Valproate attenuates hyperactive and perseverative behaviors in mutant mice with a dysregulated dopamine system.
BACKGROUND
Dopamine transporter (DAT) knockdown (KD) mice, with approximately 90% loss of expression of the DAT, allow for the examination of the behavioral consequences of a chronically dysregulated dopamine system. The DAT KD mice have hyperdopaminergic tone, are hyperactive, and show impaired response inhibition in a number of paradigms. We hypothesized that the DAT KD mice would also display deficits in prepulse inhibition (PPI) and would be perseverative in their locomotor behavior.


METHODS
Basal levels of PPI and patterns of locomotor behavior were measured in two cohorts of DAT KD mice. In addition, measurements of locomotor behavior were recorded after pretreatment with 100 mg/kg valproate in both DAT KD and wildtype mice.


RESULTS
The DAT KD mice were hyperactive and displayed perseverative motor behavior but had normal levels of PPI. The clinically effective antimania drug valproate significantly attenuated the hyperactivity and perseverative locomotor behavior in the DAT KD mice and had no effect in control mice.


CONCLUSIONS
The DAT KD mice appear to provide a model of some aspects of manic behavior. With limited models of bipolar disorder, the DAT KD mice might provide a vehicle to screen for new psychiatric therapies to treat mania and its related symptoms.
Ralph-Williams
Rebecca J
RJ
Alcohol and Drug Abuse Research Center, Harvard Medical School and McLean Hospital, Belmont, Massachusetts, USA.
Paulus
Martin P
MP
Zhuang
Xiaoxi
X
Hen
Rene
R
Geyer
Mark A
MA
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D004298:Dopamine / Q000235:genetics* / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D006948:Hyperkinesis / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins; D010641:Phenotype; D051381:Rats; D013216:Reflex, Startle / Q000187:drug effects* / Q000235:genetics*; D014635:Valproic Acid / Q000494:pharmacology*
D018692:Antimanic Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493215:Slc6a3 protein, mouse; C493216:Slc6a3 protein, rat; D014635:Valproic Acid; D004298:Dopamine