title: The modulation of BDNF expression and signalling dissects the antidepressant from the reinforcing properties of ketamine: Effects of single infusion vs. chronic self-administration in rats.
abstract: Ketamine is a drug of abuse with a unique profile, which besides its inherent mechanism of action as a non-competitive antagonist of the NMDA glutamate receptor, displays both antidepressant and reinforcing properties. The major aim of our study was to find a molecular signature of ketamine that may help in discriminating between its reinforcing and antidepressant effects. To this end, we focused our attention on BDNF, a neurotrophin that has been shown to play a role in both antidepressant and reinforcing properties of several drugs. Rats were exposed to self-administer intravenous (IV) ketamine (S/A) for 43 days or to receive a single IV ketamine 0.5mg/kg, or vehicle infusion. Although the dose we employed is lower than that reported by the literature, it however yields Cmax values that correspond to those achieved in humans after antidepressant treatment. Our results show that while the single infusion of ketamine increased the neurotrophin expression in the hippocampus while reducing it in the ventral striatum, a feature shared with other antidepressants, the repeated self-administration reduced mBDNF expression and its downstream signalling in both ventral striatum and hippocampus. Further, we here show that phosphorylation of Akt is oppositely regulated by ketamine, pointing to this pathway as central to the different actions of the drug. Taken together, we here point to BDNF and its downstream signalling pathway as a finely tuned mechanism whose modulation might subserve the different features of ketamine.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Caffino
authors.affiliation: Neuropsychopharmacology Lab, Section Pharmacology, Dept Diagnostic & Public Health, P.le Scuro 10, University of Verona, Verona, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Di Chio
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannotti
authors.affiliation: Neuropsychopharmacology Lab, Section Pharmacology, Dept Diagnostic & Public Health, P.le Scuro 10, University of Verona, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Venniro
authors.affiliation: Neuropsychopharmacology Lab, Section Pharmacology, Dept Diagnostic & Public Health, P.le Scuro 10, University of Verona, Verona, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Mutti
authors.affiliation: Neuropsychopharmacology Lab, Section Pharmacology, Dept Diagnostic & Public Health, P.le Scuro 10, University of Verona, Verona, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Padovani
authors.affiliation: Brain Research Centre, School of Biomedical Science, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region.
authors.forename: David
authors.initials: D
authors.lastname: Cheung
authors.affiliation: Neuropsychopharmacology Lab, Section Pharmacology, Dept Diagnostic & Public Health, P.le Scuro 10, University of Verona, Verona, Italy.
authors.forename: Guido F
authors.initials: GF
authors.lastname: Fumagalli
authors.affiliation: Brain Research Centre, School of Biomedical Science, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region.
authors.forename: David T
authors.initials: DT
authors.lastname: Yew
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fumagalli
authors.affiliation: Neuropsychopharmacology Lab, Section Pharmacology, Dept Diagnostic & Public Health, P.le Scuro 10, University of Verona, Verona, Italy. Electronic address: cristiano.chiamulera@univr.it.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Chiamulera
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D007262:Infusions, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration; D015398:Signal Transduction
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D007649:Ketamine; D051057:Proto-Oncogene Proteins c-akt
keywords: Antidepressant; BDNF; Ketamine; Rat; Reinforcement; Zif-268