Distinct functions of the two isoforms of dopamine D-2 receptors

Signalling through dopamine D2 receptors governs physiological functions re lated to locomotion, hormone production and drug abuse(1-7). D2 receptors a re also known targets of antipsychotic drugs that are used to treat neurops ychiatric disorders such as schizophrenia(8). By a mechanism of alternative splicing, the D2 receptor gene encodes two molecularly distinct isoforms(9 ), 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 po stsynaptic sites and D2S serves presynaptic autoreceptor functions. The cat aleptic effects of the widely used antipsychotic haloperidol(1) are absent in D2L-deficient mice. This suggests that D2L is targeted by haloperidol, w ith implications for treatment of neuropsychiatric disorders. The absence o f D2L reveals that D2S inhibits D1 receptor-mediated functions, uncovering a circuit of signalling interference between dopamine receptors.