Role of dopamine D3 receptors in methamphetamine-induced behavioural sensitization and the characterization of dopamine receptors (D1R-D5R) gene expression in the brain.

INTRODUCTION: As a central nervous system stimulant, methamphetamine (METH) can cause lasting changes after being abused, including possible changes of gene expression in the brain. The dopamine (DA) system plays a fundamental role in METH-induced behavioural changes, but the expression levels of various subtypes of DA receptors, especially the dopamine D3 receptor (D3R), remains unclear. MATERIAL AND METHODS: We explored the effect of the D3R on METH-induced behavioural sensitization by comparing D3R knockout (D3R-/-) mice with wild type (WT) mice. The quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of the five DA receptor (D1R, D2R, D3R, D4R, and D5R) genes in four brain regions: the prefrontal cortex (PFc), nucleus accumbens (NAc), caudate-putamen (CPu), and hippocampus (Hip). RESULTS: The behavioural test results revealed that METH could induce behavioural sensitization both in WT and D3R-/- mice. Moreover, in D3R-/- mice, the increase in movement distance induced by methamphetamine was significantly less than that of wild-type mice. The response of the five DA receptors to METH exposure varies in different brain regions. To be more specific, METH increased the expression of the D3R gene in most brain regions of WT mice, decreased D1R and D2R gene expression both in the NAc and CPu of WT mice and in CPu of D3R-/- mice. CONCLUSIONS: These results suggested that D3R may play a positive regulatory role in the locomotor effects of METH, and five DA receptors, especially D1R, D2R, and D3R, may concurrently participate in the adaptive changes and the regulation of METH-induced behavioural sensitization.

The distinct roles of various neurotransmitters in modulating methamphetamine-induced conditioned place preference in relevant brain regions in mice.

OBJECTIVES: Previous studies have shown that methamphetamine (METH) can induce complex adaptive changes in the reward system in the brain, including the changes in the content of neurotransmitters in the signal transduction pathway. However, how the changes of various neurotransmitters in relevant brain reward circuits contribute to METH-induced conditioned place preference (CPP) remains unclear. METHODS: In this study, first, we designed an animal model of METH-induced CPP. Then we used liquid chromatography-mass spectrometry (LC-MS) to simultaneously determine the contents of various neurotransmitters - dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), glutamic acid (Glu) and glutamine (Gln) - in different brain regions of the prefrontal cortex (PFc), nucleus accumbens (NAc), caudate-putamen (CPu) and hippocampus (Hip), which are believed to be relevant to the drug's reward effect. RESULTS: The results of the behavioral experiment suggested that 1.0 mg/kg METH could induce obvious CPP in mice. The results about various neurotransmitters showed that: DA significantly increased in NAc in the METH group; Glu increased significantly in the METH group in PFc and NAc and Gln increased significantly in the METH group in PFc. CONCLUSIONS: These results suggested that the neurotransmitters of DA, Glu and Gln may work together and play important roles in METH-induced CPP in relevant brain reward circuits, especially in PFc and NAc. These findings therefore could help to advance the comprehensive understanding of the neurochemic and psychopharmacologic properties of METH in reward effect, which is important for future improvements in the treatment of drug addiction.