Grooming behavior in rodents has long been related to dopamine receptors in the brain. However, the relative contribution of dopamine D1-like receptors (D1 and D5) and D2-like receptors (D2, D3 and D4) in this behavior has not been established yet. Spontaneous novelty-induced grooming (as assessed with a 30-min sampling test) was reduced in knockout mice lacking the dopamine D1, receptor. Furthermore, the intracerebroventricular (i.c.v.) injection of small quantities of oxytocin, prolactin or the adrenocorticotrophic hormone 1-24 fragment, ACTH-(1-24) was followed by a diminished level of novelty-induced excessive grooming. These neuropeptides caused a sustained increase in grooming level of control animals (wild type). Interestingly, the i.c.v. injection of beta-endorphin enhanced novelty-induced grooming to a level similar in control and knockout mice. The systemic administration of the dopamine D2 receptor antagonist, sulpiride did not suppress the residual grooming activity shown by animals injected with oxytocin, prolactin or ACTH-(1-24), and did not change the behavioral expression of those injected with beta-endorphin. In contrast, the systemic administration of the opioid receptor antagonist, naloxone, totally suppressed the residual grooming activity of oxytocin-, prolactin- or ACTH-(1-24)-injected mice and of those treated with beta-endorphin. In contrast with the behavioral deficit observed in dopamine D1 receptor-deficient mice, dopamine D2 receptor-null animals showed a normal expression of spontaneous novelty-induced grooming and a high level of grooming activity induced by i.c.v. injection of oxytocin, prolactin, ACTH-(1-24) or beta-endorphin. Again, the peripheral injection of naloxone was followed by a suppression of neuropeptide-induced excessive grooming in these animals. These data suggest that dopamine D1 receptors are involved in the expression of novelty-induced grooming in mice. In contrast, dopamine D2 receptors seem not to be important for the expression of this behavior. Furthermore, neuropeptide-enhanced grooming involves dopamine D1, but not dopamine D2 receptors. However, neurotransmitters other than dopamine (e.g., endorphins) may play a supplementary role in neuropeptide-enhanced grooming in mice.