期刊
NEUROPSYCHOPHARMACOLOGY
卷 29, 期 2, 页码 221-228出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.npp.1300343
关键词
animal model; behavior; dopamine transporter; mice; M 100907; serotonin-2A receptor; prepulse inhibition; startle
资金
- NIDA NIH HHS [DA02925] Funding Source: Medline
- NIMH NIH HHS [MH60451, MH61326] Funding Source: Medline
A hyperdopaminergic state in humans has been hypothesized to contribute to the pathology of a number of psychiatric illnesses, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. Mice that display elevated synaptic levels of dopamine due to a genetically engineered deletion of the dopamine transporter (DAT) model behavioral deficits that simulate the above conditions. As novel treatment strategies for these disorders have focused on the serotonin (5-HT) 2A receptor, we determined the capacity of the highly selective 5-HT2A receptor antagonist M 100907 to reverse behavioral defcits in DAT knockout (KO) mice. Prior to drug treatment, DAT KO mice exhibited increased levels of locomotor activity and highly linearized movement in a novel environment, as well as reduced prepulse inhibition (PPI) of acoustic startle, compared to wild-type littermates. Treatment with M 100907 (0.3-1.0 mg/kg, but not 0.1 mg/kg) reversed locomotor deficits in DAT KO mice. Similarly, treatment with 1.0 mg/kg M 100907 reversed the PPI deficits in DAT KO mice. These data indicate that selective 5-HT2A receptor antagonists, such as M 100907, may represent a class of drugs that can be used to treat conditions in which a chronic, elevated dopaminergic tone is present and contributes to abnormal behavior and sensorimotor gating deficits.
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