• Links between circadian rhythms, metabol

    From ScienceDaily@1:317/3 to All on Friday, March 11, 2022 21:30:42
    Links between circadian rhythms, metabolism and addiction
    Findings reveal possible role for peripheral organs in substance use
    disorders

    Date:
    March 11, 2022
    Source:
    University of California - Irvine
    Summary:
    A new study establishes important conceptual connections between
    the fields of circadian rhythms, metabolism, and addiction. Going
    beyond current studies on substance use disorders, which focus
    on the impact of addictive drugs on the brain, this new research
    highlights an existing connection between specific neurons and
    peripheral organs.



    FULL STORY ==========================================================================
    A new University of California, Irvine-led study establishes important conceptual connections between the fields of circadian rhythms,
    metabolism, and addiction. Going beyond current studies on substance use disorders, which focus on the impact of addictive drugs on the brain,
    this new research highlights an existing connection between specific
    neurons and peripheral organs.


    ==========================================================================
    The study, titled "Dopamine D2 receptor signaling in the brain modulates circadian liver metabolomic profiles," was published today in the
    Proceedings of the National Academy of Sciences.

    "Our findings provide a link to substance use disorders and metabolic dysfunctions," explained Emiliana Borrelli, PhD, professor of Microbiology
    & Molecular Genetics at UCI School of Medicine who, for this study, collaborated with the late Paolo Sassone-Corsi, PhD, professor of
    Biological Chemistry at UCI. "Through our research we explored how the disruption of normal neuronal functions affects metabolic activity and
    may move the body to an altered state away from homeostasis, which
    could contribute to the drug seeking behaviors exhibited by people
    with substance use disorders." By analyzing the liver metabolome of
    mice deficient in the expression of the dopamine D2 receptor (D2R) in
    striatal medium spiny neurons, the researchers found profound changes in
    the liver circadian metabolome compared to control mice. In addition,
    they found that activation of dopaminergic circuits by acute cocaine administration reprograms the circadian liver metabolome.

    "D2R signaling in medium spiny neurons is key for striatal output and is essential for regulating the first response to the cellular and rewarding effects of cocaine," said Borrelli. "Thus, our results suggest that
    changes in dopamine signaling in specific striatal neurons evoke major
    changes in liver physiology. Dysregulation of liver metabolism could
    contribute to an altered allostatic state and therefore be involved in continued use of drugs." The circadian clock is tightly intertwined
    with metabolism and relies heavily on multifaceted interactions between
    organ systems to maintain proper timing.

    Genetic and/or environmental causes can disrupt communication between
    organs and alter rhythmic activities. Substance use leads to altered
    dopamine signaling followed by reprogramming of circadian gene expression
    and metabolism in the reward system.

    This study shows that dopamine D2 receptors (D2R) in striatal medium spiny neurons (MSNs) play a key role in regulating diurnal liver metabolic activities. In addition, drugs that increase dopamine levels, such as
    cocaine, disrupt circadian metabolic profiles in the liver, which is exacerbated by loss of D2R signaling in MSNs. These results uncover a
    strict communication between neurons/brain areas and liver metabolism
    as well as the association between substance use and systemic deficits,"
    said Borrelli.

    Substance use disorders affect millions of people worldwide. The
    rewarding properties of substances, such as alcohol, nicotine, opioids,
    and psychostimulants, are linked to their ability to increase dopamine
    levels in brain areas that control emotions and induce pleasure. Drug
    intake modifies neuronal plasticity and is at the start of the process
    of addiction, which leads vulnerable individuals to continually seek and
    abuse these substances despite the adverse consequences on their lives.

    This study was funded by grants from the National Institutes of Health
    under Award Number DA035600 and by the French Institut National de la
    Sante et de la Recherche Medicale (INSERM).

    Future studies will examine whether the alterations in the specific
    metabolites identified in this study contribute to susceptibility to
    drug use.


    ========================================================================== Story Source: Materials provided by
    University_of_California_-_Irvine. Note: Content may be edited for style
    and length.


    ========================================================================== Journal Reference:
    1. Marlene Cervantes, Robert G. Lewis, Maria Agnese Della-Fazia,
    Emiliana
    Borrelli, Paolo Sassone-Corsi. Dopamine D2 receptor signaling in the
    brain modulates circadian liver metabolomic profiles. Proceedings
    of the National Academy of Sciences, 2022; 119 (11) DOI:
    10.1073/pnas.2117113119 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220311115311.htm

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