Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis

Bubier, Jason A.; Philip, Vivek; Dickson, Price E.; Mittleman, Guy; Chesler, Elissa J.

doi:10.3389/fnins.2020.00721

Cited by 5 publications

(4 citation statements)

References 49 publications

(63 reference statements)

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“…For instance, Rab3d , a synaptic vesicular GTP-binding protein ( 39 ), was downregulated in both sexes during cocaine-seeking. Supporting our finding, Rab3 expression, including isoform Rab3d , has previously been associated with increased cocaine responses ( 40 ). Although Rab3d expression was downregulated in cocaine-seeking for both sexes, expression was increased only in females for both sucrose-seeking and overlapping ensembles, suggesting that Rab3d has a sex-dependent alternative role in natural reward signaling.…”

Section: Discussionsupporting

confidence: 89%

Differential genetic expression within reward-specific ensembles in mice

Litif,

Flom,

Sandum

et al. 2023

Preprint

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Maladaptive reward seeking is a hallmark of cocaine use disorder. To develop therapeutic targets, it is critical to understand the neurobiological changes specific to cocaine-seeking without altering the seeking of natural rewards, e.g., sucrose. The prefrontal cortex (PFC) and the nucleus accumbens core (NAcore) are known regions associated with cocaine- and sucrose-seeking ensembles, i.e., a sparse population of co-activated neurons. Within ensembles, transcriptomic alterations in the PFC and NAcore underlie the learning and persistence of cocaine- and sucrose-seeking behavior. However, transcriptomes exclusively driving cocaine seeking independent from sucrose seeking have not yet been defined using a within-subject approach. Using FosiCreERT2/+/Ai14 transgenic mice in a dual cocaine and sucrose self-administration model, we fluorescently sorted (FACS) and characterized (RNAseq) the transcriptomes defining cocaine- and sucrose-seeking ensembles. We found reward-, sex-, and region-specific transcriptomic changes that refine clinically relevant genetic approaches to decrease cocaine-seeking behavior without altering non-drug reward-based positive reinforcement.

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Section: Discussionsupporting

confidence: 89%

Differential genetic expression within reward-specific ensembles in mice

Litif,

Flom,

Sandum

et al. 2023

Preprint

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“…These behavioral data, along with gene expression data from fentanyl exposed and drug naïve mice, would be integrated with publicly available genotype data and used in a comprehensive systems genetics analysis 18 . Using this approach, we have previously identified genetic mechanisms influencing addiction-relevant phenotypes including intravenous cocaine self-administration 6 , 19 , 21 . Collectively, the data presented here provide a path for discovery and dissection of genetic mechanisms driving fentanyl addiction.…”

Section: Discussionmentioning

confidence: 99%

Intravenous fentanyl self-administration in male and female C57BL/6J and DBA/2J mice

Leonardo

Brunty

Huffman

et al. 2023

Sci Rep

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The genetic mechanisms underlying fentanyl addiction, a highly heritable disease, are unknown. Identifying these mechanisms will lead to better risk assessment, early diagnosis, and improved intervention. To this end, we used intravenous fentanyl self-administration to quantify classical self-administration phenotypes and addiction-like fentanyl seeking in male and female mice from the two founder strains of the BXD recombinant inbred mouse panel (C57BL/6J and DBA/2J). We reached three primary conclusions from these experiments. First, mice from all groups rapidly acquired intravenous fentanyl self-administration and exhibited a dose–response curve, extinction burst, and extinction of the learned self-administration response. Second, fentanyl intake (during acquisition and dose response) and fentanyl seeking (during extinction) were equivalent among groups. Third, strain effects, sex effects, or both were identified for several addiction-like behaviors (cue-induced reinstatement, stress-induced reinstatement, escalation of intravenous fentanyl self-administration). Collectively, these data indicate that C57BL/6J and DBA/2J mice of both sexes were able to acquire, regulate, and extinguish intravenous fentanyl self-administration. Moreover, these data reveal novel strain and sex effects on addiction-like behaviors in the context of intravenous fentanyl self-administration in mice and indicate that the full BXD panel can be used to identify and dissect the genetic mechanisms underlying these effects.

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“…Several previous studies have highlighted the association between cocaine addiction and RHO GTPases, such as PDZ-RHOGEF/RAP1B (Rho-guanine nucleotide exchange factor PDZ/Ras-related protein Rap-1b) and KAL-7/RAC1/PAK [kalirin-7/rac family small GTPase 1/ p21 (RAC1)-activated kinase] pathways (53)(54)(55)(56)(57). These pathways have been implicated in synaptic remodeling and the plasticity of dendritic spines in NAc, particularly during cocaine withdrawal.…”

Section: Further Analysis Of the Nac Proteome After Prolonged Withdrawalmentioning

confidence: 99%

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

Mews,

Sosnick,

Gurung

et al. 2024

Sci. Signal.

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Cocaine use disorder (CUD) is a chronic neuropsychiatric condition that results from enduring cellular and molecular adaptations. Among substance use disorders, CUD is notable for its rising prevalence and the lack of approved pharmacotherapies. The nucleus accumbens (NAc), a region that is integral to the brain’s reward circuitry, plays a crucial role in the initiation and continuation of maladaptive behaviors that are intrinsic to CUD. Leveraging advancements in neuroproteomics, we undertook a proteomic analysis that spanned membrane, cytosolic, nuclear, and chromatin compartments of the NAc in a mouse model. The results unveiled immediate and sustained proteomic modifications after cocaine exposure and during prolonged withdrawal. We identified congruent protein regulatory patterns during initial cocaine exposure and reexposure after withdrawal, which contrasted with distinct patterns during withdrawal. Pronounced proteomic shifts within the membrane compartment indicated adaptive and long-lasting molecular responses prompted by cocaine withdrawal. In addition, we identified potential protein translocation events between soluble-nuclear and chromatin-bound compartments, thus providing insight into intracellular protein dynamics after cocaine exposure. Together, our findings illuminate the intricate proteomic landscape that is altered in the NAc by cocaine use and provide a dataset for future research toward potential therapeutics.

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Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis

Cited by 5 publications

References 49 publications

Differential genetic expression within reward-specific ensembles in mice

Differential genetic expression within reward-specific ensembles in mice

Intravenous fentanyl self-administration in male and female C57BL/6J and DBA/2J mice

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

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