The selective serotonin-2A receptor antagonist M100907 reverses behavioral deficits in dopamine transporter knockout mice.
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-HT(2A) receptor antagonist M100907 to reverse behavioral deficits 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 M100907 (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 M100907 reversed the PPI deficits in DAT KO mice. These data indicate that selective 5-HT(2A) receptor antagonists, such as M100907, 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.
Barr
Alasdair M
AM
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA, USA.
Lehmann-Masten
Virginia
V
Paulus
Martin
M
Gainetdinov
Raul R
RR
Caron
Marc G
MG
Geyer
Mark A
MA
D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005464:Fluorobenzenes / Q000494:pharmacology* / Q000627:therapeutic use; D020233:Gait Disorders, Neurologic / Q000188:drug therapy*; D007266:Inhibition, Psychological; D008124:Locomotion / Q000187:drug effects; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D001523:Mental Disorders / Q000188:drug therapy; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D012022:Reflex, Acoustic / Q000187:drug effects; D012193:Reversal Learning / Q000187:drug effects; D058830:Serotonin 5-HT2 Receptor Antagonists; D013037:Spatial Behavior / Q000187:drug effects
D050483:Dopamine Plasma Membrane Transport Proteins; D005464:Fluorobenzenes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010880:Piperidines; D058830:Serotonin 5-HT2 Receptor Antagonists; C493215:Slc6a3 protein, mouse; C079049:volinanserin