title: Implications of cellular models of dopamine neurons for schizophrenia.
abstract: Midbrain dopamine neurons are pacemakers in vitro, but in vivo they fire less regularly and occasionally in bursts that can lead to a temporary cessation in firing produced by depolarization block. The therapeutic efficacy of antipsychotic drugs used to treat the positive symptoms of schizophrenia has been attributed to their ability to induce depolarization block within a subpopulation of dopamine neurons. We summarize the results of experiments characterizing the physiological mechanisms underlying the ability of these neurons to enter depolarization block in vitro, and our computational simulations of those experiments. We suggest that the inactivation of voltage-dependent Na(+) channels, and, in particular, the slower component of this inactivation, is critical in controlling entry into depolarization block. In addition, an ether-a-go-related gene (ERG) K(+) current also appears to be involved by delaying entry into and speeding recovery from depolarization block. Since many antipsychotic drugs share the ability to block this current, ERG channels may contribute to the therapeutic effects of these drugs.
authors.affiliation: Department of Cell Biology and Anatomy, Neuroscience Center of Excellence, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Yu
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Kristal R
authors.initials: KR
authors.lastname: Tucker
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Levitan
authors.affiliation: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Shepard
authors.affiliation: Department of Cell Biology and Anatomy, Neuroscience Center of Excellence, LSU Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Canavier
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008959:Models, Neurological; D012559:Schizophrenia / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology
chemical_list: D014150:Antipsychotic Agents
keywords: Antipsychotic drugs; Bursting; Depolarization block; Ether-a-go-go-related gene (ERG) potassium current; K(v)11; Pacemaker; Substantia nigra; Ventral tegmental area