Sugar and fat intake in rodents are mediated in part by brain dopamine (DA) and opioid neurotransmitter systems although important strain differences exist. Thus, whereas sucrose intake of BALB/c and SWR mice was reduced by DA D1 (SCH23390: SCH) receptor antagonism, opioid (naltrexone: NTX) receptor antagonism reduced intake only in BALB/c mice. Both SCH and NTX reduced fat (Intralipid) intake in SWR, but not BALB/c mice. The present study extended this pharmacological analysis to caloric and non-caloric sweeteners by examining whether fructose (8%) or saccharin (0.2%) intakes were differentially suppressed in BALB/c and SWR mice by SCH (50-1600nmol/kg) or NTX (0.01-5mg/kg) over a 5- to 120-min time course. SCH significantly reduced fructose (200-1600nmol/kg) and saccharin (50-1600nmol/kg) intakes in both strains as did NTX (0.1-5mg/kg). Antagonist ID40 potencies were <50nmol/kg for SCH and 0.9mg/kg for NTX in inhibiting saccharin intake, and 1234nmol/kg for SCH and 5mg/kg for NTX in inhibiting fructose intake in BALB/c mice. For SWR mice, the ID40 potencies were <50nmol/kg for SCH and 0.02mg/kg for NTX in inhibiting saccharin intake, and 298nmol/kg for SCH and 2.6mg/kg for NTX in inhibiting fructose intake. Thus, saccharin intake was similarly reduced by SCH and NTX in BALB/c and SWR mice, but greater potencies of opioid (1.9-fold) and DA D1 (4-fold) receptor antagonism of fructose intake were observed in SWR relative to BALB/c mice, indicating strong strain differences.