Alcohol-induced serotonergic modulation: the role of histone deacetylases.
Previous studies have demonstrated that alcohol use disorders (AUDs) are regulated by multiple mechanisms such as neurotransmitters and enzymes. The neurotransmitter, serotonin (5-hydroxytryptamine, 5-HT) may contribute to alcohol effects and serotonin receptors, including 5-HT3, play an important role in AUDs. Recent studies have also implicated histone deacetylases (HDACs) and acetyltransferases (HATS) in regulation of drug addiction, and HDAC inhibitors (HDACi) have been reported as transcriptional modulators of monoaminergic neurotransmission. Therefore, we hypothesize that HDACs may play a role in ethanol-induced serotonergic modulation. The effects of ethanol on serotonin and 5-HT3, and the role HDACs, HDAC activity and the HDACi, trichostatin A (TSA), play in alcohol-induced serotonergic effects were studied. Human SK-N-MC and neurons, were treated with ethanol (0.05, 0.1 and 0.2%), and/or TSA (50 nM), and 5-HT3 levels were assessed at 24-72 h. Gene expression was evaluated by qRT-PCR and protein by western blot and flow cytometry. Serotonin release was assessed by ELISA and HDAC activity by fluorometric assay. Our results show an increase in 5-HT3 gene after ethanol treatment. Further, ethanol significantly increased HDACs 1 and 3 genes accompanied by an increased in HDAC activity while TSA significantly inhibited HDACs. Studies with TSA show a significant upregulation of ethanol effects on 5-HT3, while surprisingly TSA inhibited ethanol-induced serotonin production. These results suggest that ethanol affects 5-HT3 and serotonin through mechanisms involving HDACs and HATs. In summary, our studies demonstrate some of the novel properties of HDAC inhibitors and contribute to the understanding of the mechanisms involve in alcohol-serotonergic modulation in the CNS.
Florida International University, Miami, 33199, USA.
Marisela
M
Agudelo
Changwon
C
Yoo
Madhavan P
MP
Nair
D015153:Blotting, Western; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000633:toxicity*; D005434:Flow Cytometry; D005470:Fluorometry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D017294:Ondansetron / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000201:enzymology; D012701:Serotonin / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation; D000099186:Histone Deacetylase 3
D000431:Ethanol; D051548:Histone Acetyltransferases; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D017294:Ondansetron; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D058831:Serotonin 5-HT3 Receptor Antagonists; D000099186:Histone Deacetylase 3; C012589:trichostatin A; C110550:HDAC1 protein, human