Dopamine neurotransmission is highly dysregulated by the psychostimulant methamphetamine, a substrate for the dopamine transporter (DAT). Through interactions with DAT, methamphetamine increases extracellular dopamine levels in the brain, leading to its rewarding and addictive properties. Methamphetamine also interacts with the sigma-1 receptor (σ1R), an inter-organelle signaling modulator. Using complementary strategies, we identified a novel mechanism for σ1R regulation of dopamine neurotransmission in response to methamphetamine. We found that σ1R activation prevents methamphetamine-induced, DAT-mediated increases in firing activity of dopamine neurons. In vitro and in vivo amperometric measurements revealed that σ1R activation decreases methamphetamine-stimulated dopamine efflux without affecting basal dopamine neurotransmission. Consistent with these findings, σ1R activation decreases methamphetamine-induced locomotion, motivated behavior, and enhancement of brain reward function. Notably, we revealed that the σ1R interacts with DAT at or near the plasma membrane and decreases methamphetamine-induced Ca2+ signaling, providing potential mechanisms. Broadly, these data provide evidence for σ1R regulation of dopamine neurotransmission and support the σ1R as a putative target for the treatment of methamphetamine addiction.

This article provides an overview of issues facing medical students in such key areas as communication, preclinical and clinical education, increased isolation, disruption to time-based curricula, inequities in virtual learning, racial trauma, medical student activism, increased conversations surrounding race and racism, LGBTQIA+ students, dual-degree students, and the virtual residency cycle. This article described challenges navigated by medical students during the COVID-19 pandemic, as well as triumphs resulting from the disruption and actionable recommendations in key areas. While the pandemic presented new challenges for medical students, it also uncovered or exacerbated long-standing problems. The intent is for medical schools and institutions to use these recommendations to create learning environments that do not depend on medical student resilience. The main takeaways for medical schools are to: (1) maintain an individualized and learner-centered ethos while remaining dynamic, flexible, and ready to embrace both immediate and incremental changes; (2) maintain open lines of communication; (3) implement policies and practices that support students’ academic, physical, and mental well-being; (4) engage and support students who bear historically disadvantaged identities on the basis of race, ethnicity, sexual orientation, gender, or disability; and (5) support creative and collaborative partnerships between medical institutions and students to ensure the ongoing evolution of medical education to meet the needs of learners and patients.

The proximal tibiofibular joint (PTFJ) is susceptible to osteoarthritis (OA), making it a rare but potential source of lateral knee pain. Because PTFJ OA is a rare presentation of knee pain, no first-line treatment has been established and it can be missed in evaluation before total knee arthroplasty. We report an unusual case of a 59-year-old man who presented with advanced OA of both the knee and PTFJ, along with a progressive peroneal nerve palsy due to a large compressive ganglion cyst from the PTFJ. He was treated with concurrent total knee arthroplasty, peroneal nerve decompression, and resection of the fibular head and ganglion cyst, resulting in full recovery from his arthritic pain and resolution of his peroneal neuropathy. He remains free of symptoms without instability 3 years from the index surgery.