Methoxetamine (MXE) is a dissociative substance of the arylcyclohexylamine class that has been present on the designer drug market as a ketamine-substitute since 2010. We have previously shown that MXE (i) possesses ketamine-like discriminative and positive rewarding effects in rats, (ii) affects brain processing involved in cognition and emotional responses, (iii) causes long-lasting behavioral abnormalities and neurotoxicity in rats and (iv) induces neurological, sensorimotor and cardiorespiratory alterations in mice. To shed light on the mechanisms through which MXE exerts its effects, we conducted a multidisciplinary study to evaluate the various neurotransmitter systems presumably involved in its actions on the brain. In vivo microdialysis study first showed that a single administration of MXE (0.25 and 0.5 mg/kg, i.v.) is able to significantly alter serotonin levels in the rat medial prefrontal cortex (mPFC) and nucleus accumbens. Then, we observed that blockade of the serotonin 5-HT₂ receptors through two selective antagonists, ketanserin (0.1 mg/kg, i.p.) and MDL 100907 (0.03 mg/kg, i.p.), at doses not affecting animals behavior per se, attenuated the facilitatory motor effect and the inhibition on visual sensory responses induced by MXE (3 mg/kg, i.p.) and ketamine (3 mg/kg, i.p.), and prevented MXE-induced reduction of the prepulse inhibition in rats, pointing to the 5-HT₂ receptors as a key target for the recently described MXE-induced sensorimotor effects. Finally, in-vitro electrophysiological studies revealed that the GABAergic and glutamatergic systems are also likely involved in the mechanisms through which MXE exerts its central effects since MXE inhibits, in a concentration-dependent manner, NMDA-mediated field postsynaptic potentials and GABA-mediated spontaneous currents. Conversely, MXE failed to alter both the AMPA component of field potentials and presynaptic glutamate release, and seems not to interfere with the endocannabinoid-mediated effects on mPFC GABAergic synapses. Altogether, our results support the notion of MXE as a NMDA receptor antagonist and shed further lights into the central mechanisms of action of this ketamine-substitute by pointing to serotonin 5-HT₂ receptors as crucial players in the expression of its sensorimotor altering effects and to the NMDA and GABA receptors as potential further important targets of action.

Methoxetamine (MXE) 是芳基环己胺类的一种解离物质，自 2010 年以来一直作为氯胺酮的替代品出现在设计药物市场上。 (ii) 影响参与认知和情绪反应的大脑处理，(iii) 导致大鼠长期的行为异常和神经毒性，以及 (iv) 诱导小鼠的神经、感觉运动和心肺功能改变。为了阐明 MXE 发挥作用的机制，我们进行了一项多学科研究，以评估可能参与其对大脑的作用的各种神经递质系统。体内微透析研究首先表明，MXE（0.25 和 0.5 mg/kg，iv ) 能够显着改变大鼠内侧前额叶皮层 (mPFC) 和伏核中的血清素水平。然后，我们观察到 5-羟色胺 5-HT 的阻断₂受体通过两种选择性拮抗剂，ketanserin (0.1 mg/kg, ip) 和 MDL 100907 (0.03 mg/kg, ip)，在不影响动物行为本身的剂量下，减弱了促进运动效应和对诱导的视觉感觉反应的抑制通过 MXE（3 毫克/公斤，腹腔注射）和氯胺酮（3 毫克/公斤，腹腔注射），并防止 MXE 诱导的大鼠前脉冲抑制的减少，指向 5-HT ₂受体作为最近描述的 MXE 诱导的感觉运动效应的关键目标。最后，体外电生理研究表明 GABA 能和谷氨酸能系统也可能参与 MXE 发挥其中枢效应的机制，因为 MXE 以浓度依赖性方式抑制 NMDA 介导的场突触后电位和 GABA 介导的自发性电流。相反，MXE 未能改变场电位的 AMPA 成分和突触前谷氨酸盐释放，并且似乎不会干扰内源性大麻素介导的对 mPFC GABA 能突触的影响。总而言之，我们的结果支持 MXE 作为 NMDA 受体拮抗剂的概念，并通过指向血清素 5-HT ₂进一步阐明了这种氯胺酮替代物的中心作用机制 受体作为其感觉运动改变作用表达的关键参与者，并将 NMDA 和 GABA 受体作为潜在的进一步重要作用目标。