Autoreceptor preference of dopamine D2 receptor agonists correlates with preferential coupling to cyclic AMP

Dopamine autoreceptors control the synaptic release and turnover of dopamine. Some dopamine agonists display a preference for modulation of autoreceptor functions rather than postsynaptic-driven behaviors. However, the nature of this apparent selectivity is still elusive. To investigate this property, we have used an heterologous expression system in which D2S receptors are coupled to both inhibition of cyclic AMP levels and stimulation of inositol triphosphate production. We show that D2-like receptor agonists display distinct potencies on these two second messenger pathways. Moreover, a strong correlation is observed between the potency of agonists to interact with adenylate cyclase and their potency to modulate autoreceptor functions. Such a correlation does not show up with the phospholipase C pathway. This suggests that autoreceptor preference of D2-like receptor agonists may be driven by a preferential interaction with a second messenger system.