Theoretically, drugs can interact with central nervous system (CNS) neurotransmitter receptors at successively greater levels of specificity, from the receptor system or class (e.g., dopamine vs. serotonin) to receptor subtype (e.g., D1 vs. D2 dopamine receptor) to receptor isoform (e.g., D2A vs. D2B) to variations in receptor coupling efficiency. The latter is particularly relevant for defining the potency and efficacy of agonist drugs. We developed several model assay systems, particularly for dopamine and serotonin receptor subtypes, to assess receptor coupling efficiency by receptor reserve analysis. Our results revealed that differences in receptor coupling efficiency are useful for explicating pharmacological variations in multiple responses mediated by apparently identical receptor subtypes and for identifying and quantifying partial agonist drugs.

Signal transduction, for many CNS neurotransmitter receptors, occurs via coupling to G proteins. Consequently, the stoichiometric relationship between receptor and G-protein molecules and the heterogeneity of a (as well as b and g) G-protein subunits are likely important determinants of receptor coupling efficiency. We are testing this hypothesis (for D2B receptors) by examining the relationship between receptor density, G-protein concentration and identity and receptor coupling efficiency in a cell line transfected with appropriate cDNA constructs to alter the expression of receptors and G proteins bidirectionally. We are also evaluating the effects of such alterations on several cellular responses, including hormone release, cAMP formation, and K+ and Ca+2 ion channel function.