2‐Fluorodeschloroketamine has similar abuse potential as ketamine

Abstract

2‐Fluorodeschloroketamine (2‐FDCK) as a substitute for ketamine has emerged among drug abusers in recent years. However, 2‐FDCK has not been controlled or regulated in many countries, which may be partly related to the lack of evidence on its abuse potential. In this study, we evaluated the abuse potential of 2‐FDCK via the tests of the conditioned place preference (CPP), locomotor sensitization, drug self‐administration and drug discrimination using ketamine as a reference. 2‐FDCK induced significant CPP at a minimum dose of 3 mg/kg in mice, an effect comparable with that of ketamine (3 mg/kg). Acute injections of 2‐FDCK or ketamine at 30 mg/kg enhanced locomotor activity. Repeated treatments with this dose of 2‐FDCK and ketamine induced locomotor sensitization after withdrawal. 2‐FDCK readily induced self‐administration with 0.5 mg/kg/infusion, the same dose for ketamine, and induced the highest seeking response at 1 mg/kg. Drug discrimination test showed that 2‐FDCK dose‐dependently substitute for ketamine with comparable ED50 to ketamine in substitution testing. Taken together, these results strongly suggested that 2‐FDCK has an abuse potential comparable with ketamine.

A comparison of reinforcing effectiveness and drug-seeking reinstatement of 2-fluorodeschloroketamine and ketamine in self-administered rats

“…The main findings of the present study are that both the α parameter and the EV of effectiveness between 2F-DCK and ketamine are similar, and the reinstatement of 2F-DCKand ketamine-seeking behaviors after extinction is also similar. These data, along with the data from previous studies, suggest that 2F-DCK and ketamine have abuse potential and can cause cravings after extinction (Huang et al, 2015;Li et al, 2022]. The value of the α parameter is inversely proportional to the intensity of reinstatement of 2F-DCK-and ketamineseeking behaviors, which could predict cravings for 2F-DCK and ketamine after withdrawal from self-administration.…”

“…Our previous studies have shown that 2F-DCK produces self-administration, conditions place preference, and generalizes discriminative stimuli effects similar to ketamine (Li et al, 2022). Behavioral economics provides a framework for quantifying 2F-DCK and ketamine abuse potential, while also offering an approach complementary to the self-administration and dose-response curve used previously to characterize the abuse-related effects of 2F-DCK and ketamine (Li et al, 2022). Thus, the α parameter and EV values of 2F-DCK and ketamine were very close, indicating that both have similar reinforcing effectiveness.…”

“…It is transformed into an EV, which is directly related to reinforcing effectiveness (Hursh and Romaa, 2016;Zanettini et al, 2018;Maguire et al, 2020). Our previous studies have shown that 2F-DCK produces self-administration, conditions place preference, and generalizes discriminative stimuli effects similar to ketamine (Li et al, 2022). Behavioral economics provides a framework for quantifying 2F-DCK and ketamine abuse potential, while also offering an approach complementary to the self-administration and dose-response curve used previously to characterize the abuse-related effects of 2F-DCK and ketamine (Li et al, 2022).…”

“…After ~7 days of recovery from surgery, the rats ( n = 16) were divided randomly into two groups, which underwent ketamine and 2F-DCK self-administration training. During the 4-h acquisition phase of self-administration starting with the green light inside the active nose-poke hole, rats were trained to respond under a fixed ratio 1 (FR1) reinforcement schedule for ketamine and 2F-DCK (0.5 mg·kg −1 ·infusion −1 ), in accordance with the protocol described in a previous study (Li et al, 2022 ). To prevent overdose, the number of infusions was limited to 200 per session.…”

“…The reinforcing effects of drugs are fundamental to the development of drug addiction and are intrinsic to most rodent models of addiction-like behaviors (Koffarnus et al, 2012 ). 2F-DCK was recently shown to produce self-administration, generalized to ketamine discriminative stimuli and induce conditioned place preference in rats (Li et al, 2022 ). Self-administration of ketamine or 2F-DCK determines their functions as reinforcers but does not provide quantitative information about their reinforcing effectiveness (Huskinson et al, 2014 ).…”