Effects of the histone deacetylase inhibitor sodium butyrate in models of depression and anxiety.
Histone modification, which affects the rate of transcription without altering DNA sequence, occurs in response to various psychiatric drugs and in several models of psychiatric disease. As increases in histone acetylation have been seen after treatment with antidepressants, we investigated whether directly increasing histone acetylation using a histone deacetylase inhibitor would have antidepressant effects. We administered sodium butyrate (NaB, 100 mg/kg, i.p.) to mice acutely (3 injections over 24 h) or chronically (twice daily for 21 days) and subjected them to a number of behavioral tests of antidepressant response. This dose of NaB had no effect on overall locomotor activity after either acute or chronic treatment. Acutely treated mice showed an increase in immobility in the forced-swim test (FST) and an increase in latency to consume in the novel environment of the novelty-induced hypophagia (NIH) paradigm, an anxiogenic effect. The effect of NaB on anxiety did not generalize to another test, the elevated zero maze, where it had no effect. Chronic treatment with NaB had no effect on latency to consume in the NIH or immobility in the FST. However, this dose did alter histone acetylation in the hippocampus. While H4 acetylation increased in the hippocampus 30 min following acute NaB, chronic treatment caused a decrease in AcH4. There were no changes in AcH3 following either treatment. While changes in chromatin structure may be involved in the mechanism of action of antidepressant drugs, these data suggest that increasing histone acetylation pharmacologically is not sufficient to produce antidepressant effects.
Gundersen
Brigitta B
BB
Department of Pharmacology, University of Pennysylvania, School of Medicine, Translational Research Labs, 125 S. 31st St, Philadelphia, PA 19104, USA.
Blendy
Julie A
JA
D000107:Acetylation / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002087:Butyrates / Q000494:pharmacology* / Q000627:therapeutic use; D002707:Chlordiazepoxide / Q000494:pharmacology / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D003891:Desipramine / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D013550:Swimming; D013997:Time Factors
D014151:Anti-Anxiety Agents; D000929:Antidepressive Agents, Tricyclic; D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D002707:Chlordiazepoxide; D006655:Histone Deacetylases; D003891:Desipramine