Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice

Seiji Hayashizaki,Masahiko Takada,Yoshiko Honda,Yosefu Arime,Shinobu Hirai,Haruo Okado,Tohru Kodama,Yumi Ito,Ichiro Sora,Stephen D Ginsberg

doi:10.1371/journal.pone.0075975

Abstract

Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor-deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behavioral response to methamphetamine. Interestingly, D5 dopamine receptor-deficient mice displayed increased ambulation in response to methamphetamine. Furthermore, dopamine transporter threonine phosphorylation levels, which regulate amphetamine-induced dopamine release, were elevated in D5 dopamine receptor-deficient mice. The increase in methamphetamine-induced locomotor activity was eliminated by pretreatment with the dopamine transporter blocker GBR12909. Taken together, these results suggest that dopamine transporter activity and threonine phosphorylation levels are regulated by D5 dopamine receptors.

Highlights

Dopamine mediates a wide variety of physiological and behavioral functions in the central nervous system (CNS), such as the response to psychomotor stimulants and reward and learning behaviors [1,2,3,4,5,6,7]
The murine D5R gene was disrupted in embryonic stem (ES) cells by homologous recombination that resulted in inactivation of the coding region (Figure 1a)
We found that D5R-KO mice were more sensitive to a METH challenge (2.5 mg/kg) than WT control mice

Summary

Introduction

Dopamine mediates a wide variety of physiological and behavioral functions in the central nervous system (CNS), such as the response to psychomotor stimulants and reward and learning behaviors [1,2,3,4,5,6,7] These roles of the dopamine system were discovered through the creation and characterization of dopamine receptor-deficient mice Genomic studies found a significant relation between a polymorphism in the D5R gene locus and vulnerability to drug abuse [13,14] Consistent with this mutation, several studies found that D5Rs play a role in mediating the response to cocaine administration. D5R-deficient mice with a C57/B6 background are more sensitive to chronic cocaine administration than wild-type (WT) littermates [16] It is unknown whether D5Rs contribute to the response to amphetamine-like drugs. METH is a derivative of amphetamine and is a major psychostimulant that is frequently abused

Methods

Results

Conclusion