Knockdown of Dopamine D2 Receptors in the Nucleus Accumbens Core Suppresses Methamphetamine-Induced Behaviors and Signal Transduction in Mice

Abstract

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 D1 receptors and D2 receptors.Methods:In the present study, we investigated the role of D2 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 D2 receptor (adeno-associated virus-miD2r vectors) in the nucleus accumbens core. The adeno-associated virus vectors containing a miRNA sequence for D2 receptor-treated mice (miD2r mice) were assessed at a reduction in D2 receptor, but at no change in dopamine D1 receptor, in the nucleus accumbens core compared with the adeno-associated virus-Mock vectors-treated mice (Mock mice).Results:miD2r 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 miD2r mice. In a place conditioning paradigm, the preferred effects of methamphetamine were significantly weaker in miD2r 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 miD2r 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 miD2r mice was also attenuated.Conclusions:These findings suggest that a D2 receptor-mediated neuronal pathway from the nucleus accumbens core plays an inhibitory role in the development of reinforcing properties.

The Role of Adenosine Receptors in Psychostimulant Addiction

“…Interestingly, reduction of AP-1 DNA binding activity and proenkephalin gene expression induced by METH exposure were reduced by CSC ( Shin et al, 2005 ). Furthermore, C57BL/6J mice with D 2 receptors knocked down in the NAc core have been reported to exhibit a reduction in METH-induced locomotion, as in other paradigms (locomotor sensitization and conditioned place preference) after repeated METH-treatment, suggesting that D 2 receptors are necessary mediators for the development of METH-induced rewarding effects ( Miyamoto et al, 2014 ). Thus, the antagonism between A 2A and D 2 receptors further supports the conclusion that the activation of A 2A receptors could be a promising way to counteract AMPH- and METH-induced rewarding effects.…”

Psilocin suppresses methamphetamine‐induced hyperlocomotion and acquisition of conditioned place preference via D2R‐mediated ERK signaling

“…During the acquisition phase of CPP, D2R expression in PFC and NAc was significantly increased in the METH group. Similarly, METH increased D2R expression associated with activation of dopaminergic neurons in the mesolimbic pathway 13 . Conversely, the level of D2R expression in the VTA was decreased in the METH group.…”

“…In the extinction phase (days [11][12][13][14][15][16][17][18][19][20][21][22], four groups including control, PI, METH-Ext1, and METH-Ext2 were subjected to extinction training and testing. The METH group with CPP was divided into METH-Ext1 and METH-Ext2 groups.…”

“…These effects are induced by the stimulation of neurotransmitter release via actions on the dopamine transporter (DAT), resulting in increased dopamine (DA) release. Indeed, acute METH increases D2R expression associated with activation of the mesolimbic dopaminergic pathway 13 . However, positron emission tomography and magnetic resonance imaging data in human indicate that persist beyond the period of METH consumption reduced the density of D2 receptor.…”

Activation of dopamine D2 receptors in the medial shell region of the nucleus accumbens increases Per1 expression to enhance alcohol consumption

“…For example, evidence suggest that D2R activation leads to the activation of MAPK pathway including the extracellular signal-regulated kinases (ERKs) and c-JunNH2-terminal kinase (JNK; also called SAPK, or stress-activated protein kinase). [42][43][44][45][46][47] Circadian genes expression is regulated by transcriptionaltranslational feedback loops in which specific transcription factors control their own activity once they reach critical levels in the cell.…”