Medication in the elderly is always challenging because of the higher risk of experiencing severe side effects associated with age. A good example is antipsychotic drugs (APDs), a common class of medication prescribed to the elderly for the treatment of psychiatric disorders and behavioral and psychological symptoms of dementia (BPSD). In aged patients, the incidence and severity of the side effects such as experiencing extrapyramidal side effects, induced by APDs is increased. Although aging changed in the body could be the cause of pharmacokinetic differences accountable for the increase in sensitivity of the side effects, age-related pharmacodynamic changes at the target receptor level may play a key role in the increased sensitivity of the elderly to the extrapyramidal side effects of APDs. However, the mechanisms underlying these age-related declines in receptor function are not well understood. Recently we identified that histone modifications alter the therapeutic actions of a typical APD, haloperidol, in aged mice6. In addition, the preliminary data in this application demonstrates that increases in the severity of motor- and memory-side effects in aged mice can be related to histone hypoacetylation of the dopamine 2 receptor (D2R) gene (Drd2) promoter that in turn decreases the expression of striatal D2Rs. Co-treatment with histone deacetylase inhibitor (HDACi) restored the expression of striatal D2Rs and reduced age-related increases in the motor- and memory-side effects of haloperidol. Our findings and preliminary results suggest that age-related histone modifications at the gene promoters of target receptors could affect APD action. In this proposal, we seek to confirm the novel epigenetic mechanisms underlying the regulation of APD action during aging and determine whether HDACi could be a candidate to improve APD treatment in the elderly. Our central hypothesis is that age-related increases in the motor- and memory-side effects of APDs are due to histone hypoacetylation on their targeted receptor genes and that these epigenetic changes and their functional consequences can be reversed by co-treatment with HDACi. To test our hypotheses, first, we will verify age-related histone modifications are one of the mechanisms underlying increased sensitivity to side effects induced by APDs. Then, we will identify the HDAC subtype(s) that contribute to histone modification and increase in the severity of APD-induced side effects in aged mice. Finally, we will evaluate the therapeutic benefits of HDACi and APD co-treatment that will reduce the severity of APD-induced side effects in aged mice and in Tg2576 mice, an animal model of Alzheimer’s disease with BPSD. The proposed study will greatly advance our understanding of the mechanisms of age-related epigenetic alterations and their effects on APD action. This mechanistic concept will have implications not only for neuropsychiatric medication but also for other fields of medication in geriatrics. Our study will serve as a guide to investigate epigenetic mechanisms on drug action with ultimate benefit for the aged population.
|Effective start/end date||5/26/16 → 2/28/22|
- National Institute of Mental Health (5R01MH109466-03)