The amygdala: A model system for novel dopamine receptor pharmacology

D1 dopamine receptors are defined as seven trans-membrane spanning (7TM) G-protein coupled receptors (GPCRs) that bind to SCH23390 with high affinity and signal through stimulatory G proteins (Galphas/Galpha olf) to activate adenylate cyclase. In the amygdala however, D 1 receptors fail to stimulate cAMP formation and SCH23390 recognizes two affinity states; two observations that clearly challenge what is known about dopamine receptor signaling. I have sought to investigate these two seemingly contradictory observations and in so doing determine (1) if an additional mode of binding at the D1 or D5 receptor is responsible for the low affinity binding of SCH23390 in the amygdala, (2) if G proteins are activated by D1 receptor stimulation in the amygdala, and if so, which ones, and (3) if select G proteins or D1 interacting proteins are colocalized with D1 receptors in the amygdala. I have successfully demonstrated that the low affinity binding of SCH23390 is not due to binding at D1 or D5 receptors in the amygdala, and that a similar binding site in the hippocampus appears to require both D2 and A2A receptors. Interestingly, despite the lack of D1 agonist stimulated AC activation in the amygdala, activation of D1 receptors in this region elicits stimulation of the total G protein pool, and specifically Galphaolf, though it does not appear that D1 receptors colocalize with Galphas or Galphaolf in the basal state. These data suggest the existence of a D1 receptor mediated activation of G-proteins that does not include stimulation of adenylate cyclase.