Pharmacologic profile of ITI-333: a novel molecule for treatment of substance use disorders.

RATIONALE: Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain. OBJECTIVE: Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays. METHODS: Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability. RESULTS: In vitro, ITI-333 is a potent 5-HT2A receptor antagonist (Ki = 8 nM) and a biased, partial agonist at µ-opioid (MOP) receptors (Ki = 11 nM; lacking ß-arrestin agonism) with lesser antagonist activity at adrenergic α1A (Ki = 28 nM) and dopamine D1 (Ki = 50 nM) receptors. In vivo, ITI-333 blocks 5-HT2A receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys. CONCLUSIONS: ITI-333 acts as a potent 5-HT2A receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal/reinstatement, supporting its potential utility as a treatment for OUD.

Attenuation of the Positive-Reinforcing Effects of Ultra-Potent Fentanyl Analogs, Along with Those of Fentanyl and Heroin, During Daily Treatment with Methocinnamox in Rhesus Monkeys.

Without substantial intervention, the opioid crisis is projected to continue, underscoring the need to develop new treatments for opioid use disorder (OUD). One drug under development is the µ opioid receptor antagonist methocinnamox (MCAM), which appears to offer advantages over currently available medications; however, some questions remain about its potential utility, including its ability to block the effects of ultra-potent fentanyl analogs. The goal of this study was to examine its effectiveness in attenuating the abuse-related effects of the fentanyl analogs carfentanil and 3-methylfentanyl in monkeys responding for food or intravenous infusions under a choice procedure. These drugs were compared with fentanyl, heroin, methamphetamine, and cocaine. Food was preferred over saline, and there was a dose-dependent increase in responding for drug over food with no marked decrease in response rates or number of choice trials completed for any of the six drugs studied. Naltrexone (0.032 mg/kg) antagonized choice of µ opioid receptor agonists, producing rightward shifts in dose-effect curves ranging from 27-fold (carfentanil) to 71-fold (heroin). In contrast, naltrexone was less effective in attenuating choice of methamphetamine or cocaine with curves obtained in the presence of naltrexone shifted <3-fold. Daily treatment with 0.032 mg/kg MCAM also antagonized the effects of opioids, shifting curves 20-fold (fentanyl) to 72-fold (heroin) rightward; MCAM did not significantly change dose-effect curves for methamphetamine or cocaine. Thus, antagonism by MCAM is similar across a variety of µ opioid receptor agonists, including ultra-potent fentanyl analogs, further supporting its potential utility as a treatment for OUD. SIGNIFICANCE STATEMENT: Treatments for opioid use disorder (OUD) should attenuate the effects of a variety of opioids, including emerging threats like the ultra-potent fentanyl analogs. The novel µ opioid receptor antagonist MCAM is being developed to treat OUD because it provides long-lasting blockade of the reinforcing effects of heroin and fentanyl. The current study shows that MCAM attenuates the abuse-related effects of the fentanyl analogs carfentanil and 3-methylfentanyl, further supporting the utility of MCAM as a treatment for OUD.

OREX-1038: a potential new treatment for pain with low abuse liability and limited adverse effects.

Drugs targeting mu opioid receptors are the mainstay of clinical practice for treating moderate-to-severe pain. While they can offer excellent analgesia, their use can be limited by adverse effects, including constipation, respiratory depression, tolerance, and abuse liability. Multifunctional ligands acting at mu opioid and nociceptin/orphanin FQ peptide receptors might provide antinociception with substantially improved adverse-effect profiles. This study explored one of these ligands, OREX-1038 (BU10038), in several assays in rodents and nonhuman primates. Binding and functional studies confirmed OREX-1038 to be a low-efficacy agonist at mu opioid and nociceptin/orphanin FQ peptide receptors and an antagonist at delta and kappa opioid receptors with selectivity for opioid receptors over other proteins. OREX-1038 had long-acting antinociceptive effects in postsurgical and complete Freund's adjuvant (CFA)-induced thermal hyperalgesia assays in rats and a warm water tail-withdrawal assay in monkeys. OREX-1038 was active for at least 24 h in each antinociception assay, and its effects in monkeys did not diminish over 22 days of daily administration. This activity was coupled with limited effects on physiological signs (arterial pressure, heart rate, and body temperature) and no evidence of withdrawal after administration of naltrexone or discontinuation of treatment in monkeys receiving OREX-1038 daily. Over a range of doses, OREX-1038 was only transiently self-administered, which diminished rapidly to nonsignificant levels; overall, both OREX-1038 and buprenorphine maintained less responding than remifentanil. These results support the concept of dual mu and nociceptin/orphanin FQ peptide receptor partial agonists having improved pharmacological profiles compared with opioids currently used to treat pain.

Effects of buprenorphine/lorcaserin mixtures on preference for heroin, cocaine, or saline over food using a concurrent choice procedure in rhesus monkeys.

BACKGROUND: The opioid epidemic continues despite the availability of medications, including buprenorphine, for opioid use disorder (OUD); identifying novel and effective treatments is critical for decreasing the prevalence of OUD and ending this crisis. Buprenorphine alone does not markedly attenuate abuse-related effects of nonopioids. Treatment outcomes might be improved by combining buprenorphine with a second medication targeting substance use disorder (SUD), such as lorcaserin, a serotonin2C (5-HT2C) receptor selective agonist that decreases abuse-related effects of drugs from several pharmacological classes in preclinical studies. METHODS: This study investigated the effectiveness of buprenorphine/lorcaserin mixtures to decrease preference for heroin or cocaine in monkeys choosing between food and i.v. infusions. RESULTS: When saline was available for self-administration, monkeys chose food; when heroin or cocaine was available, monkeys dose-dependently increased choice of infusions. Noncontingent administration of heroin, cocaine, or buprenorphine before sessions increased preference for saline over food. Daily noncontingent administration of buprenorphine increased saline choice, decreased heroin choice, and increased variability across monkeys and sessions; preference for cocaine was not altered. Adding lorcaserin to daily treatment reduced variability such that choice of saline and heroin was consistently less than 20%; choice of cocaine did not change. CONCLUSIONS: Because buprenorphine/lorcaserin mixtures would not likely alter abuse of cocaine, they might not be useful for treating SUDs; nevertheless, mixtures reduced variability and decreased preference for heroin, compared with buprenorphine alone, perhaps suggesting that a different drug mixture, in which buprenorphine is combined with a second, nonopioid drug, might offer advantages over treatment with buprenorphine alone.

Countermeasures for Preventing and Treating Opioid Overdose.

The only medication available currently to prevent and treat opioid overdose (naloxone) was approved by the US Food and Drug Administration (FDA) nearly 50 years ago. Because of its pharmacokinetic and pharmacodynamic properties, naloxone has limited utility under some conditions and would not be effective to counteract mass casualties involving large-scale deployment of weaponized synthetic opioids. To address shortcomings of current medical countermeasures for opioid toxicity, a trans-agency scientific meeting was convened by the US National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) on August 6 and 7, 2019, to explore emerging alternative approaches for treating opioid overdose in the event of weaponization of synthetic opioids. The meeting was initiated by the Chemical Countermeasures Research Program (CCRP), was organized by NIAID, and was a collaboration with the National Institute on Drug Abuse/NIH (NIDA/NIH), the FDA, the Defense Threat Reduction Agency (DTRA), and the Biomedical Advanced Research and Development Authority (BARDA). This paper provides an overview of several presentations at that meeting that discussed emerging new approaches for treating opioid overdose, including the following: (1) intranasal nalmefene, a competitive, reversible opioid receptor antagonist with a longer duration of action than naloxone; (2) methocinnamox, a novel opioid receptor antagonist; (3) covalent naloxone nanoparticles; (4) serotonin (5-HT)1A receptor agonists; (5) fentanyl-binding cyclodextrin scaffolds; (6) detoxifying biomimetic "nanosponge" decoy receptors; and (7) antibody-based strategies. These approaches could also be applied to treat opioid use disorder.

Behavioral effects of benzylideneoxymorphone (BOM), a low efficacy µ opioid receptor agonist and a δ opioid receptor antagonist.

RATIONALE: Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects often limit use. Drugs acting concomitantly as agonists at µ opioid receptors and antagonists at δ opioid receptors produce antinociceptive effects with a reduced profile of adverse effects; one such drug, benzylideneoxymorphone (BOM), might further limit adverse effects because it appears to have lower pharmacological efficacy than other µ opioid receptor agonists. OBJECTIVES: The current study compared the acute behavioral effects of BOM with the effects of other µ opioid receptor agonists. METHODS: Discriminative stimulus and rate-decreasing effects were studied in 1 group of 7 rats discriminating 3.2 mg/kg morphine while responding under a fixed-ratio 10 schedule of food presentation. Antinociceptive effects were determined in a second group of 8 rats using a warm water tail withdrawal procedure. Reinforcing effects were evaluated in a third group of 12 rats with a history of remifentanil self-administration. RESULTS: BOM produced morphine-lever responding and both discriminative stimulus and rate-decreasing effects were antagonized by naltrexone. BOM did not markedly increase tail-withdrawal latencies from water maintained at 50 °C and did not substantially attenuate the antinociceptive effects of morphine. BOM was not self-administered and did not change remifentanil self-administration. CONCLUSIONS: Some effects of BOM (e.g., discriminative stimulus effects) appear to be mediated by µ opioid receptors; however, BOM is not self-administered by rats, suggesting that it might have limited abuse liability and a reduced profile of adverse effects compared with currently prescribed opioids.

Effects of acute and repeated treatment with methocinnamox, a mu opioid receptor antagonist, on fentanyl self-administration in rhesus monkeys.

Methocinnamox (MCAM), a mu opioid receptor antagonist with a long duration of action, attenuates heroin self-administration in rhesus monkeys, suggesting it could be an effective treatment for opioid use disorder (OUD). This study examined effects of acute and repeated MCAM administration on self-administration of the high-efficacy mu opioid receptor agonist fentanyl and characterized MCAM pharmacokinetics. Four rhesus monkeys self-administered i.v. infusions of fentanyl (0.00032 mg/kg/infusion) or cocaine (0.032 mg/kg/infusion). MCAM (0.1-0.32 mg/kg) or the opioid receptor antagonist naltrexone (0.001-0.032 mg/kg) was injected prior to test sessions to evaluate acute effects. On a separate occasion, 0.32 mg/kg MCAM was injected every 12 days for 5 total injections to evaluate the effectiveness of repeated treatment. Following acute injection, MCAM and naltrexone decreased fentanyl self-administration on the day of treatment, with attenuation lasting for up to 2 weeks after the larger MCAM dose and <1 day after naltrexone. Repeated MCAM administration decreased fentanyl self-administration for more than 2 months without altering cocaine self-administration. MCAM plasma concentrations peaked 15-45 min after injection, with a half-life ranging from 13.7 to 199.8 min, and decreased markedly 1 day after injection. MCAM selectively reduced opioid self-administration and remained effective with repeated administration. Moreover, MCAM was effective at times when plasma levels were very low, suggesting that pharmacodynamic (i.e., pseudoirreversible binding to mu opioid receptors) and not pharmacokinetic factors play a significant role in its long-lasting effects. Taken together with previous studies, these data indicate that MCAM could be a safe, effective, and long-acting treatment for OUD.

Behavioral Pharmacology of Drugs Acting at Mu Opioid Receptors.

Despite the therapeutic utility of opioids for relieving pain, other behavioral effects, including their potential for abuse and overdose, can be quite detrimental to individuals as well as society and have contributed to the ongoing opioid crisis. The dramatic escalation in overdose deaths over the last 15 years was initially driven by abuse of prescription opioids, although abuse of heroin, fentanyl, and fentanyl analogs has been increasing, largely due to increased availability and lower cost compared with prescription opioids. All of these opioids share pharmacological properties, acting as agonists at mu opioid receptors, and produce similar behavioral effects, including abuse-related, pain-relieving, dependence-producing, and respiratory-depressant effects. Despite their similarities, opioids are not pharmacologically identical. In fact, drugs that act at mu opioid receptors, including abused opioids, can vary on a number of dimensions, including pharmacological efficacy, drug-receptor interactions, receptor selectivity, and pharmacokinetics. Overall, these differences impact behavioral effects of drugs acting at mu opioid receptors, and this chapter describes variations in those behavioral effects and how these differences continue to provide new strategies that can be developed to address the ongoing opioid epidemic.

OREX-1019: A Novel Treatment of Opioid Use Disorder and Relapse Prevention.

There is an urgent need for new pharmacological treatments for substance use disorders, including opioid use disorder, particularly for use in relapse prevention. A combination of buprenorphine with naltrexone has shown particular promise, with clinical studies indicating a substantial improvement over treatment with naltrexone alone. OREX-1019 (formerly BU10119) is a compound that mimics the pharmacology of the buprenorphine/naltrexone combination. This study evaluated, in rhesus monkeys, the therapeutic potential of OREX-1019 for treating opioid use disorder. Pretreatment with OREX-1019 (0.01-0.3 mg/kg s.c.) dose-dependently decreased responding for the µ opioid receptor agonist remifentanil in rhesus monkeys but did not maintain levels of responding above vehicle when it was available for self-administration. OREX-1019 (0.01-1.0 mg/kg s.c.) also decreased cue- plus heroin-primed reinstatement of extinguished responding in monkeys that self-administered remifentanil but did not alter cue- plus cocaine-primed reinstatement of responding in monkeys that self-administered cocaine. OREX-1019 (0.3 mg/kg s.c.), like naltrexone (0.1 mg/kg s.c.), increased heart rate and blood pressure, produced overt observable signs, and eliminated food-maintained responding in monkeys treated chronically with morphine. These results confirm that OREX-1019 has little or no efficacy at µ opioid receptorsand has low abuse potential, and, combined with promising safety (clean profile vs. other off-target proteins including the hERG (human ether-a-go-go-related gene) K+ channel) and pharmacokinetic data (supporting administration by subcutaneous or sublingual routes, but with low oral bioavailability), suggest it could be a safe and effective alternative to current treatments for opioid use disorders particularly as applied to relapse prevention. SIGNIFICANCE STATEMENT: The novel opioid OREX-1019 potentially provides an improved relapse prevention agent for use in opioid use disorder. The current study demonstrates that in monkeys OREX-1019 is able to inhibit the self-administration of, and cue- plus heroin-primed reinstatement of, responding previously maintained by remifentanil.

Methocinnamox Produces Long-Lasting Antagonism of the Behavioral Effects of µ-Opioid Receptor Agonists but Not Prolonged Precipitated Withdrawal in Rats.

A novel µ-opioid receptor antagonist, methocinnamox (MCAM), attenuates some abuse-related and toxic effects of opioids. This study further characterized the pharmacology of MCAM in separate groups of rats using procedures to examine antinociception, gastrointestinal motility, and withdrawal in morphine-dependent rats. Antinociceptive effects of opioid receptor agonists were measured before and after MCAM (1-10 mg/kg) using warm water tail withdrawal and sensitivity to mechanical stimulation in inflamed paws (complete Freund's adjuvant). Before MCAM, morphine, fentanyl, and the κ-opioid receptor agonist spiradoline dose dependently increased tail-withdrawal latency from 50°C water; MCAM attenuated the antinociceptive effects of morphine and fentanyl, but not spiradoline. Morphine increased sensitivity to mechanical stimulation and decreased gastrointestinal motility, and MCAM blocked both effects. These antagonist effects of 10 mg/kg MCAM were persistent, lasting for 2 weeks or longer. Withdrawal emerged after discontinuation of morphine treatment or administration of 10 mg/kg MCAM or 17.8 mg/kg naloxone; other than the day of antagonist administration when withdrawal signs were greater in rats that received antagonist compared with rats that received vehicle, there was no difference among groups in directly observable withdrawal signs or decreased body weight. These results confirm that MCAM is a selective µ-opioid receptor antagonist with an exceptionally long duration of action, likely due to pseudoirreversible binding. Despite its sustained antagonist effects, the duration of withdrawal precipitated by MCAM is not different from that precipitated by naloxone, suggesting that the long duration of antagonism provided by MCAM could be particularly effective for treating opioid abuse and overdose. SIGNIFICANCE STATEMENT: The opioid receptor antagonist MCAM attenuates some abuse-related and toxic effects of opioids. This study demonstrates that MCAM selectively antagonizes multiple effects mediated by µ-opioid receptor agonists for 2 weeks or longer, and like naloxone, MCAM precipitates withdrawal in morphine-dependent rats. Despite this persistent antagonism, withdrawal signs precipitated by MCAM are not significantly different from signs precipitated by naloxone or occurring after discontinuation of morphine, suggesting that using MCAM for opioid abuse or overdose would not produce sustained withdrawal.

Effects of the synthetic cannabinoid receptor agonist JWH-018 on abuse-related effects of opioids in rhesus monkeys.

Opioid abuse remains a public health crisis despite a tremendous outpouring of resources to address the problem. One factor that might complicate this issue is polydrug abuse. While cannabis is increasingly available due to legalization by states, phytocannabinoids do not appear to alter the abuse-related effects of opioids. Synthetic cannabinoids, which are not pharmacologically identical to phytocannabinoids, are also increasingly available, and differences among cannabinoids might affect their interactions with opioids. This study assessed the impact of one synthetic cannabinoid, JWH-018, on the effects of two µ opioid receptor agonists using two procedures that address different aspects of abuse. First, four monkeys could choose to self-administer the opioid remifentanil alone (0.32 µg/kg/infusion) or a mixture containing 0.32 µg/kg/infusion remifentanil and JWH-018 (1-10 µg/kg/infusion). On separate occasions, monkeys could choose between remifentanil available alone or combined with 100 µg/kg/infusion cocaine. While monkeys chose the remifentanil/cocaine mixture over remifentanil alone, they responded equally for remifentanil alone and the remifentanil/JWH-018 mixture. The ability of JWH-018 to reinstate extinguished responding previously maintained by heroin was examined in four other monkeys. When presented with drug-associated stimuli, heroin, but not JWH-018, reinstated responding, and when combined, JWH-018 did not increase the potency of heroin. While opioids and synthetic cannabinoids, including JWH-018, are abused, these results indicate that JWH-018 does not modify the behavioral effects of opioids in monkeys in a manner that would predict greater abuse liability of cannabinoid/opioid mixtures, a result that is consistent with a growing literature on mixtures of opioids and phytocannabinoids.

Effects of lorcaserin on reinstatement of responding previously maintained by cocaine or remifentanil in rhesus monkeys.

Drug abuse remains a serious public health issue, underscoring the need for additional treatment options. Agonists at serotonin (5-HT)2C receptors, particularly lorcaserin, are being considered as pharmacotherapies for abuse of a variety of drugs, including cocaine and opioids. The current study compared the capacity of lorcaserin to attenuate reinstatement of extinguished responding previously maintained by either cocaine or an opioid; this type of procedure is thought to model relapse, an important aspect of drug abuse. Six rhesus monkeys responded under a fixed-ratio schedule for cocaine (0.032 mg/kg/infusion) or remifentanil (0.00032 mg/kg/infusion). Reinstatement of extinguished responding was examined following administration of noncontingent infusions of cocaine (0.32 mg/kg) or heroin (0.0032-0.1 mg/kg) combined with response-contingent presentations of the drug-associated stimuli, or heroin alone without presentation of drug-associated stimuli. When combined with drug-associated stimuli, cocaine and heroin increased extinguished responding. On average, monkeys emitted fewer reinstated responses following 0.32 mg/kg cocaine, compared with the number of responses emitted when cocaine was available for self-administration or when extinguished responding was reinstated by 0.032 mg/kg heroin. When drug-associated stimuli were not presented, heroin did not increase responding. Lorcaserin dose dependently attenuated reinstated responding, and its potency was similar regardless of whether cocaine or heroin was given before reinstatement sessions. The generality of this effect of lorcaserin across pharmacological classes of abused drugs might make it particularly useful for reducing relapse-related behaviors in polydrug abusers. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Reversal and Prevention of the Respiratory-Depressant Effects of Heroin by the Novel µ-Opioid Receptor Antagonist Methocinnamox in Rhesus Monkeys.

One consequence of the ongoing opioid epidemic is a large number of overdose deaths. Naloxone reverses opioid-induced respiratory depression; however, its short duration of action limits the protection it can provide. Methocinnamox (MCAM) is a novel opioid receptor antagonist with a long duration of action. This study examined the ability of MCAM to prevent and reverse the respiratory-depressant effects (minute volume [VE]) of heroin in five monkeys. MCAM (0.32 mg/kg) was given before heroin to determine whether it prevents respiratory depression; heroin dose-effect curves were generated 1, 2, 4, and 8 days later, and these effects were compared with those of naltrexone (0.032 mg/kg). Heroin dose dependently decreased VE MCAM and naltrexone prevented respiratory depression, shifting the heroin dose-effect curve rightward at least 10-fold. MCAM, but not naltrexone, attenuated these effects of heroin for 4 days. MCAM (0.1-0.32 mg/kg) was given 30 minutes after heroin to determine whether it reverses respiratory depression; heroin dose-effect curves were generated 1, 2, 4, 8, and 16 days later, and these effects were compared with those of naloxone (0.0032-0.1 mg/kg). MCAM and naloxone reversed respiratory depression within 30 minutes, although only MCAM antagonized heroin on subsequent days. Thus, MCAM prevents and reverses respiratory depression, the potentially lethal effect of heroin, longer than opioid receptor antagonists currently in use. Because of its sustained effects, MCAM might provide more effective rescue from and protection against the fatal respiratory-depressant effects of opioids, thereby improving treatment of opioid overdose.

Long-Lasting Effects of Methocinnamox on Opioid Self-Administration in Rhesus Monkeys.

Opioid abuse remains a serious public health challenge, despite the availability of medications that are effective in some patients (naltrexone, buprenorphine, and methadone). This study explored the potential of a pseudoirreversible mu-opioid receptor antagonist [methocinnamox (MCAM)] as a treatment for opioid abuse by examining its capacity to attenuate the reinforcing effects of mu-opioid receptor agonists in rhesus monkeys. In one experiment, monkeys responded for heroin (n = 5) or cocaine (n = 4) under a fixed-ratio schedule. Another group (n = 3) worked under a choice procedure with one alternative delivering food and the other alternative delivering the mu-opioid receptor agonist remifentanil. A third group (n = 4) responded for food and physiologic parameters were measured via telemetry. The effects of MCAM were determined in all experiments and, in some cases, were compared with those of naltrexone. When given immediately before sessions, naltrexone dose-dependently decreased responding for heroin and decreased choice of remifentanil while increasing choice of food, with responding returning to baseline levels 1 day after naltrexone injection. MCAM also decreased responding for heroin and decreased choice of remifentanil while increasing choice of food; however, opioid-maintained responding remained decreased for several days after treatment. Doses of MCAM that significantly decreased opioid-maintained responding did not decrease responding for cocaine or food. MCAM did not impact heart rate, blood pressure, body temperature, or activity at doses that decreased opioid self-administration. Because MCAM selectively attenuates opioid self-administration for prolonged periods, this novel drug could be a safe and effective alternative to currently available treatments for opioid abuse.

Ventilatory-depressant effects of opioids alone and in combination with cannabinoids in rhesus monkeys.

Pain is a serious health problem that is commonly treated with opioids, although the doses of opioids needed to treat pain are often similar to those that decrease respiration. Combining opioids with drugs that relieve pain through non-opioid mechanisms can decrease the doses of opioids needed for analgesia, resulting in an improved therapeutic window, but only if the doses of opioids that decrease respiration are not similarly decreased. Using small doses of opioids to treat pain has the potential to reduce the number of overdoses and deaths. This study investigated whether the cannabinoid receptor agonists Δ9-tetrahydrocannabinol (Δ9-THC) and CP 55,940 modify the ventilatory-depressant effects of morphine and fentanyl in three monkeys. Ventilatory parameters, including minute volume (VE), were monitored with a head plethysmograph. When given alone, morphine (0.032 - 10 mg/kg) and fentanyl (0.00032 - 0.1 mg/kg) dose dependently decreased VE. Doses of Δ9-THC (1 mg/kg) and CP 55,940 (0.01 mg/kg) that enhance the potency of opioids to produce antinociception modestly decreased ventilation when given alone but did not significantly change morphine or fentanyl dose-effect curves. A larger dose of CP 55,940 (0.032 mg/kg) shifted the fentanyl dose-effect curve downward in two monkeys, without significantly changing the morphine dose-effect curve. In summary, cannabinoid receptor agonists, which increase the potency of opioids to produce antinociception, did not increase their potency to depress ventilation. Thus, the therapeutic window is greater for opioids when they are combined with cannabinoid receptor agonists, indicating a possible advantage for these drug mixtures in treating pain.

The behavioral pharmacology and therapeutic potential of lorcaserin for substance use disorders.

Substance abuse is serious public health problem for which there are few effective pharmacotherapies. Traditional strategies for drug development have focused on antagonists to block the abuse-related effects of a drug at its site of action, and agonists to replace/mimic the effects of the abused substance. However, recent efforts have targeted receptors, such as serotonin (5-HT)2 receptors, that can indirectly modulate dopamine neurotransmission with the goal of developing a pharmacotherapy that might be effective at reducing the abuse-related effects of drugs more generally. Lorcaserin is a 5-HT2C receptor-preferring agonist that is approved by the US Food and Drug Administration for the treatment of obesity. Mounting evidence from preclinical and clinical studies suggests that lorcaserin might also be effective at reducing the abuse-related effects of drugs with different pharmacological mechanisms (e.g., cocaine, heroin, ethanol, and nicotine). Lorcaserin represents a promising and important first step towards the development a new class of pharmacotherapies that have the potential to dramatically improve the treatment of substance abuse. This article will review the behavioral pharmacology of 5-HT2C receptor-preferring agonists, with a focus on lorcaserin, and evaluate the preclinical evidence supporting the development of lorcaserin for treating substance abuse. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Preference for an Opioid/Benzodiazepine Mixture over an Opioid Alone Using a Concurrent Choice Procedure in Rhesus Monkeys.

Increased abuse of opioids is contributing to an escalation in overdose deaths. Benzodiazepines are frequently abused with opioids, possibly because they increase the potency and/or effectiveness of opioids to produce reinforcing effects. This study used a concurrent-choice procedure to determine whether monkeys would choose to self-administer a mixture of the opioid remifentanil and the benzodiazepine midazolam over remifentanil alone. Initially, three monkeys could respond on one lever for saline and on a second lever for either remifentanil alone or midazolam alone. Thereafter, monkeys chose between a dose of remifentanil (0.32 µg/kg/infusion) that did not change and a dose of remifentanil that varied across sessions; for some sessions, midazolam was combined with varying doses of remifentanil. All monkeys received more infusions of remifentanil (0.0032-0.32 µg/kg/infusion) than saline, whereas only two monkeys responded more for midazolam than for saline. When 0.32 µg/kg/infusion remifentanil was available on one lever and a dose of remifentanil that varied across sessions (0.1-1 µg/kg/infusion) was available on the other lever, monkeys chose the larger dose. Combining 3.2 µg/kg/infusion midazolam with 0.32 µg/kg/infusion remifentanil increased responding for the mixture over 0.32 µg/kg/infusion remifentanil alone, although monkeys chose remifentanil alone over mixtures containing smaller doses of remifentanil. When 10 µg/kg/infusion midazolam was combined with 0.1 µg/kg/infusion remifentanil, monkeys chose the mixture over 0.32 µg/kg/infusion remifentanil alone. Thus, monkeys prefer some opioid/benzodiazepine mixtures to larger doses of the opioid alone, suggesting that opioid/benzodiazepine coabuse might be due to increased potency (and possibly effectiveness) of opioids to produce reinforcing effects.

Effects of Lorcaserin on Cocaine and Methamphetamine Self-Administration and Reinstatement of Responding Previously Maintained by Cocaine in Rhesus Monkeys.

Stimulant abuse is a serious public health issue for which there is no effective pharmacotherapy. The serotonin2C [5-hydroxytryptamine2C (5-HT2C)] receptor agonist lorcaserin decreases some abuse-related effects of cocaine in monkeys and might be useful for treating stimulant abuse. The current study investigated the effectiveness of lorcaserin to reduce self-administration of either cocaine or methamphetamine and cocaine-induced reinstatement of extinguished responding. Four rhesus monkeys responded under a progressive-ratio (PR) schedule in which the response requirement increased after each cocaine infusion (32-320 µg/kg/infusion). A separate group of four monkeys responded under a fixed-ratio (FR) schedule for cocaine (32 µg/kg/infusion) and reinstatement of extinguished responding was examined following administration of noncontingent infusions of cocaine (0.1-1 mg/kg) that were combined with response-contingent presentations of the drug-associated stimuli. Finally, three monkeys responded under a FR schedule for methamphetamine (0.32-100 µg/kg/infusion). Lorcaserin (3.2 mg/kg) significantly decreased the final ratio completed (i.e., decreased break point) in monkeys responding under the PR schedule and reduced the reinstatement of responding for drug-associated stimuli following a noncontingent infusion of cocaine; these effects did not appear to change when lorcaserin was administered daily. The same dose of lorcaserin decreased responding for methamphetamine in two of the three monkeys, and the effect was maintained during daily lorcaserin administration; larger doses given acutely (10-17.8 mg/kg) significantly decreased responding for methamphetamine, although that effect was not sustained during daily lorcaserin administration. Together, these results indicate that lorcaserin might be effective in reducing cocaine and methamphetamine abuse and cocaine relapse at least in some individuals.

Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats.

RATIONALE: Gaboxadol is a selective agonist at γ-aminobutyric acidA (GABAA) receptors that contain α4-δ subunits, and it produces anxiolytic and sedative effects. Although adverse effects preclude its clinical use, its mechanism of action suggests that those receptors might provide novel therapeutic targets, particularly for modulators of those GABAA receptor subtypes, by retaining therapeutic effects of gaboxadol and not adverse effects. OBJECTIVES: The current study compared discriminative stimulus effects of gaboxadol with those of modulators acting at GABAA receptors containing α4-δ subunits. MATERIALS: Eight rats discriminated 5.6 mg/kg gaboxadol from vehicle while responding under a fixed - ratio 10 schedule for food. Modulators acting at GABAA receptors containing α4-δ subunits (pregnanolone, ethanol, and flumazenil) and receptors that do not contain those subunits (midazolam) were studied alone; pregnanolone and ethanol were also combined with gaboxadol. In addition, gaboxadol was studied in separate groups discriminating 0.32 mg/kg midazolam, 3.2 mg/kg pregnanolone, or 0.75 g/kg ethanol from vehicle. RESULTS: Gaboxadol produced ≥80 % gaboxadol-lever responding and did not alter rates. No other drug produced, on average, ≥80 % drug-lever responding up to doses that decreased rates, although 1.78 mg/kg midazolam produced 32 % gaboxadol-lever responding. Ethanol and pregnanolone did not enhance the effects of gaboxadol. Rats discriminating midazolam, pregnanolone, or ethanol from vehicle responded predominantly on the vehicle lever after receiving gaboxadol. CONCLUSIONS: Drugs that modulate GABAA receptors containing α4-δ subunits neither mimicked nor enhanced the discriminative stimulus effects of gaboxadol, indicating that at least some effects of gaboxadol are not shared with modulators of that GABAA receptor subtype.

Delay discounting of the µ-opioid receptor agonist remifentanil in rhesus monkeys.

Although increased impulsivity (delay discounting) is an important risk factor for drug abuse, the impact of delay on drug taking has received relatively little attention. This study examined delay discounting of the µ-opioid receptor agonist remifentanil in rhesus monkeys (n=4) responding for intravenous infusions under a concurrent choice procedure. Dose-effect curves for remifentanil were determined by varying the dose available on one lever (0.001-0.32 µg/kg/infusion) while keeping the dose available on the other lever (0.1 µg/kg/infusion) the same. Dose-effect curves were determined when both infusions were delivered immediately and when delivery of the fixed dose was delayed (15-180 s). When both doses of remifentanil were delivered immediately, monkeys chose the large dose. Delaying delivery of the fixed dose reduced choice of that dose and increased choice of small immediately available doses. Extending previous studies, these results show that the effects of delay on choice between two doses of a µ-opioid receptor agonist are consistent with hyperbolic discounting. Delaying delivery of a preferred reinforcer (e.g. large dose of drug) reduces its effectiveness and increases the effectiveness of small immediately available doses. This effect of delay, particularly on drug self-administration, might contribute to drug abuse.