Neuroadaptations associated with cocaine sensitization in putative DA neurons of the VTA are reverted using an HDACi

Abstract

Drugs of abuse are known to cause long-term changes in the brain that possibly contribute to the individuals vulnerability to develop addiction. These modifications of brain function are mediated by epigenetic modifications in gene expression, chromatin remodeling being one of them. One common type of chromatin remodeling is histone acetylation, which is under the control of histone acetyltransferases (HATs) and histone deacetylases (HDACs). It has been shown that cocaine sensitization alters the intrinsic properties of dopamine (DA) neurons of the ventral tegmental area (VTA), which in turn alter dopamine transmission in the mesocorticolimbic network. One intrinsic property of VTA neurons affected by exposure of drugs of abuse is the hyperpolarization-activated cation current (Ih), which is mediated by HCN channels. Previously, our laboratory has demonstrated a reduction in Ih in VTA DA neurons from cocaine-sensitized rats. Little is known about epigenetic regulation of ion channels by drug exposure, and no studies of epigenetic regulation of h-current have been performed. Using the whole-cell patch clamp technique, we investigated the effects of an HDAC inhibitor (SAHA) on cocaine-induced changes in Ih current. Additionally, we explored the effect of SAHA on rebound excitation in brain slices from cocaine-sensitized rats. In vitro incubation of midbrain slices with SAHA (3 µM for two hours) reversed the cocaine-induced reduction in VTA DA Ih to baseline levels. Current clamp traces also demonstrated SAHA reversal of cocaine-induced Ih reduction concomitant with a reduced action potential firing. These results support the idea that the decreased h-current in VTA DA neurons after cocaine sensitization is epigenetically regulated, and suggests the possibility that HDAC inhibitors could reverse cocaine-induced neuroadaptations in reward circuits.