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Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability.

ABSTRACT: Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers, has been used as an anesthetic, analgesic and more recently, as an antidepressant. However, ketamine has known abuse liability (the tendency of a drug to be used in non-medical situations due to its psychoactive effects), which raises concerns for its therapeutic use. (S)-ketamine was recently approved by the United States' FDA for treatment-resistant depression. Recent studies showed that (R)-ketamine has greater efficacy than (S)-ketamine in preclinical models of depression, but its clinical antidepressant efficacy has not been established. The behavioral effects of racemic ketamine have been studied extensively in preclinical models predictive of abuse liability in humans (self-administration and conditioned place preference [CPP]). In contrast, the behavioral effects of each enantiomer in these models are unknown. We show here that in the intravenous drug self-administration model, the gold standard procedure to assess potential abuse liability of drugs in humans, rats self-administered (S)-ketamine but not (R)-ketamine. Subanesthetic, antidepressant-like doses of (S)-ketamine, but not of (R)-ketamine, induced locomotor activity (in an opioid receptor-dependent manner), induced psychomotor sensitization, induced CPP in mice, and selectively increased metabolic activity and dopamine tone in medial prefrontal cortex (mPFC) of rats. Pharmacological screening across thousands of human proteins and at biological targets known to interact with ketamine yielded divergent binding and functional enantiomer profiles, including selective mu and kappa opioid receptor activation by (S)-ketamine in mPFC. Our results demonstrate divergence in the pharmacological, functional, and behavioral effects of ketamine enantiomers, and suggest that racemic ketamine's abuse liability in humans is primarily due to the pharmacological effects of its (S)-enantiomer.

SUBMITTER: Bonaventura J

PROVIDER: S-EPMC8517038 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RATIONALE:Subanesthetic ketamine (KET) elicits rapid, robust, but transient antidepressant effects. KET's antidepressant actions can be augmented and maintained for a longer duration when repeatedly delivered. However, KET is recreationally abused, raising long-term treatment safety concerns. Women are more likely than men to seek treatment for depression, escalate from casual to compulsive drug use, and are more sensitive to antidepressants. Similarly, female rodents are more sensitive than males to KET's rapid antidepressant-like behavioral effects; dose-response thresholds in these assays equal 2.5 and 5.0mg/kg (i.p.), respectively. This suggests the utility of preclinical rodent models in optimizing sex-differential KET therapy protocols and minimizing adverse drug reactions. OBJECTIVES:Here, we assessed behavioral and biochemical correlates of abuse liability following six serial KET treatments on alternating days at three subanesthetic, antidepressant-like doses (2.5, 5.0, or 10mg/kg, i.p.) in adult male and female rats. A potential role for ?FosB-mediated transcription in the nucleus accumbens is outlined in the context of KET-mediated locomotor sensitization. RESULTS:Antidepressant-like threshold doses (2.5, 5.0mg/kg KET) failed to evoke a conditioned place preference in all animals, but only males positively responded to a higher dose (10mg/kg). Behavioral sensitization to 5.0 or 10mg/kg KET's locomotor-activating effects was established in both sexes, and females' sensitized response to 5.0mg/kg was greater than males'. KET-induced hyperlocomotion positively correlated with ?FosB protein expression in the nucleus accumbens. rAAV-?JunD inhibition of ?FosB-mediated transcription in the accumbens failed to block locomotor sensitization to 10mg/kg KET. CONCLUSIONS:These data suggest that in rats, six alternating-day treatments with 2.5mg/kg KET do not induce apparent behavioral signatures of abuse liability despite accumulation of ?FosB protein in the accumbens. Additionally, females are more sensitive than males to KET's locomotor-stimulant properties, both acutely and after repeated treatments. More studies are needed to determine brain regions and neural mechanisms responsible for KET-induced behavioral adaptations and to extrapolate these data to inform sex-dependent strategies for long-term KET therapy protocols for depression.

Project description:It is estimated that nearly a third of people who abuse drugs started with prescription opioid medicines. Approximately, 11.5 million Americans used prescription drugs recreationally in 2016, and in 2018, 46,802 Americans died as the result of an opioid overdose, including prescription opioids, heroin, and illicitly manufactured fentanyl (National Institutes on Drug Abuse (2020) Opioid Overdose Crisis. https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis . Accessed 06 June 2020). Yet physicians will continue to prescribe oral opioids for moderate-to-severe pain in the absence of alternative therapeutics, underscoring the importance in understanding how drug choice can influence detrimental outcomes. One of the opioid prescription medications that led to this crisis is oxycodone, where misuse of this drug has been rampant. Being one of the most highly prescribed opioid medications for treating moderate-to-severe pain as reflected in the skyrocketed increase in retail sales of 866% between 1997 and 2007, oxycodone was initially suggested to be less addictive than morphine. The false-claimed non-addictive formulation of oxycodone, OxyContin, further contributed to the opioid crisis. Abuse was often carried out by crushing the pills for immediate burst release, typically by nasal insufflation, or by liquefying the pills for intravenous injection. Here, we review oxycodone pharmacology and abuse liability as well as present the hypothesis that oxycodone may exhibit a unique pharmacology that contributes to its high likability and abuse susceptibility. We will discuss various mechanisms that likely contribute to the high abuse rate of oxycodone including clinical drug likability, pharmacokinetics, pharmacodynamics, differences in its actions within mesolimbic reward circuity compared to other opioids, and the possibility of differential molecular and cellular receptor interactions that contribute to its selective effects. We will also discuss marketing strategies and drug difference that likely contributes to the oxycodone opioid use disorders and addiction.

Project description:Marijuana substitutes often contain blends of multiple psychoactive synthetic cannabinoids (SCBs), including the prevalent SCBs (1-pentyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-018) and (1-butyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-073). Because SCBs are frequently used in combinations, we hypothesized that coadministering multiple SCBs induces synergistic drug-drug interactions. Drug-drug interactions between JWH-018 and JWH-073 were investigated in vivo for ?(9)-tetrahydrocannabinol (?(9)-THC)-like discriminative stimulus effects, analgesia, task disruption, and hypothermia. Combinations (JWH-018:JWH-073) of these drugs were administered to mice in assays of ?(9)-THC discrimination, tail-immersion, and food-maintained responding, and rectal temperatures were measured. Synergism occurred in the ?(9)-THC discrimination assay for two constant dose ratio combinations (1:3 and 1:1). A 1:1 and 2:3 dose ratio induced additivity and synergy, respectively, in the tail-immersion assay. Both 1:1 and 2:3 dose ratios were additive for hypothermia, whereas a 1:3 dose ratio induced subadditive suppression of food-maintained responding. In vitro drug-drug interactions were assessed using competition receptor-binding assays employing mouse brain homogenates and cannabinoid 1 receptor (CB1R)-mediated inhibition of adenylyl cyclase activity in Neuro2A wild-type cells. Interestingly, synergy occurred in the competition receptor-binding assay for two dose ratios (1:5 and 1:10), but not in the adenylyl cyclase activity assay (1:5). Altogether, these data indicate that drug-drug interactions between JWH-018 and JWH-073 are effect- and ratio-dependent and may increase the relative potency of marijuana substitutes for subjective ?(9)-THC-like effects. Combinations may improve the therapeutic profile of cannabinoids, considering that analgesia but not hypothermia or task disruption was potentiated. Importantly, synergy in the competition receptor-binding assay suggests multiple CB1R-SCB binding sites.

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Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability.

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