Journal Article

Ketamine Self-Administration Reduces the Homeostasis of the Glutamate Synapse in the Rat Brain

Piva, Alessandro, Chiamulera, Cristiano, Giannotti, Giuseppe, Caffino, Lucia, Fumagalli, Fabio, Yew, David T., Mottarlini, Francesca, Di Chio, Marzia, Venniro, Marco

2017

Overview

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.

• Publisher: Springer US,Springer Nature B.V
• Subject: Anesthesia / Animal models / Animals / Attention / Biomedical and Life Sciences / Biomedicine / Brain / Brain - drug effects / Brain - metabolism / Cell Biology / Cognitive ability / Drug addiction / Drug therapy / Excitatory Amino Acid Antagonists - administration & dosage / Excitatory Amino Acid Antagonists - toxicity / Glutamate receptors / Glutamic Acid - metabolism / Glutamic acid receptors (ionotropic) / Glutamic acid receptors (metabotropic) / Hip / Homeostasis / Homeostasis - drug effects / Homeostasis - physiology / Ketamine / Ketamine - administration & dosage / Ketamine - toxicity / Male / Mental disorders / Metabotropic receptors / N-Methyl-D-aspartic acid receptors / Neurobiology / Neurology / Neurons / Neurosciences / Prefrontal cortex / Rats / Rats, Sprague-Dawley / Receptor, Metabotropic Glutamate 5 - antagonists & inhibitors / Receptor, Metabotropic Glutamate 5 - metabolism / Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors / Receptors, N-Methyl-D-Aspartate - metabolism / Rodents / Schizophrenia / Self Administration / Synapses / Synapses - drug effects / Synapses - metabolism / α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid / α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors