Table_1_Integrin αVβ3 Function Influences Citalopram Immobility Behavior in the Tail Suspension Test.DOCX

Human studies first identified genetic and expression interactions between integrin β3 and serotonin (5-HT) transporter (SERT) genes. This association has been further strengthened by our discovery that integrin β3-containing receptors (αvβ3) physically interact with, and thereby define, a subpopulation of SERTs that may represent the main target of selective serotonin reuptake inhibitors (SSRIs). In this study, we examine how integrin αvβ3 function influences the behavioral response to the highly SSRI citalopram in the tail suspension test. Mice bearing a conditional deletion of the integrin β3 gene in neurons, or those expressing a constitutively active αvβ3 receptor, have decreased sensitivity to citalopram, when compared to wild-type littermates. To identify potential signaling pathways downstream of integrin αvβ3 that could be altered in these mouse lines, and consequently influence citalopram response in vivo, we performed antibody array analyses of midbrain synaptosomes isolated from mice bearing genetically altered integrin β3. We then pharmacologically targeted focal adhesion (FAK) and extracellular-signal-regulated (ERK) kinases and determined that FAK and ERK activity are critical for the actions of citalopram. Taken together, our studies have revealed a complex relationship between integrin αvβ3 function, SERT-dependent 5-HT uptake, and the effective dose of citalopram in the TST, thus implicating a role for integrin signaling pathways in the behavioral response to SSRIs.