Growth hormone (GH) replacement in hypopituitary patients improves well-being and initiative. Experimental studies indicate that these psychic effects may be reflected in enhanced locomotor activity in mice. It is unknown whether these phenomena are mediated directly by GH or by circulating IGF-I. IGF-I production in the liver was inactivated at 6-10 weeks of age (LI-IGF-I^-/- mice), resulting in an 80-85 % reduction of circulating IGF-I, and secondary to this, increased GH secretion. Using activity boxes at 3 different occasions during one week, 6-month-old LI-IGF-I^-/- mice had similar activity level, and 14-month-old mice had a moderate but significant decrease in activity level, as compared with control mice. At 20 months of age, the LI-IGF-I^-/- mice displayed a more prominent decrease in activity level with decreased horizontal activity throughout the test period and at Day 1, there were several signs of an altered habituation process with different time patterns of locomotor activity and horizontal activity as compared with the control mice. At Day 3 and 5, rearing activity was lower in the 20-month-old LI-IGF-I^-/- mice. Anxiety level was unaffected in all age groups as measured using the Montgomery's elevated plus-maze. In conclusion, old LI-IGF-I^-/- mice displayed a decrease in both horizontal and rearing (exploratory) activity level, and an altered habituation process. These results indicate that liver-derived IGF-I mediates at least part of the effects of GH on exploratory activity in mice.