Abstract
Dopamine is involved in multiple neural functions including motor control, reward and motivational processing, learning and reinforcement, and cognitive attention. Dopamine binds to two distinct classes of receptors, namely D1 and D2, to exert these functions. Various endogenous substances regulate dopamine signaling, although their physiological functions are not fully understood. Here, we examined the role of prostaglandin E2 (PGE2) and one of its receptors, EP1, in dopaminergic function in the striatum. EP1 was expressed in both preprodynorphin-containing D1 and preproenkephalin-containing D2 neurons, and PGE2 was produced in striatal slices in response to both D1 and D2 dopamine receptor stimulation. EP1-deficient mice exhibited significant suppression of hyperlocomotion induced by cocaine or SKF81297 (6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine hydrobromide), a D1 agonist, and significant attenuation of catalepsy induced by raclopride, a D2 antagonist. Despite these behavioral defects, the extracellular concentration of dopamine was not suppressed in the striatum of EP1-deficient mice, and the densities of D1 and D2 receptors in the striatum were not different between the two genotypes. Stimulation of the D1 receptor induced phosphorylation of dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr34 in striatal slices, and the addition of indomethacin, a PG synthesis inhibitor, attenuated the D1 agonist-induced increase in DARPP-32-Thr34 phosphorylation. The further addition of an EP1 agonist restored the indomethacin-attenuated phosphorylation. Furthermore, both D1- and D2-mediated changes in the DARPP-32-Thr34 phosphorylation were attenuated in EP1-/- slices. These results suggest that PGE2 is formed in response to dopamine receptor stimulation in the striatum and amplifies both D1 and D2 receptor signaling via EP1.