In this study, we investigated the effect of histone acetylation on the transcription of adrenergic-induced genes in rat pinealocytes. We found that treatment of pinealocytes with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, caused hyperacetylation of histone H3 Lys14 at nanomolar concentrations. Hyperacetylation of histone H3 was also observed following treatment with scriptaid, a structurally unrelated HDAC inhibitor. The effects of TSA and scriptaid were inhibitory on the adrenergic induction of arylalklyamine-N-acetyltransferase (aa-nat) mRNA, protein and enzyme activity, and on melatonin production. TSA at higher concentrations also inhibited the adrenergic induction of mapk phosphatase-1 (mkp-1) and inducible cAMP early repressor (icer) mRNAs. In contrast, the effect of TSA on the NE induction of the c-fos mRNA was stimulatory. Moreover, the effect of TSA on adrenergic-induced gene transcription was dependent on the time of its addition; its effect was only observed during the active phase of transcription. Chromatin immunoprecipitation with antibodies against acetylated Lys14 of histone H3 showed an increase in DNA recovery of the promoter regions of aa-nat, mkp-1 and c-fos following treatment with TSA. Together, our results demonstrate that histone acetylation differentially influences the transcription of adrenergic-induced genes; an enhancing effect for c-fos but inhibitory for aa-nat, mkp-1 and icer. Moreover, both inhibitory and enhancing effects appear to be mediated through specific modification of promoter-bound histones during gene transcription.