Allosteric modulation of human dopamine transporter activity under conditions promoting its dimerization.

The human dopamine (DA) transporter (hDAT) is a key regulator of neurotransmission and a target for antidepressants and addictive drugs. Despite the recent resolution of dDAT structures from Drosophila melanogaster, complete understanding of its mechanism of function and even information on its biological assembly is lacking. The resolved dDAT structures are monomeric, but growing evidence suggests that hDAT might function as a multimer, and its oligomerization may be relevant to addictive drug effects. Here, using structure-based computations, we examined the possible mechanisms of hDAT dimerization and its dynamics in a lipid bilayer. Using a combination of site-directed mutagenesis, DA-uptake, and cross-linking experiments that exploited the capacity of Cys-306 to form intermonomeric disulfide bridges in the presence of an oxidizing agent, we tested the effects of mutations at transmembrane segment (TM) 6 and 12 helices in HEK293 cells. The most probable structural model for hDAT dimer suggested by computations and experiments differed from the dimeric structure resolved for the bacterial homolog, LeuT, presumably because of a kink at TM12 preventing favorable monomer packing. Instead, TM2, TM6, and TM11 line the dimer interface. Molecular dynamics simulations of the dimeric hDAT indicated that the two subunits tend to undergo cooperative structural changes, both on local (extracellular gate opening/closure) and global (transition between outward-facing and inward-facing states) scales. These observations suggest that hDAT transport properties may be allosterically modulated under conditions promoting dimerization. Our study provides critical insights into approaches for examining the oligomerization of neurotransmitter transporters and sheds light on their drug modulation.

Adapting Mindfulness-Based Cognitive Therapy for Perinatal Depression to Improve Access and Appeal of Preventive Care.

Existing and emerging evidence indicates that perinatal depression is a key contributor to preventable morbidity and mortality during and after childbearing. Despite this, there are few effective options for prevention and treatment that are readily accessible for and appealing to pregnant people. Aspects of routine health care systems contribute to this situation. Furthermore, societal and health care systems factors create additional barriers for people of color, people living in rural regions, and people living in poverty. Our interprofessional team of perinatal care providers, mental health providers, community partners, health services scientists, health equity scientists, and business leaders developed and are piloting a perinatal mental health preventive intervention designed to increase access and appeal of a program incorporating mindfulness cognitive behavioral therapy with proven efficacy in preventing perinatal depression. In this article, we briefly summarize key systems barriers to delivering preventive care for perinatal depression in standard prenatal care clinics. We then describe Mindfulness-Based Cognitive Therapy for Perinatal Depression and outline our adaptation of this intervention, Center M. Finally, we identify next steps, challenges, and opportunities for this recent innovation.

Stakeholder Perspectives on Advancing Understanding of Prenatal Opioid Exposure and Brain Development From the iOPEN Consortium of the Healthy Brain and Child Development Study.

Introduction: There is a dire need for research regarding the implications of opioid use during pregnancy on fetal and childhood development to better inform both medical practice and policy. The Healthy Brain and Child Development Study will examine brain and behavioral development from birth through the first decade of life. Due to large scope and anticipated complexity of this initiative, an 18-month planning phase was implemented across 28 sites across the nation. A core element of the Phase I initiative involved the development of Stakeholder Advisory Committees to inform the next phase of the initiative. Methods: Phase I stakeholder meetings were conducted at Oregon Health and Science University, New York University Langone Medical Center, the University of Pittsburgh, and the University of Vermont to better understand perspectives and inform upcoming research. Despite differences in the structure of the stakeholder meetings by site, the overarching goals for the meetings included establishing relationships, gathering input, and learning about research engagement. Documents from each meeting were reviewed for location, duration, attendees, common research themes, and pertinent suggestions for improving research approaches. Results: All stakeholders had high levels of interest in research for pregnant people with substance use disorders and agreed on research priorities including collaboration, connection, communication, and support. Different stakeholders offered unique perspectives on various aspects of study design and themes that emerged through meetings. Discussion: Overall, there was excitement about the research, especially the opportunity to include the voices of people with lived experience; collaboration between providers, peer support specialists, patients, and others; and excitement around contributing to research that could elucidate new and pertinent findings in the realm of addiction medicine and child development. Sites also found that there is mistrust between people with substance use disorder and the medical system, and this could be addressed by including people with lived experience on the research team, forming connections, communicating clearly, training the research team in implicit bias, and practicing trauma-informed care. In conclusion, these stakeholder meetings provided valuable information for structuring upcoming studies; however, researchers would have benefitted from more time and more opportunities for in-person connection.