Dopamine is known to regulate several behavioral phenomena, including sensorimotor gating and aspects of motor activity. The roles of dopamine D1 and D2 receptors in these behaviors have been documented in the rat literature, but few reports exist on their role in mice. We used dopamine transporter (DAT) (−/−) mice to examine the behavioral consequences of a chronically hyperdopaminergic state, challenging them with the preferential dopamine D2 receptor antagonist raclopride and D1 receptor antagonist SCH23390. At baseline, DAT (−/−) mice exhibited deficient sensorimotor gating as measured by prepulse inhibition (PPI) of the startle response, exhibited nonfocal perseverative patterns of locomotion, and were hyperactive in a novel environment. Pretreatment with raclopride significantly increased PPI in the DAT (−/−) mice, whereas SCH23390 had no significant effect. Blockade of D2 receptors did not affect the predominantly straight patterns of motor behavior produced by the DAT (−/−) mice, but antagonism of D1 receptors significantly attenuated the perseverative patterns, producing more of a meandering behavior seen in the DAT (+/+) control mice. Both D1 and D2 receptor antagonists decreased the hyperactivity seen in the DAT (−/−) mice. These findings support the role of the D2, but not the D1, receptor in the modulation of PPI in mice. Furthermore, D1 receptor activation appears to be the critical substrate for the expression of perseverative patterns of motor behavior, whereas both D1 and D2 receptors appear to regulate the amount of motor activity.

The role of the dopamine transporter (DAT) in mediating the neurotoxic effects of methamphetamine (METH) was tested in mice lacking DAT. Dopamine (DA) and serotonin (5-HT) content, glial fibrillary acidic protein (GFAP) expression, and free radical formation were assessed as markers of METH neurotoxicity in the striatum and/or hippocampus of wild-type, heterozygote, and homozygote (DAT −/−) mice. Four injections of METH (15 mg/kg, s.c.), each given 2 hr apart, produced 80 and 30% decreases in striatal DA and 5-HT levels, respectively, in wild-type animals 2 d after administration. In addition, GFAP mRNA and protein expression levels, extracellular DA levels, and free radical formation were increased markedly. Hippocampal 5-HT content was decreased significantly as well (43%). Conversely, no significant changes were observed in total DA content, GFAP expression, extracellular DA levels, or free radical formation in the striatum of DAT −/− mice after METH administration. However, modest decreases were observed in striatal and hippocampal 5-HT levels (10 and 17%, respectively). These observations demonstrate that DAT is required for, and DA is an essential mediator of, METH-induced striatal dopaminergic neurotoxicity, whereas serotonergic deficits are only partially dependent on DAT.