexant treatment. Rat experiments were conducted at a dose range resulting in daridorexant plasma concentrations equaling or exceeding those achieved at the clinically recommended dose of 50 mg in humans. RESULTS: Daridorexant had no reinforcing effects, was dissimilar to zolpidem in the drug discrimination task, and did not induce any withdrawal-related signs upon treatment discontinuation that would be indicative of physical dependence. OUTCOMES: Daridorexant showed no signs of abuse or dependence potential in rats. Our data indicate that daridorexant, like other DORAs, has a low potential for abuse in humans.

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The synthetic forms of delta-9-tetrahydrocannabinol (Δ9-THC), dronabinol or nabilone, have been approved to treat several indications. However, due to safety concerns their clinical utility remains limited. Consequently, there is a need for developing cannabinoid (CB) ligands that display better behavioral pharmacological profiles than Δ9-THC. Here, we utilized drug discrimination methods to compare the interoceptive effects of CB ligands that vary in potency, efficacy, and selectivity at the CB receptors, including two ligands, AM411 and AM4089, that show CB1 partial agonist-like actions in vitro. Male rats were trained to discriminate 0.1 mg/kg AM2201 from saline under a fixed-ratio (FR) 10 response schedule of food reinforcement. After establishing AM2201's discriminative-stimulus effects, pretreatment tests with the CB1 antagonist/inverse agonist rimonabant blocked AM2201's effects, whereas the peripherally-restricted antagonist AM6545 had no effect. Next, the generalization profiles of AM411 and AM4089 with CB1 full agonists (JWH-018, CP-55,940, AM8936), partial agonist (Δ9-THC), and non-cannabinoids (fentanyl, atropine) were compared. The CBs either fully (AM2201, CP-55,940, JWH-018, AM8936, Δ9-THC) or partially (AM411, AM4089) substituted for AM2201, whereas fentanyl and atropine did not produce AM2201-like effects. All CB drugs were more potent than Δ9-THC and correlation analysis confirmed that the relative behavioral potencies of CBs corresponded strongly with their relative affinities at the CB1 but not CB2 receptors. Together, our results further demonstrate that AM411 and AM4089 exhibit better pharmacological profiles compared to Δ9-THC, in that they are more potent and display in vivo partial agonist-like actions that are centrally mediated via CB1 receptors.

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For abuse potential assessment, U.S. Food and Drug Administration (FDA) requests that new, brain-penetrating drugs are ideally compared with approved drugs that share the mechanism of action and are judged to have abuse liability by the Drug Enforcement Agency. For development of the dual orexin receptor antagonist (DORA) daridorexant, the FDA recommended conducting a rat drug discrimination paradigm against the approved, schedule IV, DORA suvorexant. Surprisingly, at suvorexant plasma levels up to three-fold the maximum concentration at the highest approved human dose, rats did not learn to discriminate the suvorexant stimulus from vehicle.

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