5-HT2A/2C receptor signaling via phospholipase A2 and arachidonic acid is attenuated in mice lacking the serotonin reuptake transporter.
METHODS
The serotonin reuptake transporter (SERT) helps to regulate brain serotonergic transmission and is the target of some antidepressants. To further understand SERT function, we measured a marker of regional brain phospholipase A2 (PLA2) activation in SERT knockout mice (SERT-/-) and their littermate controls (SERT+/+).


METHODS
Following administration of 1.5 mg/kg s.c. (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), a 5-HT(2A/2C) receptor agonist, to unanesthetized mice injected intravenously with radiolabeled arachidonic acid (AA), PLA2 activation, represented as the regional incorporation coefficient k* of AA, was determined with quantitative autoradiography in each of 71 brain regions.


RESULTS
In SERT+/+ mice, DOI significantly increased k* in 27 regions known to have 5-HT(2A/2C) receptors, including the frontal, motor, somatosensory, pyriform and cingulate cortex, white matter, nucleus accumbens, caudate putamen, septum, CA1 of hippocampus, thalamus, and hypothalamus. In contrast, DOI did not increase k* significantly in any brain region of SERT-/- mice. Head twitches following DOI, which also were measured, were robust in SERT+/+ mice but were markedly attenuated in SERT-/- mice.


CONCLUSIONS
These results show that a lifelong elevation of the synaptic 5-HT concentration in SERT-/- mice leads to downregulation of 5-HT(2A/2C) receptor-mediated PLA2 signaling via AA and of head twitches, in response to DOI.
Qu
Ying
Y
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Building 9, Room 1S128, Bethesda, MD, 20892, USA. yqu1@prdus.jnj.com
Villacreses
Nelly
N
Murphy
Dennis L
DL
Rapoport
Stanley I
SI
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000096:biosynthesis*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010741:Phospholipases A / Q000096:biosynthesis*; D054467:Phospholipases A2; D011877:Radionuclide Imaging; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology*; D058826:Serotonin 5-HT2 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*
D000662:Amphetamines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D016718:Arachidonic Acid; D010741:Phospholipases A; D054467:Phospholipases A2; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine