The poor effectiveness of antidepressants is hypothesized to be attributable, in part, to high volume transporters with low selectivity (i.e., “uptake‐2” mechanisms) that undermine antidepressant blockade of highly selective, low volume transporters (i.e., “uptake‐1” transporters) such as the serotonin transporter. Compared to other uptake‐2 transporters in brain, plasma membrane monoamine transporter (PMAT, Slc29a4) preferentially transports serotonin and dopamine, both heavily implicated in the pathophysiology of depression. Therefore, we hypothesized that reduced function of PMAT would enhance the ability of antidepressants to elicit antidepressant‐like behaviors in a forced swim or tail suspension test, and to impair clearance of extracellular serotonin. Because a selective pharmacologic inhibitor of PMAT has yet to be identified, genetic knockout of PMAT is currently the best available method for investigating PMAT's functional role. Using a mouse line recently developed in the lab of Dr. Joanne Wang, we compared male and female wildtype (+/+) controls against mice with reduced (+/−) or completely ablated (−/−) PMAT function to evaluate how PMAT deficiency affects behavioral responses to antidepressants in the forced swim and tail suspension tests. Sub‐effective doses of the serotonin transporter inhibitors fluvoxamine or escitalopram, or the dopamine/norepinephrine transporter inhibitor bupropion, were given 30 min prior to a forced swim or tail suspension test. Behaviors were scored by observers blind to sex, genotype, and treatment. Preliminary findings indicate that male −/− mice may selectively exhibit antidepressant‐like responses to bupropion and fluvoxamine through an increase in swimming behavior. In contrast, female −/− mice appear to exhibit a depressive‐like response specifically to bupropion. These studies are continuing. Ongoing experiments are measuring serotonin clearance in the nucleus accumbens of male +/+ and −/− mice using in vivo high‐speed chronoamperometry in the presence or absence of uptake‐1 inhibitors. These initial results support our hypothesis and suggest an unexpected sex‐specific contribution of PMAT function in the poor effectiveness of uptake‐1 targeting antidepressant drugs. Though chronoamperometry experiments are still in early stages, these will afford insight into possible neurochemical differences that could explain these intriguing sex differences. Given our early behavioral findings, greater focus on drug discovery for PMAT‐selective inhibitors could reveal compounds that are useful as antidepressant adjuvants. Future work will focus on identifying potential mechanisms through which these sex‐ and genotype‐dependent antidepressant responses are mediated.Support or Funding InformationThis work was supported by a Brain & Behavior Research Foundation and Vital Projects Fund, Inc., NARSAD Young Investigator Grant (26249) to TLG and National Institute of Mental Health grants (R01 MH093320 and R01 MH106978) to LCD. TLG is supported by a National Institute on Drug Abuse grant (T32 DA031115) to Charles P. France.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.