Larry Stein: pioneer neuropsychopharmacology researcher, mentor, and friend

Abstract

On May 30, 2019, the field of neuropsychopharmacology lost Professor Larry Stein, Professor Emeritus of Pharmacology, University of California, Irvine, College of Medicine, and American College of Neuropsychopharmacology (ACNP) Fellow Emeritus. Dr. Stein was accepted for ACNP membership in 1963. His research career spanned over five decades. His pioneering research places him among the most prominent and seminal researchers at the origins of our field of neuropsychopharmacology. He was a brilliant pharmacologist, dynamic leader and mentor, and wonderful, well-loved human being. Indeed, one might argue that he was the driving force in the new scientific pursuit of the intersection of behavior, pharmacology, and neurochemistry, which ultimately became the field of neuropsychopharmacology as we know it today. His personal qualities of quick insight, genuine care, passion for research, and great sense of humor place him forever in the hearts of those who knew him. Dr. Stein was born in 1931 in New York. He attended New York University, earning a B.A. in 1952. He subsequently was awarded a Ph.D. under the mentorship of Dr. Kenneth Spence at the University of Iowa. Dr. Spence was one of the most prominent American psychologists of his time, known for both his theoretical and experimental contributions to learning theory and motivation. Dr. Spence built on the work of Clark Hull and hypothesized that learning was the result of the interaction between drive and incentive motivation. Dr. Stein then performed postdoctoral work at the Walter Reed Army Institute of Research with two other very prominent and towering figures in behavioral biology, Dr. Joseph Brady and Dr. Murray Sidman. This lineage of training provided Dr. Stein with the skills and theoretical framework to make his own very seminal discoveries. In 1957, Dr. Stein served as Supervisory Research Psychologist, Veterans Administration Research Laboratories in Neuropsychiatry, in Pittsburgh. From 1959 to 1979, he worked at Wyeth Laboratories in Radnor, PA, where he became Senior Research Scientist and Head of the Department of Psychopharmacology. During this period, he was also a Visiting Lecturer and Adjunct Professor, Department of Psychology, Bryn Mawr College, in PA and Adjunct Professor, Departments of Psychiatry and Psychology, University of Pennsylvania. In 1979, he moved to Irvine, CA, where he served as Professor and Chair (1979–2000) of the Department of Pharmacology, College of Medicine, University of California, Irvine, and Adjunct Professor, Department of Psychiatry and Human Behavior, University of California, Irvine. In 2000, he retired as Chair and took the position of Chief Scientific Officer, Corporate Affairs and Initiatives, at the UC Irvine College of Medicine until 2007. From 2007 until his passing, he was Professor Emeritus of Pharmacology, UC Irvine College of Medicine. Dr. Stein was one of the most influential and forward-thinking scientists of the past 50 years. The discovery of brain stimulation reward by Jim Olds and Peter Milner in 1954 provided a significant boost to the hypothesis that there were neural systems in the brain that mediated positive reinforcement, but it was the seminal work of Larry Stein that linked brain stimulation reward to specific neurochemical systems, notably catecholamines. Dr. Stein discovered that amphetamine, a catecholamine-enhancing drug, facilitated self-stimulation behavior by lowering the threshold current intensity for brain stimulation reinforcement. He also showed that brain stimulation not only could serve as a primary reinforcer but also could establish secondary reinforcing powers to previously neutral stimuli (process of conditioned reinforcement), further supporting the hypothesis that brain stimulation reward tapped into neurocircuitry that mediated natural reinforcement. Linking the observation that dopamine and norepinephrine fibers ascend in the brain via the lateral hypothalamic medial forebrain bundle and the observation that this pathway generated the highest rates of self-stimulation, Dr. Stein hypothesized that positive reinforcement, also termed reward, was mediated by brain catecholamine systems. Furthermore, he demonstrated that amphetamines worked via the indirect release of catecholamines. This hypothesis and its explanation for the behavioral effects of psychostimulants and, more importantly, the reinforcing actions of psychostimulants launched the modern era of our