Study, Dec 22: Aspartame-induced anxiety and changes in glutamate-GABA signaling

The full title of this American study is “Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala”.

https://pubmed.ncbi.nlm.nih.gov/36459641/

Significance

Exposure of mice to aspartame, an artificial sweetener found in nearly 5,000 diet foods and drinks, at doses equivalent to below 15% of the FDA recommended maximum daily intake for humans, produces anxiety-like behavior. The anxiety is alleviated by diazepam, a drug used in the treatment of generalized anxiety disorder. The aspartame exposure produces changes in the expression of genes regulating excitation-inhibition balance in the amygdala, a brain region that regulates anxiety and fear. The anxiety, its response to diazepam and the changes in amygdala gene expression are not limited to the aspartame-exposed individuals but also appear in up to two generations descending from the aspartame-exposed males.

Abstract

We report the effects of aspartame on anxiety-like behavior, neurotransmitter signaling and gene expression in the amygdala, a brain region associated with the regulation of anxiety and fear responses. C57BL/6 mice consumed drinking water containing 0.015% or 0.03% aspartame, a dose equivalent of 8 to 15% of the FDA recommended maximum human daily intake, or plain drinking water. Robust anxiety-like behavior (evaluated using open field test and elevated zero maze) was observed in male and female mice consuming the aspartame-containing water. Diazepam, an allosteric modulator of the GABA-A receptor, alleviated the anxiety-like behavior. RNA sequencing of the amygdala followed by KEGG biological pathway analysis of differentially expressed genes showed glutamatergic and GABAergic synapse pathways as significantly enriched. Quantitative PCR showed upregulation of mRNA for the glutamate NMDA receptor subunit 2D (Grin2d) and metabotropic receptor 4 (Grm4) and downregulation of the GABA-A receptor associated protein (Gabarap) mRNA. Thus, taken together, our diazepam and gene expression data show that aspartame consumption shifted the excitation-inhibition equilibrium in the amygdala toward excitation. Even more strikingly, the anxiety-like behavior, its response to diazepam, and changes in amygdala gene expression were transmitted to male and female offspring in two generations descending from the aspartame-exposed males. Extrapolation of the findings to humans suggests that aspartame consumption at doses below the FDA recommended maximum daily intake may produce neurobehavioral changes in aspartame-consuming individuals and their descendants. Thus, human population at risk of aspartame’s potential mental health effects may be larger than current expectations, which only include aspartame-consuming individuals.

Full text available at:

https://www.pnas.org/doi/10.1073/pnas.2213120119