This paper actually was a result of writing a proposal for a center grant on schizophrenia research. The center grant itself was an exciting project, in that I had the opportunity to interact with senior colleagues from a variety of basic and clinical disciplines, focused on developing an integrated research program in the study of schizophrenia. My particular role was to be in charge of writing a section that was to integrate physiology and neurochemistry of the dopamine system, in terms of cortical/subcortical interactions. In doing this, I ran into a wall in trying to bring the data together. This was a result of trying to resolve data showing that cortical afferents to subcortical regions can cause the release of dopamine, and could modulate the levels of dopamine present in the extracellular space in the striatum. However, there were also behavioral data showing that lesions of cortical regions tended to augment subcortical dopamine responses! In reviewing this literature, I noticed that the levels of dopamine triggered by cortical stimulation and measured in the extracellular space with dialysis tended to be several orders of magnitude lower than the amount of dopamine that is released into synapses by dopamine neuron firing. Therefore, it would be very unlikely that the low tonic extracellular levels of dopamine could augment the phasic dopamine released into the synapse by spike-dependent processes. On the other hand, the extracellular dopamine level is tightly regulated, since these tonic levels were maintained even in the face of massive lesions of the dopamine innervation. Therefore, one would predict that they would have biological significance. It occurred to me that one site at which such low tonic levels of dopamine could act would be at the presynaptic dopamine terminal. In fact, drawing from my earlier studies of dopamine autoreceptors, one would predict that this tonic level of extracellular dopamine would stimulate these autoreceptors, causing a decrease in spike-dependent dopamine release!

I thought that this hypothesis could explain a lot of what we know about cortical-subcortical dopamine interactions, as well as account for a lot of discrepancies between electrophysiological measures of dopamine cell firing and biochemical correlates of dopamine levels in the striatum. It also could provide an explanation for my previous data related to antipsychotic drug-induced depolarization block of dopamine neuron firing, and why the biochemistry studies didn't seem to correlate with the physiology as I would have predicted. But it was new territory for me, being an electrophysiologist, so I thought that I would try to present it as a poster at a neurosciences meeting, so that someone could point out the fatal flaw in my thinking in time to save the grant! To my great surprise, the poster was very well received, even though it was mostly text and models rather than interesting data. For this reason, I decided to try to write it up as a model paper. Although I enjoyed developing models before, they were always as a component of a data paper; this was my first attempt to write a purely theoretical paper. I also wanted it to have the attention of basic scientists as well as those with a research interest in schizophrenia. For this reason, I chose to submit it for consideration as a commentary in Neuroscience. I was happy to get it published, although I really didn’t expect it to be more than another interesting idea that would rapidly be forgotten soon after its publication. No one is more surprised than I about the attention it generated!

Although the paper was developed as a model of schizophrenia, this work has actually attracted a lot of attention from other disciplines. In particular, Dr. Jakie McGinty read my paper and thought that it might have implications for the field of drug abuse, and invited me to present at a CPDD meeting, in which I was to be the last speaker who would provide an "integrated overview" of how my tonic/phasic model could account for findings in drug abuse. Needless to say, such a prospect was frightening, as I knew nothing about the field. But, since a manuscript was expected as a result of the meeting, I spent a few months reading as much of the drug abuse literature as I could. The result was the publication of another model paper on tonic/phasic dopamine and its implications for drug abuse¹. As a result of this literature search, I began an interest in this line of research that has continued to the present day.

My real surprise was the impact that this work seems to have had on those performing imaging studies. It seems that the tonic/phasic model has been useful in accounting for many of the results currently being uncovered in this exciting discipline. In particular, Dr. Dean Wong has been kind enough to involve me as a consultant in several of his research projects that examine imaging of dopamine receptors in human patients, which I have found to be exciting and informative. This too has greatly shaped my thinking about the functions of this system.

So, like so much else in science, this idea was the product of circumstances related to the stress of resolving conflicting issues in time for submission of a grant, rather than any carefully planned intellectual exercise! Such ideas are also the outgrowth of the outstanding training by my mentors Dr. Steve Bunney and Dr. Rodolfo Llinas, and the inspiration of my friends and colleagues in this field who stimulated my interest in diverse disciplines, and with whom I continue to have stimulating and thought-provoking discussions.