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    Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function

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    Authors
    Sweeney, Carolyn G.
    Kearney, Patrick J.
    Fagan, Rita R.
    Smith, Lindsey A.
    Bolden, Nicholas C.
    Zhao-Shea, Rubing
    Rivera, Iris V.
    Kolpakova, Jenya
    Xie, Jun
    Gao, Guangping
    Tapper, Andrew R.
    Martin, Gilles E.
    Melikian, Haley E.
    Show allShow less
    UMass Chan Affiliations
    Graduate School of Biomedical Sciences, Neuroscience Program
    Tapper Lab
    Martin Lab
    Melikian Lab
    Viral Vector Core
    Gene Therapy Center
    Neurobiology
    Brudnick Neuropsychiatric Research Institute
    Document Type
    Journal Article
    Publication Date
    2019-07-05
    Keywords
    Addiction
    Anxiety
    Excitability
    Gene delivery
    Transporters in the nervous system
    Amino Acids, Peptides, and Proteins
    Behavioral Neurobiology
    Enzymes and Coenzymes
    Nervous System
    Neuroscience and Neurobiology
    Pharmacology
    Substance Abuse and Addiction
    Show allShow less
    
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    Link to Full Text
    https://doi.org/10.1038/s41386-019-0457-x
    Abstract
    Dopamine (DA) signaling is critical for movement, motivation, and addictive behavior. The neuronal GTPase, Rit2, is enriched in DA neurons (DANs), binds directly to the DA transporter (DAT), and is implicated in several DA-related neuropsychiatric disorders. However, it remains unknown whether Rit2 plays a role in either DAergic signaling and/or DA-dependent behaviors. Here we leveraged the TET-OFF system to conditionally silence Rit2 in Pitx3(IRES2-tTA) mouse DANs. Following DAergic Rit2 knockdown (Rit2-KD), mice displayed an anxiolytic phenotype, with no change in baseline locomotion. Further, males exhibited increased acute cocaine sensitivity, whereas DAergic Rit2-KD suppressed acute cocaine sensitivity in females. DAergic Rit2-KD did not affect presynaptic TH and DAT protein levels in females, nor was TH was affected in males; however, DAT was significantly diminished in males. Paradoxically, despite decreased DAT levels in males, striatal DA uptake was enhanced, but was not due to enhanced DAT surface expression in either dorsal or ventral striatum. Finally, patch recordings in nucleus accumbens (NAcc) medium spiny neurons (MSNs) revealed reciprocal changes in spontaneous EPSP (sEPSP) frequency in male and female D1+ and D2+ MSNs following DAergic Rit2-KD. In males, sEPSP frequency was decreased in D1+, but not D2+, MSNs, whereas in females sEPSP frequency decreased in D2+, but not D1+, MSNs. Moreover, DAergic Rit2-KD abolished the ability of cocaine to reduce sEPSP frequency in D1+, but not D2+, male MSNs. Taken together, our studies are among the first to acheive AAV-mediated, conditional and inducible DAergic knockdown in vivo. Importantly, our results provide the first evidence that DAergic Rit2 expression differentially impacts striatal function and DA-dependent behaviors in males and females.
    Source

    Neuropsychopharmacology. 2019 Jul 5. doi: 10.1038/s41386-019-0457-x. [Epub ahead of print] Link to article on publisher's site

    DOI
    10.1038/s41386-019-0457-x
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/37974
    PubMed ID
    31277075
    Notes

    A preprint version of this paper is available at https://escholarship.umassmed.edu/faculty_pubs/1618/.

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    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1038/s41386-019-0457-x
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    Morningside Graduate School of Biomedical Sciences Scholarly Publications
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