Ketamine offers a fast-acting approach to relieving treatment-resistant depression, but its abuse potential is an issue of concern. As ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) ion channel blocker, modulation of NMDAR might be an effective strategy to counteract the abuse liability of ketamine and even to treat ketamine use disorder. This study evaluated whether NMDAR modulators that act on glycine binding sites can decrease motivation to obtain ketamine and reduce reinstatement to ketamine-seeking behavior. Two NMDAR modulators, D-serine and sarcosine were examined. Male Sprague-Dawley rats underwent training to acquire the ability to self-administer ketamine. The motivation to self-administer ketamine or sucrose pellets was examined under a progressive ratio (PR) schedule. The reinstatement of ketamine-seeking and sucrose pellet-seeking behaviors were assessed after extinction. The results showed that both D-serine and sarcosine significantly decreased the breakpoints for ketamine and prevented reinstatement of ketamine seeking. However, these modulators did not alter motivated behavior for sucrose pellets, the ability of the cue and sucrose pellets to reinstate sucrose-seeking behavior or spontaneous locomotor activity. These findings indicate that two NMDAR modulators can specifically reduce the measures of motivation and relapse for ketamine in rats, suggesting that targeting the glycine binding site of the NMDAR is a promising approach for preventing and treating ketamine use disorder.
Abstract Conditioned place preference (CPP) paradigm in zebrafish has been used to measure drug reward, but there is limited research on CPP reinstatement to determine relapse vulnerability. The present study aimed to investigate extinction and reinstatement of methamphetamine (MA)‐induced CPP in zebrafish and evaluate the model's predictive validity. Zebrafish received different doses of MA (0–60 mg/kg) during CPP training. The preferred dose of MA at 40 mg/kg was used for extinction via either confined or nonconfined procedures. The extinguished CPP was reinstated by administering a priming dose of MA (20 mg/kg) or various stressors. To assess persistent susceptibility to reinstatement, MA CPP and reinstatement were retested following 14 days of abstinence. In addition, the effects of SCH23390, naltrexone, and clonidine on MA CPP during acquisition, expression, or reinstatement phases were monitored. MA induced CPP in a dose‐dependent manner. Both nonconfined and confined extinction procedures time‐dependently reduced the time spent on the MA‐paired side. A priming dose of MA, chasing stress, or yohimbine reinstated the extinguished CPP. After 14 days of abstinence, the MA CPP remained extinguished and was significantly reinstated by MA priming or chasing stress. Similar to the observations in rodents, SCH23390 suppressed the acquisition of MA CPP, naltrexone reduced the expression and MA priming‐induced reinstatement, while clonidine prevented stress‐induced reinstatement of MA CPP. This work expanded the zebrafish CPP paradigm to include extinction and reinstatement phases, demonstrating predictive validity and highlighting its potential as a valuable tool for exploring drug relapse.
Abstract The antinociceptive effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis , were investigated on animal paw licking responses and thermal hyperalgesia induced by glutamate receptor agonists including glutamate, N-methyl-D-aspartate (NMDA), and metabotropic glutamate 5 receptor (mGluR5) activator (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), as well as inflammatory mediators such as substance P and prostaglandin E 2 (PGE 2 ) in mice. The actions of honokiol and magnolol on glutamate-induced c-Fos expression in the spinal cord dorsal horn were also examined. Our data showed that honokiol and magnolol blocked glutamate-, substance P- and PGE 2 -induced inflammatory pain with similar potency and efficacy. Consistently, honokiol and magnolol significantly decreased glutamate-induced c-Fos protein expression in superficial (I-II) laminae of the L4-L5 lumbar dorsal horn. However, honokiol was more selective than magnolol for inhibition of NMDA-induced licking behavioral and thermal hyperalgesia. In contrast, magnolol was more potent to block CHPG-mediated thermal hyperalgesia. These results demonstrate that honokiol and magnolol effectively decreased the inflammatory pain. Furthermore, their different potency on inhibition of nociception provoked by NMDA receptor and mGluR5 activation should be considered.
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