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NIDA T32 Postdoctoral Trainee Lee Gilman, PhD was awarded a 2017 NARSAD Young Investigator Award from the Brain & Behavior Research Foundation

Lee Gilman, Ph.D., in the laboratory of Lynette C. Daws, Ph.D., is a recipient of a 2017 NARSAD Young Investigator Award from the Brain & Behavior Research Foundation. Dr. Gilman’s project, titled “Probing the contribution of PMAT function to depressive behaviors and poor antidepressant efficacy”, will commence in January 2018. The following is a summary of her proposal:

Current antidepressant drugs are ineffective in a majority of individuals suffering from depression. Most antidepressants block highly selective, low volume transporters (i.e., uptake-1 mechanisms) such as the dopamine transporter or serotonin transporter. This is believed to prolong signaling by dopamine or serotonin, ultimately eliciting antidepressant effects. Recently, however, high volume transporters with less selectivity (i.e., uptake-2 mechanisms) have been identified. Their compensatory role in neurotransmitter uptake is thought to be pronounced under conditions of reduced uptake-1 function (e.g., antidepressant treatment). Therefore, the poor efficacy of antidepressants is hypothesized to be attributable, in part, to uptake-2 mechanisms by undermining antidepressant blockade of uptake-1 transporters. Little is currently known about the behavioral or neurochemical consequences of selectively blocking different uptake-2 transporters, which include the plasma membrane monoamine transporter (PMAT) and organic cation transporter 3 (OCT3). Both highly expressed in the brain, PMAT preferentially transports dopamine and serotonin, whereas OCT3 preferentially transports histamine, epinephrine, and norepinephrine. As selective pharmacologic inhibitors for these transporters have not yet been identified, genetic knockout of these transporters is one of the best currently available methods for investigating their functional roles in behavior and neurotransmission. Of particular interest are the consequences of PMAT deficiency, given its preferential transport of the neurotransmitters dopamine and serotonin, each heavily implicated in the pathophysiology of depression. Using a recently developed mouse line with PMAT function reduced or completely ablated, we will compare against wildtype controls to evaluate how PMAT deficiency affects depressive-like and other neuropsychiatric-relevant behaviors (e.g., anxiety-like, social, and compulsive behaviors). In addition, we will probe the neurochemical changes resulting from decreased PMAT function by measuring uptake of dopamine and serotonin, and evaluate how PMAT reductions impact neurochemical responses to antidepressants. These pioneering investigations will be the first to uncover the influence of PMAT function in vivo on emotion-related behaviors, homeostatic uptake of dopamine and serotonin, and neurochemical responses to uptake-1-targeting antidepressants.