title: Serotonin/dopamine interactions in a hyperactive mouse: reduced serotonin receptor 1B activity reverses effects of dopamine transporter knockout.
abstract: Knockout (KO) mice that lack the dopamine transporter (SL6A3; DAT) display increased locomotion that can be attenuated, under some circumstances, by administration of drugs that normally produce psychostimulant-like effects, such as amphetamine and methylphenidate. These results have led to suggestions that DAT KO mice may model features of attention deficit hyperactivity disorder (ADHD) and that these drugs may act upon serotonin (5-HT) systems to produce these unusual locomotor decreasing effects. Evidence from patterns of brain expression and initial pharmacologic studies led us to use genetic and pharmacologic approaches to examine the influence of altered 5-HT1B receptor activity on hyperactivity in DAT KO mice. Heterozygous 5-HT1B KO and pharmacologic 5-HT1B antagonism both attenuated locomotor hyperactivity in DAT KO mice. Furthermore, DAT KO mice with reduced, but not eliminated, 5-HT1B receptor expression regained cocaine-stimulated locomotion, which was absent in DAT KO mice with normal levels of 5-HT1B receptor expression. Further experiments demonstrated that the degree of habituation to the testing apparatus determined whether cocaine had no effect on locomotion in DAT KO or reduced locomotion, helping to resolve differences among prior reports. These findings of complementation of the locomotor effects of DAT KO by reducing 5-HT1B receptor activity underscore roles for interactions between specific 5-HT receptors and dopamine (DA) systems in basal and cocaine-stimulated locomotion and support evaluation of 5-HT1B antagonists as potential, non-stimulant ADHD therapeutics.
authors.affiliation: Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio, United States of America; Molecular Neurobiology Branch, National Institute on Drug Abuse - Intramural Research Program, Baltimore, Maryland, United States of America.
authors.forename: Frank Scott
authors.initials: FS
authors.lastname: Hall
authors.affiliation: Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sora
authors.affiliation: Departments of Pharmacology, Neuroscience and Pharmacology, Columbia University, New York, New York, United States of America; Division of Integrative Neuroscience, The New York State Psychiatric Institute, New York, New York, United States of America.
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.affiliation: Molecular Neurobiology Branch, National Institute on Drug Abuse - Intramural Research Program, Baltimore, Maryland, United States of America.
authors.forename: George R
authors.initials: GR
authors.lastname: Uhl
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics; D010881:Piperidones / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D010881:Piperidones; D044302:Receptor, Serotonin, 5-HT1B; C108518:SB 22489G; D058829:Serotonin 5-HT1 Receptor Antagonists; D013141:Spiro Compounds; D012701:Serotonin; D003042:Cocaine; D004298:Dopamine