title: Ketamine Self-Administration Reduces the Homeostasis of the Glutamate Synapse in the Rat Brain.
abstract: 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.
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
authors: Lucia
authors: L
authors: Caffino
authors: Neuropsychopharmacology Lab, Section Pharmacology, Department Diagnostic & Public Health, University of Verona, P.le Scuro 10, Verona, Italy.
authors: Alessandro
authors: A
authors: Piva
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
authors: Giuseppe
authors: G
authors: Giannotti
authors: Neuropsychopharmacology Lab, Section Pharmacology, Department Diagnostic & Public Health, University of Verona, P.le Scuro 10, Verona, Italy.
authors: Marzia
authors: M
authors: Di Chio
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
authors: Francesca
authors: F
authors: Mottarlini
authors: Neuropsychopharmacology Lab, Section Pharmacology, Department Diagnostic & Public Health, University of Verona, P.le Scuro 10, Verona, Italy.
authors: Marco
authors: M
authors: Venniro
authors: Brain Research Centre, School of Biomedical Science, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T, Hong Kong.
authors: David T
authors: DT
authors: Yew
authors: Neuropsychopharmacology Lab, Section Pharmacology, Department Diagnostic & Public Health, University of Verona, P.le Scuro 10, Verona, Italy.
authors: Cristiano
authors: C
authors: Chiamulera
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy. Fabio.Fumagalli@unimi.it.
authors: Fabio
authors: http://orcid.org/0000-0002-8814-7706
authors: F
authors: Fumagalli
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage* / Q000633:toxicity; D018698:Glutamic Acid / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D007649:Ketamine / Q000008:administration & dosage* / Q000633:toxicity; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D012646:Self Administration; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D007649:Ketamine
keywords: AMPA receptors; Ketamine; Metabotropic receptors; NMDA receptors; Schizophrenia; glutamate