Histone deacetylase inhibitors modulates the induction and expression of amphetamine-induced behavioral sensitization partially through an associated learning of the environment in mice.
The behavioral sensitization produced by repeated amphetamine treatment may represent the neural adaptations underlying some of the features of psychosis and addiction in humans. Chromatin modification (specifically histone hyperacetylation) was recently recognized as an important regulator of psychostimulant-induced plasticity. We have investigated the effects of treatment with the histone deacetylase (HDAC) inhibitors butyric acid (BA, 630mg/kg, i.p.) and valproic acid (VPA, 175mg/kg, i.p.) on the psyhcostimulant locomotor sensitization induced by amphetamine (AMPH, 2.0mg/kg, i.p.). Neither BA nor VPA had locomotor effects alone, but both significantly potentiated the amphetamine-induced behavioral sensitization in mice. At the molecular level, VPA and amphetamine produced an increase of histone H4 acetylation in the striatum as detected by Western blot analysis, while co-treatment with VPA and AMPH produced an additive effect on histone H4 acetylation. We then administered the HDAC inhibitors after treatment with amphetamine for 8 days to establish locomotor sensitization. We found that repeated administration of VPA or BA for 6 days inhibited the expression of sensitized response following amphetamine challenge. Finally, in a context-specific model we studied the effect of HDAC inhibitors on amphetamine-induced association of the treatment environment (associative learning). We found that VPA and BA enhance the context-specificity of expression of amphetamine sensitization. Thus, HDAC inhibitors differentially modulate the induction and expression of amphetamine-induced effects. Together, these results suggest that dynamic changes in chromatin modification may be an important mechanism underlying amphetamine-induced neuronal plasticity and associative learning.
Kalda
Anti
A
Department of Pharmacology, Centre of Excellence of Molecular and Clinical Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia. anti.kalda@ut.ee
Heidmets
Lenne-Triin
LT
Shen
Hai-Ying
HY
Zharkovsky
Alexander
A
Chen
Jiang-Fan
JF
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001245:Association Learning / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D020148:Butyric Acid / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004347:Drug Interactions; D004777:Environment; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology
D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D006657:Histones; D020148:Butyric Acid; D014635:Valproic Acid; D000661:Amphetamine