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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