Dopamine-Galanin Receptor Heteromers Modulate Cholinergic Neurotransmission in the Rat Ventral Hippocampus.

Previous studies have shown that dopamine and galanin modulate cholinergic transmission in the hippocampus, but little isknownabout the mechanisms involved and their possible interactions. By using resonance energy transfer techniques in transfected mammalian cells, we demonstrated the existence of heteromers between the dopamine D₁-like receptors (D₁ and D₅ ) and galanin Gal₁ , but not Gal₂ receptors. Within the D₁-Gal₁ and D₅-Gal₁ receptor heteromers, dopamine receptor activation potentiated and dopamine receptor blockade counteracted MAPK activation induced by stimulation of Gal₁ receptors, whereas Gal₁ receptor activation or blockade did not modify D₁-like receptor-mediated MAPK activation. Ability of a D₁-like receptor antagonist to block galanin-induced MAPK activation (cross-antagonism) was used as a "biochemical fingerprint" of D₁-like-Gal₁ receptor heteromers, allowing their identification in the rat ventral hippocampus. The functional role of D₁-like-Gal receptor heteromers was demonstrated in synaptosomes from rat ventral hippocampus, where galanin facilitated acetylcholine release, but only with costimulation of D₁-like receptors. Electrophysiological experiments in rat ventral hippocampal slices showed that these receptor interactions modulate hippocampal synaptic transmission. Thus, a D₁-like receptor agonist that was ineffective when administered alone turned an inhibitory effect of galanin into an excitatory effect, an interaction that required cholinergic neurotransmission. Altogether, our results strongly suggest that D₁-like-Gal₁ receptor heteromers act as processors that integrate signals of two different neurotransmitters, dopamine and galanin, to modulate hippocampal cholinergic neurotransmission. [ABSTRACT FROM AUTHOR]