Behavioral and neurochemical effects of 5-{4-[4-(5-cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl}-benzofuran-2 -carboxamide (EMD 68843): A combined selective inhibitor of serotonin reuptake and 5-hydroxytryptamine_1A receptor partial agonist

5-{4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl}-benzofuran-2 -carboxamide (EMD 68843; vilazodone) is a novel compound with combined high affinity and selectivity for the 5-hydroxytryptamine (5-HT) transporter and 5-HT_1A receptors. EMD 68843 was tested as a prototype compound, which benefits from dual pharmacological effects that could increase extracellular 5-HT to levels higher than those produced by conventional selective serotonin reuptake inhibitors (SSRIs). In Sf9 cells, EMD 68843 increased guanosine 5′-O-(3-[³⁵S]thiotriphosphate) binding to 69% of the magnitude of the full 5-HT_1A receptor agonist R-(1)-trans-8-hydroxy-2-[N-n-propyl-N-(39 iodo-29-propenyl)] aminotetralin (8-OH-PIPAT), indicating that it is a partial agonist at 5-HT_1A receptors. Acute, systemic administration of EMD 68843 produced a larger maximal increase of extracellular 5-HT than the SSRI fluoxetine in both the ventral hippocampus (HPv) (558 versus 274%) and the frontal cortex (FC) (527 versus 165%). Regional differences in the response to the two drugs were also observed. These effects may be attributed to the differential regulation of 5-HT release in the HPv and FC by 5-HT_1A autoreceptors. When challenged with the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), EMD 68843-induced increases in extracellular 5-HT were greatly reduced in the HPv but to a lesser extent in the FC. In behavioral studies, EMD 68843 produced antidepressant-like effects in the forced swimming test in both rats and mice but only within a narrow dosage range. Like fluoxetine, EMD 68843 did not produce the symptoms of the 5-HT behavioral syndrome in rats but, unlike fluoxetine, pretreatment with EMD 68843 blocked expression of the 5-HT behavioral syndrome induced by 8-OH-DPAT. Taken together, the results show that EMD 68843 augments extracellular 5-HT levels in forebrain regions to a greater extent than fluoxetine. At higher doses, however, weak efficacy of EMD 68843 at postsynaptic 5-HT_1A receptors may inhibit the expression of rodent antidepressant-like behaviors.