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

Abstract

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+/+). 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. 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. 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.