Spontaneous locomotor activity in diabetic mice was significantly greater than that in non-diabetic mice. Haloperidol and SCH23390, a selective dopamine D1-receptor antagonist, significantly reduced spontaneous locomotor activity in diabetic mice, but not in non-diabetic mice. Spontaneous locomotor activity in diabetic mice was also reduced by pretreatment with naltrindole, a selective delta-opioid receptor antagonist, and 7-benzylidenenaltrexone, a selective delta1-opioid receptor antagonist. The rate of dopamine turnover in the limbic forebrain in diabetic mice was significantly higher than that in non-diabetic mice. These findings suggest that the enhanced spontaneous locomotor activity in diabetic mice may result from increased dopamine neurotransmission, which might be due to an increase in dopamine release in mesolimbic dopamine systems. The increased dopamine neurotransmission in diabetic mice may also be due to the up-regulation of delta-opioid receptor-mediated functions.