Knockdown of Dopamine D(2) Receptors in the Nucleus Accumbens Core Suppresses Methamphetamine-Induced Behaviors and Signal Transduction in Mice

BACKGROUND: Addictive drugs lead to reinforcing properties by increasing dopamine in the nucleus accumbens, which is composed of a core and shell regions. Neurons in the nucleus accumbens are divided into 2 subtypes based on the differential gene expression of the dopamine D(1) receptors and D(2) receptors. METHODS: In the present study, we investigated the role of D(2) receptors in the nucleus accumbens core in behaviors and signal transduction induced by psychostimulant methamphetamine in mice that were microinjected with adeno-associated virus vectors containing a microRNA (miRNA) sequence for D(2) receptor (adeno-associated virus-miD(2)r vectors) in the nucleus accumbens core. The adeno-associated virus vectors containing a miRNA sequence for D(2) receptor-treated mice (miD(2)r mice) were assessed at a reduction in D(2) receptor, but at no change in dopamine D(1) receptor, in the nucleus accumbens core compared with the adeno-associated virus-Mock vectors-treated mice (Mock mice). RESULTS: miD(2)r mice exhibited a reduction in hyperlocomotion that was induced by a single treatment with methamphetamine. The development of locomotor sensitization induced by repeated treatment with methamphetamine exhibited less extension in miD(2)r mice. In a place conditioning paradigm, the preferred effects of methamphetamine were significantly weaker in miD(2)r mice than in Mock mice. Furthermore, the single treatment with methamphetamine-induced phosphorylation of extracellular signal regulated kinase and cyclic adenosine monophosphate response element-binding protein in the nucleus accumbens core of miD(2)r mice was decreased compared with that in Mock mice. Repeated treatment with methamphetamine-induced delta FBJ murine osteosarcoma viral oncogene homolog B accumulation in the nucleus accumbens core of miD(2)r mice was also attenuated. CONCLUSIONS: These findings suggest that a D(2) receptor-mediated neuronal pathway from the nucleus accumbens core plays an inhibitory role in the development of reinforcing properties.