Signalling through dopamine D2 receptors governs physiological functions related to locomotion, hormone production and drug abuse1,2,3,4,5,6,7. D2 receptors are also known targets of antipsychotic drugs that are used to treat neuropsychiatric disorders such as schizophrenia8. By a mechanism of alternative splicing, the D2 receptor gene encodes two molecularly distinct isoforms9, D2S and D2L, previously thought to have the same function. Here we show that these receptors have distinct functions in vivo; D2L acts mainly at postsynaptic sites and D2S serves presynaptic autoreceptor functions. The cataleptic effects of the widely used antipsychotic haloperidol1 are absent in D2L-deficient mice. This suggests that D2L is targeted by haloperidol, with implications for treatment of neuropsychiatric disorders. The absence of D2L reveals that D2S inhibits D1 receptor-mediated functions, uncovering a circuit of signalling interference between dopamine receptors.
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We thank A. Saiardi for help in the initial phase of this work and D. Vallone, C. Mathis, M. Omori and J. Clifford for useful discussions. We are grateful to V. Heidt, Muriel Petit and Nelly Charrier for technical help. We thank A. Giovanni for the generous gift of SKF 81297. This work was supported by grants from INSERM, CNRS, HUS, MILDT and ARC (to E.B.), INSERM and Université de Bordeaux II (to P.V.P.) and from the Mariano Scippacercola Foundation and FRM fellowships to A.U.
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