The effects of diabetes on methamphetamine-induced place preference in mice were examined. Methamphetamine caused a dose-dependent place preference in both diabetic and non-diabetic mice. Methamphetamine preferentially induced place preference in diabetic mice as compared to those in non-diabetic mice. Indeed, methamphetamine-induced place preference at a dose of 0.3 mg/kg in diabetic mice was similar to that at 3 mg/kg in non-diabetic mice. Furthermore, methamphetamine-induced place preference in both diabetic and non-diabetic mice was significantly antagonized by pretreatment with quinpirole, a dopamine D2/D3 receptor agonist. Methamphetamine-induced place preference was also antagonized by pretreatment with 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), a selective dopamine D3 receptor agonist. On the other hand, 7-OH-DPAT produced significant place aversion in non-diabetic mice. 7-OH-DPAT produced neither place preference nor place aversion in diabetic mice. These results suggest that methamphetamine-induced place preference may be modulated by dopamine D3 receptors. Furthermore, increased dopamine neurotransmission associated with the down-regulation of presynaptic dopamine D3 receptor-mediated functions may account for the enhancement of methamphetamine's reinforcing effect in diabetic mice.