title: Hyperdopaminergia and altered locomotor activity in GABAB1-deficient mice.
abstract: GABAB1-/- mice, which are devoid of functional GABAB receptors, consistently exhibit marked hyperlocomotion when exposed to a novel environment. Telemetry recordings now revealed that, in a familiar environment, GABAB1-/- mice display an altered pattern of circadian activity but no hyperlocomotion. This indicates that hyperlocomotion is only triggered when GABAB1-/- mice are aroused by novelty. In microdialysis experiments, GABAB1-/- mice exhibited a 2-fold increased extracellular level of dopamine in the striatum. Following D-amphetamine administration, GABAB1-/- mice released less dopamine than wild-type mice, indicative of a reduced cytoplasmic dopamine pool. The hyperdopaminergic state of GABAB1-/- mice is accompanied by molecular changes, including reduced levels of tyrosine hydroxylase mRNA, D1 receptor binding-sites and Ser40 phosphorylation of tyrosine hydroxylase. Tyrosine hydroxylase activity, tissue dopamine content and dopamine metabolism do not appear to be measurably altered. Pharmacological and electrophysiological experiments support that the hyperdopaminergic state of GABAB1-/- mice is not severe enough to inactivate dopamine D2 receptors and to disrupt D2-mediated feedback inhibition of tyrosine hydroxylase activity. The data support that loss of GABAB activity results in a sustained moderate hyperdopaminergic state, which is phenotypically revealed by contextual hyperlocomotor activity. Importantly, the presence of an inhibitory GABA tone on the dopaminergic system mediated by GABAB receptors provides an opportunity for therapeutic intervention.
authors.affiliation: Institute of Physiology, Department of Clinical Biological Sciences, University of Basel, Basel, Switzerland.
authors.forename: Claire-Marie
authors.initials: CM
authors.lastname: Vacher
authors.forename: Martin
authors.initials: M
authors.lastname: Gassmann
authors.forename: Sandrine
authors.initials: S
authors.lastname: Desrayaud
authors.forename: Etienne
authors.initials: E
authors.lastname: Challet
authors.forename: Amyaouch
authors.initials: A
authors.lastname: Bradaia
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoyer
authors.forename: Peter
authors.initials: P
authors.lastname: Waldmeier
authors.forename: Klemens
authors.initials: K
authors.lastname: Kaupmann
authors.forename: Paul
authors.initials: P
authors.lastname: Pévet
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001928:Brain Diseases, Metabolic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D006948:Hyperkinesis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009433:Neural Inhibition / Q000235:genetics; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017447:Receptors, Dopamine D1 / Q000737:chemistry / Q000378:metabolism; D018080:Receptors, GABA-B / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine