Parvalbumin Interneurons of the Mouse Nucleus Accumbens are Required For Amphetamine-Induced Locomotor Sensitization and Conditioned Place Preference

ABSTRACTElucidation of the underlying mechanism of dopamine signaling to ERK that underlies plasticity in dopamine D1 receptor expressingneurons leadingto acquired cocaine preference is incomplete. NCS-Rapgef2 is a novel cAMP effector, expressed in neuronal and endocrine cells in adult mammals, that is required for D1 dopamine receptor-dependent ERK phosphorylation in mouse brain. In this report, we studied the effects of abrogating NCS-Rapgef2 expression on cAMP-dependent ERK→Egr-1/zif268 signaling in cultured neuroendocrine cells; in D1 medium spiny neurons (MSNs) of nucleus accumbens slices; and in mouse brain in a region-specific manner. NCS-Rapgef2 gene deletion in the nucleus accumbens (NAc) in adult mice, using AAV-mediated expression of cre recombinase, eliminated cocaine-induced ERK phosphorylation and Egr-1/Zif268 upregulation in D1-MSNs and cocaine-induced behaviors including locomotor sensitization and conditioned place preference (CPP). Abrogation of NCS-Rapgef2 gene expression in medium prefrontal cortex and basolateral amygdala, by crossing mice bearing a floxed Rapgef2 allele with a cre mouse line driven by calcium/calmodulin-dependent kinase IIα promoter also eliminated cocaine-induced phospho-ERK activation and Egr-1/Zif268 induction, but without effect on the cocaine-induced behaviors. Our results indicate that NCS-Rapgef2 signaling to ERK in dopamine D1-receptor expressing neurons in the NAc, butnotin corticolimbic areas, contributes to cocaine-induced locomotor sensitization and CPP. Ablation of cocaine-dependent ERK activation by elimination of NCS-Rapgef2 occurred with no effect on phosphorylation of CREB in D1 dopaminoceptive neurons of NAc. This study reveals a new cAMP-dependent signaling pathway for cocaine-induced behavioral adaptations, mediated through NCS-Rapgef2/phospho-ERK activation, independently of PKA/CREB signaling.SIGNIFICANCE STATEMENTERK phosphorylation in dopamine D1 receptor expressing neurons exerts a pivotal role in psychostimulant-induced neuronal gene regulation and behavioraladaptation, including locomotor sensitization and drug preference in rodents. In this study, we examined the role of dopamine signaling through the D1 receptor via a novel pathway initiated through the cAMP-activated guanine nucleotide exchange factor NCS-Rapgef2 in mice. NCS-Rapgef2 in the nucleus accumbens is required for activation of ERK and Egr-1/Zif268 in D1 dopaminoceptive neurons after acute cocaine administration, and subsequentenhanced locomotor response anddrugseeking behavior after repeated cocaine administration. This novel component in dopamine signaling provides a potential new target for intervention in psychostimulant-shaped behaviors, and new understanding of how D1-MSNs encode the experience of psychomotor stimulant exposure.

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Loss of β-arrestin2 in D2 cells alters neuronal excitability in the nucleus accumbens and behavioral responses to psychostimulants and opioids

10.1101/685719 ◽

2019 ◽

Author(s):

Kirsten A. Porter-Stransky ◽

Alyssa K. Petko ◽

Saumya L. Karne ◽

L. Cameron Liles ◽

Nikhil M. Urs ◽

...

Keyword(s):

Nucleus Accumbens ◽

G Protein ◽

Conditioned Place Preference ◽

Neuronal Excitability ◽

Drugs Of Abuse ◽

Behavioral Responses ◽

Place Preference ◽

Locomotor Sensitization ◽

Drug Induced ◽

G Protein Coupled

AbstractPsychostimulants and opioids increase dopamine (DA) neurotransmission, activating D1 and D2 G protein-coupled receptors. β-arrestin2 (βarr2) desensitizes and internalizes these receptors and initiates G protein-independent signaling. Previous work revealed that mice with a global or cell-specific knockout of βarr2 have altered responses to certain drugs; however, the effects of βarr2 on the excitability of medium spiny neurons (MSNs) and its role in mediating the rewarding effects of drugs of abuse are unknown. D1-Cre and D2-Cre transgenic mice were crossed with floxed βarr2 mice to eliminate βarr2 specifically in cells containing either D1 (D1βarr2-KO) or D2 (D2βarr2-KO) receptors. We used slice electrophysiology to characterize the role of βarr2 in modulating D1 and D2 nucleus accumbens MSN intrinsic excitability in response to DA and tested the locomotor-activating and rewarding effects of cocaine and morphine in these mice. We found that eliminating βarr2 attenuated the ability of DA to inhibit D2-MSNs but had little effect on the DA response of D1-MSNs. While D1βarr2-KO mice had mostly normal drug responses, D2βarr2-KO mice showed dose-dependent reductions in acute locomotor responses to cocaine and morphine, attenuated locomotor sensitization to cocaine, and blunted cocaine reward measured with conditioned place preference. Both D2βarr2-KO and D1βarr2-KO mice displayed an enhanced conditioned place preference for the highest dose of morphine. These results indicate that D2-derived βarr2 functionally contributes to the ability of DA to inhibit D2-MSNs and multiple behavioral responses to psychostimulants and opioids, while loss of βarr2 in D1 neurons has little impact on D1-MSN excitability or drug-induced behaviors.

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