Methamphetamine-induced locomotor activity and sensitization in dopamine transporter and vesicular monoamine transporter 2 double mutant mice
- 338 Downloads
The dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) play pivotal roles in the action of methamphetamine (MAP), including acute locomotor effects and behavioral sensitization. However, the relative impact of heterozygous DAT and VMAT2 knockouts (KOs) on the behavioral effects of MAP remains unknown.
To evaluate the roles of DAT and VMAT2 in MAP-induced locomotor behavior, we examined locomotor activity and sensitization in heterozygous DAT KO (DAT+/−), heterozygous VMAT2 KO (VMAT2+/−), double heterozygous DAT/VMAT2 KO (DAT+/−VMAT2+/−), and wild-type (WT) mice.
Acute 1 mg/kg MAP injection induced significant locomotor increases in WT and VMAT2+/− mice but not in DAT+/− and DAT+/−VMAT2+/− mice. Acute 2 mg/kg MAP significantly increased locomotor activity in all genotypes. Repeated 1 mg/kg MAP injections revealed a delayed and attenuated development of sensitization in DAT+/− and DAT+/−VMAT2+/− mice compared to WT mice and delayed development in VMAT2+/− mice. In repeated 2 mg/kg MAP injections, DAT+/− and DAT+/−VMAT2+/− mice showed delayed but not attenuated development of sensitization, while there was no difference in the onset of sensitization between VMAT2+/− and WT mice. In DAT+/−VMAT2+/− mice, all of MAP-induced behavioral responses were similar to those in DAT+/− but not VMAT2+/− mice.
Heterozygous deletion of DAT attenuates the locomotor effects of MAP and may play larger role in behavioral responses to MAP compared to heterozygous deletion of VMAT2.
KeywordsSensitization Dopamine transporter Vesicular monoamine transporter 2 Methamphetamine Knockout mice Locomotor activity Heterozygote
We thank Maki Naka for technical assistance. This study was supported in part by the Intramural Research Program of the NIH, NIDA (USA), Grant-in-Aid for Health and Labor Science Research (Research on Psychiatric and Neurological Diseases, Research on Pharmaceutical and Medical Safety) from the Ministry of Health, Labor and Welfare of Japan; by Grants-in-Aid for Scientific Research (B), Scientific Research on Priority Areas-System study on higher-order brain functions and Research on Pathomechanisms of Brain Disorders-, Core Research for Evolutional Science and Technology (CREST), from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 17390315, 17022007, 18023007); and by the Mitsubishi Pharma Research Foundation.
- Dews PB, Wenger WG (1977) Rate-dependency of the behavioral effects of amphetamine. In: Thompson T, Dews PB (eds) Advances in behavioral pharmacology. Academic, New York, pp 167–227Google Scholar
- Robbins TW (1977) A critique of the methods available for the measurement of spontaneous motor activity. In: Iverson LL, Synder SH (eds) Handbook of psychopharmacology. Plenum, New York, pp 37–82Google Scholar
- Segal DS, Schuckit MA (1983) Animal models of stimulant-induced psychosis. In: Grees I (ed) Stimulants: neurochemical, behavioral and clinical perspectives. Reven, New York, pp 131–167Google Scholar
- Shen HW, Hagino Y, Kobayashi H, Shinohara-Tanaka K, Ikeda K, Yamamoto H, Yamamoto T, Lesch KP, Murphy DL, Hall FS, Uhl GR, Sora I (2004) Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters. Neuropsychopharmacology 29:1790–1799CrossRefPubMedGoogle Scholar
- Takahashi N, Miner LL, Sora I, Ujike H, Revay RS, Kostic V, Jackson-Lewis V, Przedborski S, Uhl GR (1997) VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proc Natl Acad Sci U S A 94:9938–9943CrossRefPubMedGoogle Scholar