Distinct functions of the two isoforms of dopamine D2 receptors

Signalling through dopamine D2 receptors governs physiological functions related to locomotion, hormone production and drug abuse^1-7. 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.