Cocaine activates Rac1 to control structural and behavioral plasticity in caudate putamen

Li, Juan; Zhang, Lei; Chen, Zhenzhong; Xie, Minjuan; Xue, Jianming; Liu, Yutong; Liu, Nuyun; Guo, Fukun; Zheng, Yi; Kong, Jiming; Lin, Zhihua

doi:10.1016/j.nbd.2014.12.031

Cited by 19 publications

(18 citation statements)

References 120 publications

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“…Lentiviral vectors expressing a constitutively active (Rac1-CA) or dominant-negative Rac1 (Rac1-DN) fused with eGFP or lentivirus-eGFP (LV-eGFP) driven by the CMV promoter were constructed as described in our previous study 24. Recombinant adeno-associated serotype 2/9 (AAV 2/9) viruses expressing mCherry driven by the dopamine D1 receptor gene promoter (Drd1-mCherry) or dopamine D2 receptor gene promoter (Drd2-mCherry) were constructed by BrainVTA (Wuhan, China).…”

Section: Methodsmentioning

confidence: 99%

“…Twenty-four h later, the animals were sacrificed by transcardial perfusion with PBS and 4% PFA. Brains were postfixed with 4% PFA overnight at 4 °C and then placed in 20% and 30% sucrose solutions for 2 d. Next, brain sections including the NAc were sliced at a thickness of 40 μm using a freezing microtome, and these NAc sections were then immunostained with an anti-GFP antibody (Abcam; 1:500) and an Alexa Fluor 488-conjugated anti-rabbit antibody (Invitrogen; 1:200) as described previously 24. All spine images were captured using a Laser Scanning Confocal Microscope (LSCM, Zeiss LSM 780, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Rac1, a member of the Rho GTPase family of small G proteins, is a crucial mediator of actin dynamics and plays a critical role in regulating spine morphological changes 20-22. Based on accumulating evidence, Rac1 contributes to addiction 23, 24 and diverse forms of learning and memory 5, 25, 26. For instance, excessive Rac1 activity in mice lacking BCR (breakpoint cluster region) or ABR (active BCR-related) impairs cognitive functions such as spatial and object recognition memory 27.…”

Section: Introductionmentioning

confidence: 99%

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Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens

Zhao¹,

Li²,

Liu³

et al. 2019

Theranostics

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Rationale: Repeated methamphetamine (METH) exposure induces long-term cognitive deficits and pathological drug-associated memory that can be disrupted by manipulating memory reconsolidation and extinction. The nucleus accumbens (NAc) is the key region of the brain reward system and predominantly consists of two subtypes of medium spiny neurons (MSNs) based on the expression of D1 or D2 dopamine receptors (D1-MSNs or D2-MSNs). Spine structural plasticity in the NAc is critical for the acquisition, reconsolidation and extinction of drug-associated memory. However, the molecular mechanisms underlying METH-associated memory and spine remodelling in each type of MSNs in the NAc remain unknown. Here, we explored whether Rac1 in the NAc mediates METH-associated contextual memory and spine remodelling.Methods: Pharmacological and genetic manipulations of Rac1 were used to investigate its role during the acquisition, reconsolidation and extinction of METH-associated contextual memory. Recombinant adeno-associated viruses expressing mCherry under the control of the dopamine D1 receptor gene promoter (Drd1-mCherry) or dopamine D2 receptor gene promoter (Drd2-mCherry) were used to specifically label D1-MSNs or D2-MSNs.Results: Using viral-mediated gene transfer, we demonstrated that decreased Rac1 activity was required for the acquisition of METH-associated contextual memory and the METH-induced increase in thin spine density, whereas increased Rac1 signalling was important for the extinction of METH-associated contextual memory and the related elimination of thin spines. Moreover, the increase of dendritic spines was both found in D1-MSNs and D2-MSNs during the acquisition process, but extinction training selectively decreased the spine density in D1-MSNs. Interestingly, Rac1 was responsible for METH-induced spine plasticity in D1-MSNs but not in D2-MSNs. Additionally, we found that microinjection of a Rac1 inhibitor or activator into the NAc was not sufficient to disrupt reconsolidation, and the pharmacological activation of Rac1 in the NAc facilitated the extinction of METH-associated contextual memory. Regarding cognitive memory, decreased Rac1 activity improved the METH-induced impairment in object recognition memory.Conclusion: Our findings indicate that Rac1 plays opposing roles in the acquisition and extinction of METH-associated contextual memory and reveal the cell-specific role of Rac1 in METH-associated spine remodelling, suggesting that Rac1 is a potential therapeutic target for reducing relapse in METH addiction and remediating METH-induced recognition memory impairment.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens

Zhao¹,

Li²,

Liu³

et al. 2019

Theranostics

Self Cite

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“…whereas mice with constitutively active Rac1 exhibited blunted morphological and behavioral changes after repeated cocaine exposure. These findings suggest a critical role for Rac1 activity in the CPu in regulating cocaine-related structural and behavioral plasticity (Li et al, 2015b). We did not observe a significant difference in AUTS2 expression, one of the upstream determinants of Rac1 activity, in the CPu after repeated heroin exposure.…”

Section: Discussionmentioning

confidence: 38%

AUTS2 in the nucleus accumbens is essential for heroin-induced behavioral sensitization

et al. 2016

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Autism susceptibility candidate 2 (AUTS2) is a gene associated with autism and mental retardation. Recent studies have suggested an association of the AUTS2 gene with heroin dependence, and reduced AUTS2 gene expression may confer increased susceptibility to heroin dependence. However, the functional role of the AUTS2 protein in regulating enduring neuroadaptations in response to heroin exposure has not been established. Here, we investigated the effects of acute and chronic heroin exposure on AUTS2 mRNA and protein expression in the nucleus accumbens (NAc) and caudate-putamen (CPu) to determine whether changes in AUTS2 expression are associated with heroin-induced locomotor sensitization in mice. Moreover, we explored whether AUST2 knockdown affects heroin-induced locomotor sensitization. AUTS2 mRNA and protein expression in the NAc, but not the CPu, was decreased after chronic heroin (1mg/kg) administration. In the NAc, the expression of heroin-induced locomotor sensitization was enhanced through the lentiviral-AUTS2-shRNA-mediated knockdown of AUTS2, while the overexpression of AUTS2 attenuated the locomotor-stimulant effects of heroin. Together, these results indicate that AUTS2 in the NAc, but not the CPu, suppresses the initiation and expression of heroin-induced behavioral sensitization, suggesting that AUST2 may be a potential target for the treatment of heroin dependence.

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“…Butts and colleagues similarly found an anatomy-specific role for Rac1 and cofilin [115]. In rodents, Rac1 in the dorsal versus ventral striatum plays opposite roles in cocaine-induced reward and spine maturation [214,215]. Furthermore, Scaplen et al recently showed that population-level dopaminergic activation encodes alcohol rewards, whereas specific microcircuits encode cued activation of alcohol memories [216].…”

Section: Future Directionsmentioning

confidence: 99%

Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism

Lathen

Merrill

Rothenfluh

2020

IJMS

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Alcohol use disorder (AUD) exacts an immense toll on individuals, families, and society. Genetic factors determine up to 60% of an individual’s risk of developing problematic alcohol habits. Effective AUD prevention and treatment requires knowledge of the genes that predispose people to alcoholism, play a role in alcohol responses, and/or contribute to the development of addiction. As a highly tractable and translatable genetic and behavioral model organism, Drosophila melanogaster has proven valuable to uncover important genes and mechanistic pathways that have obvious orthologs in humans and that help explain the complexities of addiction. Vinegar flies exhibit remarkably strong face and mechanistic validity as a model for AUDs, permitting many advancements in the quest to understand human genetic involvement in this disease. These advancements occur via approaches that essentially fall into one of two categories: (1) discovering candidate genes via human genome-wide association studies (GWAS), transcriptomics on post-mortem tissue from AUD patients, or relevant physiological connections, then using reverse genetics in flies to validate candidate genes’ roles and investigate their molecular function in the context of alcohol. (2) Utilizing flies to discover candidate genes through unbiased screens, GWAS, quantitative trait locus analyses, transcriptomics, or single-gene studies, then validating their translational role in human genetic surveys. In this review, we highlight the utility of Drosophila as a model for alcoholism by surveying recent advances in our understanding of human AUDs that resulted from these various approaches. We summarize the genes that are conserved in alcohol-related function between humans and flies. We also provide insight into some advantages and limitations of these approaches. Overall, this review demonstrates how Drosophila have and can be used to answer important genetic questions about alcohol addiction.

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Cocaine activates Rac1 to control structural and behavioral plasticity in caudate putamen

Cited by 19 publications

References 120 publications

Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens

Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens

AUTS2 in the nucleus accumbens is essential for heroin-induced behavioral sensitization

Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism

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