title: Mutant DISC1 affects methamphetamine-induced sensitization and conditioned place preference: a comorbidity model.
abstract: Genetic factors involved in neuroplasticity have been implicated in major psychiatric illnesses such as schizophrenia, depression, and substance abuse. Given its extended interactome, variants in the Disrupted-In-Schizophrenia-1 (DISC1) gene could contribute to drug addiction and psychiatric diseases. Thus, we evaluated how dominant-negative mutant DISC1 influenced the neurobehavioral and molecular effects of methamphetamine (METH). Control and mutant DISC1 mice were studied before or after treatment with non-toxic escalating dose (ED) of METH. In naïve mice, we assessed METH-induced conditioned place preference (CPP), dopamine (DA) D2 receptor density and the basal and METH-induced activity of DISC1 partners, AKT and GSK-3β in the ventral striatum. In ED-treated mice, 4 weeks after METH treatment, we evaluated fear conditioning, depression-like responses in forced swim test, and the basal and METH-induced activity of AKT and GSK-3β in the ventral striatum. We found impairment in METH-induced CPP, decreased DA D2 receptor density and altered METH-induced phosphorylation of AKT and GSK-3β in naïve DISC1 female mice. The ED regimen was not neurotoxic as evidenced by unaltered brain regional monoamine tissue content. Mutant DISC1 significantly delayed METH ED-produced sensitization and affected drug-induced phosphorylation of AKT and GSK-3β in female mice. Our results suggest that perturbations in DISC1 functions in the ventral striatum may impact the molecular mechanisms of reward and sensitization, contributing to comorbidity between drug abuse and major mental diseases.
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD 21287, USA.
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Pogorelov
authors.forename: Jun
authors.initials: J
authors.lastname: Nomura
authors.forename: Jongho
authors.initials: J
authors.lastname: Kim
authors.forename: Geetha
authors.initials: G
authors.lastname: Kannan
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Ayhan
authors.forename: Chunxia
authors.initials: C
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Bagrat
authors.initials: B
authors.lastname: Abazyan
authors.forename: Heather
authors.initials: H
authors.lastname: Valentine
authors.forename: Irina N
authors.initials: IN
authors.lastname: Krasnova
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kamiya
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pletnikov
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015897:Comorbidity; D003216:Conditioning, Operant / Q000187:drug effects*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D001523:Mental Disorders / Q000235:genetics; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D019966:Substance-Related Disorders / Q000235:genetics
chemical_list: C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D008694:Methamphetamine; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3