--- - |2+ Abstract Aim Therapeutic use of lithium in bipolar disorder is limited by the development of nephrogenic diabetes insipidus (NDI). We reported that pharmacological blockade of P2Y12 receptor (R) with clopidogrel or prasugrel significantly ameliorated lithium‐induced NDI in rodents. Using mice genetically lacking P2Y12‐R we evaluated whether the observed amelioration is mediated through P2Y12‐R Methods P2ry12−/− mouse line (C57/BL6) was rederived from cryopreserved embryos of the knockout (KO) mice generated by Deltagen Inc. Syngeneic wild type (WT) mice obtained by heterozygous crossing were inbred. Groups of adult WT and KO mice were fed lithium‐added (40 mmol LiCl/kg food) or regular diet, and euthanized after 2 or 4 weeks. Twenty‐four hour urine samples and terminal blood and kidney samples were analyzed. Results At both time points, lithium‐induced polyuria and decrease in aquaporin‐2 (AQP2) protein abundance in the kidney medulla were less marked in KO vs WT mice. Immunofluorescence microscopy revealed that lithium‐induced alterations in the cellular disposition of AQP2 protein in the medullary collecting ducts of WT mice were blunted in KO mice. Serum lithium, sodium and osmolality were similar in both genotypes after lithium treatment. After 2 weeks, lithium induced marked increases in urinary excretion of Na, K, and arginine vasopressin in WT mice but not in KO mice. Conclusion Taken together, our data show that similar to pharmacological blockade, deletion of P2Y12‐R significantly ameliorates lithium‐induced NDI, without reducing serum lithium levels. Hence, targeting P2Y12‐R with currently available drugs in the market offers a novel and safer method for treating NDI. - 'Acta Physiologica, EarlyView. '