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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.

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2-Fluorodeschloroketamine (2F-DCK), a structural analog of ketamine, has been reported to cause impaired consciousness, agitation, and hallucination in abuse cases. It has similar reinforcing and discriminative effects as ketamine. However, the reinforcing efficacy and drug-seeking reinstatement of this analog have not been clarified to date. In this study, the effectiveness of 2F-DCK and ketamine was compared using a behavioral economics demand curve. The reinstatement of 2F-DCK- and ketamine-seeking behaviors induced by either conditioned cues or self-priming was also analyzed. Rats were intravenously self-administered 2F-DCK and ketamine at a dose of 0.5 mg/kg/infusion under a reinforcing schedule of fixed ratio 1 (FR1) with 4 h of daily training for at least 10 consecutive days. The elasticity coefficient parameter α and the essential value of the demand curve in the two groups were similar. Both groups of rats showed significant drug-seeking behavior induced either by conditional cues or by 2F-DCK and ketamine priming. Moreover, the α parameter was inversely related to the degree of reinstatement induced by cues or drug priming in both groups. In total, the expression levels of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding protein (p-CREB) in the nucleus accumbens in both extinguished and reinstated rats were significantly lower than those in the control. The expression of total Akt, glycogen synthase kinase (GSK)-3β, mammalian target of rapamycin (mTOR), and extracellular signal-related kinase (ERK) also decreased, but p-Akt, p-GSK-3β, p-mTOR, and p-ERK levels increased in both extinguished and reinstated rats. This is the first study to demonstrate that 2F-DCK has similar reinforcing efficacy, effectiveness, and post-withdrawal cravings as ketamine after repeated use. These data suggest that the downregulation of CREB/BDNF and the upregulation of the Akt/mTOR/GSK-3β signaling pathway in the nucleus accumbens may be involved in ketamine or 2F-DCK relapse.

Buprenorphine, which has been approved for the treatment of opioid dependence, reduces cocaine consumption by co-activating μ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. However, the role of buprenorphine in methamphetamine (METH) reinforcement and drug-seeking behavior remains unclear. This study investigated the effects of buprenorphine on METH self-administration and reinstatement of METH-seeking behavior in rats. We found that buprenorphine pretreatment had an inhibitory effect on METH self-administration behavior, and that buprenorphine at a dose of 0.3 mg/kg could inhibit motivation to respond for METH. Pretreatment with the NOP receptor antagonist thienorphine (0.5 mg/kg) or SB-612111 (1 mg/kg) could reverse the inhibitory effect of buprenorphine (0.1 mg/kg) on the METH self-administration. Moreover, treatment with buprenorphine (0.1 mg/kg and 0.3 mg/kg) significantly reduced the drug-seeking behavior induced by context or by METH priming but failed to reduce the drug-seeking behavior induced by conditional cues. Additionally, the NOP receptor antagonist SB-612111 reversed the inhibitory action of buprenorphine on the drug-seeking behavior induced by METH priming. The results demonstrated that buprenorphine reduced either METH intake or the drug-seeking behavior by activating NOP receptors, providing empirical evidence for the clinical use of buprenorphine in the treatment of METH relapse and addiction.