title: Monoaminergic dysregulation in glutathione-deficient mice: possible relevance to schizophrenia?
abstract: Several lines of research have implicated glutathione (GSH) in schizophrenia. For instance, GSH deficiency has been reported in the prefrontal cortex of schizophrenics in vivo. Further, in rats postnatal GSH-deficiency combined with hyperdopaminergia led to cognitive impairments in the adult. In the present report we studied the effects of 2-day GSH-deficiency with L-buthionine-(S,R)-sulfoximine on monoaminergic function in mice. The effect of GSH-deficiency per se and when combined with the amphetamine and phencyclidine (PCP) models of schizophrenia was investigated. GSH-deficiency significantly altered tissue levels of dopamine (DA), 5-hydroxytryptamine (5-HT) and their respective metabolites homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in a region-specific fashion. The effects of GSH-deficiency on tissue monoamines were distinct from and, generally, did not interact with the effects of amphetamine (5 mg/kg; i.p.) on tissue monoamines. Microdialysis studies showed that extracellular DA-release after amphetamine (5 mg/kg, i.p.) was two-fold increased in the nucleus accumbens of GSH-deficient mice as compared with control mice. Basal DA was unaltered. Further, extracellular levels of HVA in the frontal cortex and hippocampus and 5-HIAA in the nucleus accumbens were elevated by GSH-deficiency per se. Spontaneous locomotor activity in the open field was unchanged in GSH-deficient mice. In contrast, GSH-deficiency modulated the locomotor responses to mid-range doses of amphetamine (1.5 and 5 mg/kg, i.p.). Further, GSH-deficient mice displayed an increased locomotor response to low (2 and 3 mg/kg, i.p.) doses of phencyclidine (PCP). In conclusion, the data presented here show that even short-term GSH-deficiency has consequences for DA and 5-HT function. This was confirmed on both neurochemical and behavioral levels. How GSH and the monoamines interact needs further scrutiny. Moreover, the open field findings suggest reduced or altered N-methyl-d-aspartate (NMDA) receptor function in GSH-deficient mice. Thus, GSH-deficiency can lead to disturbances in DA, 5-HT and NMDA function, a finding that may have relevance for schizophrenia.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Cell Biology and Medicine (Endocrinology), Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, USA. jprj@u.washington.edu
authors.forename: J P R
authors.initials: JP
authors.lastname: Jacobsen
authors.forename: R M
authors.initials: RM
authors.lastname: Rodriguiz
authors.forename: A
authors.initials: A
authors.lastname: Mørk
authors.forename: W C
authors.initials: WC
authors.lastname: Wetsel
mesh_terms: D000661:Amphetamine / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D005978:Glutathione / Q000172:deficiency*; D006213:Hallucinogens / Q000633:toxicity; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010622:Phencyclidine / Q000633:toxicity; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012559:Schizophrenia / Q000139:chemically induced / Q000503:physiopathology*; D012701:Serotonin / Q000032:analysis / Q000378:metabolism*
chemical_list: D006213:Hallucinogens; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D000661:Amphetamine; D005978:Glutathione; D010622:Phencyclidine; D004298:Dopamine; D006719:Homovanillic Acid