5-HT2A/2C receptor signaling via phospholipase A2 and arachidonic acid is attenuated in mice lacking the serotonin reuptake transporter

Subjects: 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 A(2) (PLA(2)) 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-HT2A/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-HT2A/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-HT2A/2C receptor-mediated PLA(2) signaling via AA and of head twitches, in response to DOI.