Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
Neuropsychopharmacology Lab, Section Pharmacology, Department Diagnostic & Public Health, University of Verona, P.le Scuro 10, Verona, Italy.
Mol Neurobiol. 2017 Nov;54(9):7186-7193. doi: 10.1007/s12035-016-0231-6. Epub 2016 Oct 29.
Ketamine is a non-competitive antagonist of the NMDA glutamate receptor with psychotomimetic and reinforcing properties, although recent work has pointed out its antidepressant action following acute exposure. Our aim was to investigate the expression of crucial components of the glutamate synapse following chronic ketamine self-administration (S/A), focusing our attention on medial prefrontal cortex (mPFC) and hippocampus (Hip), two brain regions involved in compulsive drug-seeking and drug-related cognitive disorders. Rats self-administered ketamine at a sub-anesthetic dose for 5-6 weeks and were sacrificed 24 h after the last drug exposure. We found a general downregulation of glutamate receptor expression that was brain region-dependent. In fact, in the mPFC, we found reduced expression of NMDA receptor subunits, whereas AMPA receptor protein levels were reduced in Hip; of note, specific scaffolding proteins of NMDA and AMPA receptors were also reduced in mPFC and Hip, respectively. Moreover, the metabotropic mGluR5 receptor was similarly downregulated in these brain regions. These findings reveal a dynamic impairment of glutamate homeostasis in the mPFC and Hip that may represent a signature of long-term exposure to ketamine S/A. Further, this decrement, similarly observed in humans and animal models of schizophrenia may represent a specific feature of the human disease endophenotype.
氯胺酮是一种非竞争性 NMDA 谷氨酸受体拮抗剂，具有致幻和强化作用，尽管最近的研究指出其在急性暴露后具有抗抑郁作用。我们的目的是研究慢性氯胺酮自我给药（S/A）后谷氨酸突触的关键成分的表达，特别关注内侧前额叶皮层（mPFC）和海马（Hip），这两个脑区与强迫性觅药和与药物相关的认知障碍有关。大鼠以亚麻醉剂量自我给予氯胺酮 5-6 周，并在最后一次药物暴露后 24 小时处死。我们发现谷氨酸受体表达普遍下调，且具有脑区依赖性。事实上，在 mPFC 中，我们发现 NMDA 受体亚基的表达减少，而在 Hip 中 AMPA 受体蛋白水平降低；值得注意的是，NMDA 和 AMPA 受体的特定支架蛋白在 mPFC 和 Hip 中也分别减少。此外，代谢型 mGluR5 受体在这些脑区也同样下调。这些发现揭示了 mPFC 和 Hip 中谷氨酸稳态的动态损伤，这可能是长期暴露于氯胺酮 S/A 的特征。此外，这种在人类和精神分裂症动物模型中都观察到的下降可能代表人类疾病表型的一个特定特征。
