scholarly journals Cocaine-dependent acquisition of locomotor sensitization and conditioned place preference requires D1 dopaminergic signaling through a cyclic AMP, NCS-Rapgef2, ERK and Egr-1/Zif268 pathway

2020 ◽  
Author(s):  
Sunny Zhihong Jiang ◽  
Sean Sweat ◽  
Sam Dahlke ◽  
Kathleen Loane ◽  
Gunner Drossel ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Conditioned Place Preference ◽  
Mouse Brain ◽  
Place Preference ◽  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Locomotor Sensitization ◽  
Erk Activation ◽  
Erk Phosphorylation ◽  
Dopamine Signaling

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.

Up-regulation of dopamine D1 receptor in the hippocampus after establishment of conditioned place preference by cocaine

2011 ◽  
Vol 61 (4) ◽  
pp. 842-848 ◽  
Author(s):  
Tomoko Tanaka ◽  
Nobuyuki Kai ◽  
Kazuto Kobayashi ◽  
Yuji Takano ◽  
Naoyuki Hironaka
Keyword(s):  
Conditioned Place Preference ◽  
Place Preference ◽  
Dopamine D1 Receptor ◽  
D1 Receptor

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

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.

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

2017 ◽  
Vol 43 (5) ◽  
pp. 953-963 ◽  
Author(s):  
Xiaoting Wang ◽  
David A Gallegos ◽  
Vladimir M Pogorelov ◽  
Justin K O’Hare ◽  
Nicole Calakos ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Conditioned Place Preference ◽  
Place Preference ◽  
Locomotor Sensitization ◽  
Parvalbumin Interneurons

scholarly journals A conditioned place preference for heroin is signaled by increased dopamine and direct pathway activity and decreased indirect pathway activity in the nucleus accumbens

2021 ◽  
Author(s):  
Timothy J O'Neal ◽  
Mollie X Bernstein ◽  
Derek J MacDougall ◽  
Susan M Ferguson
Keyword(s):  
Nucleus Accumbens ◽  
Conditioned Place Preference ◽  
Place Preference ◽  
Indirect Pathway ◽  
Pathway Activity ◽  
Principal Role ◽  
Direct Pathway ◽  
Dopamine Signaling

Initial drug use promotes the development of conditioned reinforcement, whereby the reinforcing properties of a drug become attributed to drug-associated stimuli, such as cues and contexts. A principal role for the nucleus accumbens (NAc) in the response to drug-associated stimuli has been well-documented. In particular, direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) have been shown to bidirectionally regulate cue-induced heroin-seeking in rats expressing addiction-like phenotypes, and a shift in NAc activity towards the direct pathway has been shown in mice following cocaine conditioned place preference (CPP). However, how NAc signaling guides heroin CPP, and whether heroin alters the balance of signaling between dMSNs and iMSNs remains unknown. Moreover, the role of NAc dopamine signaling in heroin reinforcement remains unclear. Here, we integrate fiber photometry for in vivo monitoring of dopamine and dMSN/iMSN calcium activity with a heroin CPP procedure in rats to address these outstanding questions. We identify a sensitization-like response to heroin in the NAc, with prominent iMSN activity during initial heroin exposure and prominent dMSN activity following repeated heroin exposure. We demonstrate a ramp in dopamine activity, dMSN activation, and iMSN inactivation preceding entry into a heroin-paired context, and a decrease in dopamine activity, dMSN inactivation, and iMSN activation preceding exit from a heroin-paired context. Finally, we show that buprenorphine is sufficient to prevent the development of heroin CPP and activation of the NAc post-conditioning. Together, these data support the hypothesis that an imbalance in NAc activity contributes to the development of addiction.

scholarly journals Pyk2 in D1 receptor-expressing neurons of the nucleus accumbens modulates the acute locomotor effects of cocaine

2019 ◽  
Author(s):  
Benoit de Pins ◽  
Enrica Montalban ◽  
Peter Vanhoutte ◽  
Albert Giralt ◽  
Jean-Antoine Girault
Keyword(s):  
Nucleus Accumbens ◽  
Protein Tyrosine Kinase ◽  
Drugs Of Abuse ◽  
Anticholinergic Drug ◽  
Dorsal Striatum ◽  
D1 Receptor ◽  
Locomotor Sensitization ◽  
Locomotor Response ◽  
Erk Phosphorylation

AbstractThe striatum is a critical brain region for locomotor response to cocaine. Although the D1 receptor-expressing neurons are centrally involved in mediating the locomotor effects of cocaine, the molecular pathways controlling this response are not fully understood. Here we studied the role of Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase, in striatum-related functions. We discovered that cocaine injection increases Pyk2 phosphorylation in the striatum of mice in vivo. Pyk2-deficient mice displayed an altered locomotor response to acute cocaine injection. In contrast, they developed normal locomotor sensitization and cocaine-conditioned place preference. Accordingly, a cocaine-activated signaling pathway essential for these late responses, ERK phosphorylation, was not altered. Specific deletion of Pyk2 in the nucleus accumbens or in D1 neurons reproduced this phenotype, whereas deletion of Pyk2 in the dorsal striatum or in A2A receptor-expressing neurons did not. Mice lacking Pyk2 in D1-neurons also displayed lower locomotor response to the D1 receptor agonist SKF-81297 but not to an anticholinergic drug. Our results identify Pyk2 as a regulator of acute locomotor responses to psychostimulants and suggest that changes in Pyk2 expression or activation may alter specific responses to drugs of abuse, or possibly other behavioral responses linked to dopamine action.

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