Abstract Body (Do not enter title and authors here): Inverse salt sensitivity, an increase in blood pressure (BP) when sodium intake is reduced, affects about 10-15% of the population, yet the mechanisms underlying this alteration in BP are not well understood. The renal dopamine D2 receptor (D2R) plays a critical role in maintaining normal BP and preventing inflammation and tissue injury. The DRD2 is highly polymorphic, and single nucleotide polymorphisms (SNPs) in this gene impair DRD2 synthesis and stability. Specifically, rs6277 SNP in exon 7 of DRD2 is associated with decreased D2R expression and is present in some individuals with hypertension. We have reported that human renal proximal tubular cells with this SNP have decreased D2R mRNA and protein expressions and increased renal Na+ pump/transporter expression. To study the effects of rs6277 on sodium balance and BP, using CRISPR-Cas9, we generated C57Bl/6 mice lacking their own Drd2 but instead express either the human DRD2 wild-type (DRD2 WT) or rs6277 (DRD2 Mut). Male and female mice were placed for one week on three distinct salt diets: normal salt (NS; 0.4% NaCl), high salt (HS; 4% NaCl), and low salt (LS; less than 0.08% NaCl) diets. On NS diet, BPs (measured by tail-cuff plethysmography under pentobarbital anesthesia) were slightly higher in male DRD2 Mut than DRD2 WT mice (79±3 vs 73±±0.5 mm Hg; P<0.04; n=5-7/group) while BPs were similar in female DRD2 Mut and DRD2 WT mice (77±3 vs 75±3 mm Hg: n=8/group). On HS diet, BPs were similar in DRD2 WT and DRD2 Mut mice (males 89±2 vs 92±3; females 79±3 vs 87±5 mm Hg). However, on LS diet DRD2 Mut had higher BPs than DRD2 WT mice (males: 72±2 vs 90±2 P<0.001; females: 68±1 vs 88±3 mm Hg, P<0.001). Thus, in DRD2 WT mice, BP increased on HS diet and decreased on LS, while in DRD2 Mut mice, BP increased on both LS and HS diets. There were no significant differences in urinary sodium excretion between DRD2 WT and DRD2 Mut male and female mice on the different diets. These findings suggest that alterations in DRD2 expression/function may be the underlying cause of inverse salt sensitivity of BP because the presence of DRD2 rs6277 is associated with inverse salt sensitivity in mice and humans. Moreover, the increased BP in DRD2 rs6277 mice on LS is independent of urinary sodium excretion.