by Tom Ray

Let's consider a brain-centered reference frame, in which the origin is based on some arbitrary absolute levels of activity at each receptor population. The origin could be the time-averaged activity at each receptor, or no activity at each receptor, it doesn't matter much. In this reference frame, the state of the brain is constantly on the move, regardless of medication. We can think of it as a complex dynamical system, in which the trajectory likely does not traverse the entire receptor space, but rather follows certain high-dimensional orbits, and switches among many "attractors", where the attractors represent the major emotional states and moods, and whatever other mental phenomena the chemical systems are mediating. Mental illnesses can be thought of as pathological attractors.

In this more dynamic reference frame, the notion of drugs perturbing the brain along a vector of binding affinities in receptor space seems simplistic. It is more likely that drugs will create a perturbation along the binding vector, thereby pushing the system into a new attractor.

As pharmacologists, we want to understand how patterns of activity at receptor populations associate with mental phenomena. We want to get to know the pharmacology of the attractors. It seems unlikely that the attractors will be on-axis, resulting from changes in the activity of single receptor populations.

We have our hands on the receptors and we are enchanted by them. We have come to think of selectivity in terms of receptors, and in the process we have lost sight of the mind that we wish to understand. There are other approaches to thinking about pharmacological selectivity. Selectivity can be defined in terms of different or distinct behavioral or subjective mental effects produced by drugs.

The conventional approach to pharmacology is to find a drug that is receptor selective, and then observe its behavioral effect. An alternative approach is to find a drug that produces a distinctive behavior, and then observe its receptor binding profile. I believe that it is this alternative approach that holds the greatest promise for understanding the pharmacology of the attractors, and thus the major mental states mediated by receptors. The two approaches are complementary, and we need both to provide the most comprehensive understanding. The new approach is only now becoming possible, as it requires the full post-genome pharmacology provided by PDSP.