The D3 dopamine receptor is expressed primarily in limbic brain areas, and appears to play an inhibitory role in rodent locomotor behavior. Evidence suggests a potentialroleforthe D3 receptor in the pathology of neuropsychiatric disease. Progress in elucidating D3receptor function has been hampered, however, by a lack of well-characterized, selective ligands and by conflicting information regardingthe behavioralphenotype of D3 receptor knockout mice. Here, we describe studies evaluating the behavioraleffects of (±)-7-hydroxy-N, N-di-n-propyl-2-aminotetralin (7-OH-DPAT) and PD 128907, two D3 receptor agonists whosein vivoselectivity has been atopic ofconsiderable controversy. We demonstrate that both compounds inhibit locomotion under novelenvironmentalconditions in wild-type(WT) mice, but are without measurable behavioraleffect under identicalconditions in D3 receptor knockout mice. Additionally, wedemonstrate that at low, D3 selective doses, these compounds are without behavioraleffect in both WT and D3 receptor knockoutmice that have acclimated to the testing environment. These findings suggest that D3 receptor stimulation inhibits novelty-stimulatedlocomotion, and establish conditions forthe use of 7-OH-DPAT and PD 128907 as D3 receptor agonistsin vivo.Potentialimplications ofthese observations are discussed. © 2003 American College of Neuropsychopharmacology.