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Histone deacetylase inhibitors reverse age-related increases in side effects of haloperidol in mice
Janitza L Montalvo-Ortiz1, Daniel W Fisher2, Guadalupe Rodríguez1
1Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward 7-103, Chicago, IL, 60611, USA.
Background:
Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility.
Methods:
In this study, we treated young (2-3 months old) and aged (22-24 months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14 days to evaluate HAL-induced motor side effects. In addition, we pretreated separate groups of young and aged mice with histone deacetylase (HDAC) inhibitors valproic acid (VPA) or entinostat (MS-275) and then administered HAL.
Results:
Our results show that the motor side effects of HAL are exaggerated in aged mice as compared to young mice and that HDAC inhibitors are able to reverse the severity of these deficits. HAL-induced motor deficits in aged mice are associated with an age- and drug-dependent decrease in striatal D2R protein levels and functionality. Further, histone acetylation was reduced while histone tri-methylation was increased at specific lysine residues of H3 and H4 within the Drd2 promoter in the striatum of aged mice. HDAC inhibitors, particularly VPA, restored striatal D2R protein levels and functionality and reversed age- and drug-related histone modifications at the Drd2 promoter.
Conclusions:
These results suggest that epigenetic changes at the striatal Drd2 promoter drive age-related increases in antipsychotic side effect susceptibility, and HDAC inhibitors may be an effective adjunct treatment strategy to reduce side effects in aged populations.
Insights
Epigenetic changes in aged mice increase susceptibility to antipsychotic side effects by reducing dopamine D2 receptor (D2R) function. Histone deacetylase (HDAC) inhibitors reversed these deficits, suggesting a potential treatment strategy.
Area of Science:
- Neuroscience
- Pharmacology
- Epigenetics
Background:
- Older adults exhibit heightened susceptibility to antipsychotic side effects.
- The underlying pharmacodynamic mechanisms remain largely unknown.
- Hypothesis: Age-related epigenetic alterations decrease dopamine D2 receptor (D2R) expression and function.
Purpose of the Study:
- Investigate the role of epigenetic modifications in age-related antipsychotic side effects.
- Determine if histone deacetylase (HDAC) inhibitors can mitigate these effects.
Main Methods:
- Young and aged mice received haloperidol (HAL), a D2R antagonist.
- Mice were pretreated with HDAC inhibitors (valproic acid or entinostat) before HAL administration.
- HAL-induced motor side effects, striatal D2R levels, and epigenetic markers at the Drd2 promoter were assessed.
Main Results:
- Aged mice exhibited exaggerated HAL-induced motor deficits compared to young mice.
- These deficits correlated with decreased striatal D2R protein and function in aged mice.
- HDAC inhibitors reversed motor deficits and restored D2R levels by reversing epigenetic changes at the Drd2 promoter.
Conclusions:
- Epigenetic alterations at the striatal Drd2 promoter contribute to increased antipsychotic side effect susceptibility in aged populations.
- HDAC inhibitors show promise as an adjunct treatment to reduce side effects in older individuals.