Abstract
Nicotine induces long-term changes in the neural activity of the mesocorticolimbic reward pathway structures. The mechanisms involved in this process have not been fully characterized. The hypothesis discussed here proposed that epigenetic regulation participates in the installation of persistent adaptations and long-lasting synaptic plasticity generated by nicotine action on the mesolimbic dopamine neurons of zebrafish. The epigenetic mechanisms induced by nicotine entail histone and DNA chemical modifications, which have been described to lead to changes in gene expression. Among the enzymes that catalyze epigenetic chemical modifications, histone deacetylases (HDACs) remove acetyl groups from histones, thereby facilitating DNA relaxation and making DNA more accessible to gene transcription. DNA methylation, which is dependent on DNA methyltransferase (DNMTs) activity, inhibits gene expression by recruiting several methyl binding proteins that prevent RNA polymerase binding to DNA. In zebrafish, phenylbutyrate (PhB), an HDAC inhibitor, abolishes nicotine rewarding properties together with a series of typical reward-associated behaviors. Furthermore, PhB and nicotine alter long- and short-term object recognition memory in zebrafish, respectively. Regarding DNA methylation effects, a methyl group donor L-methionine (L-met) was found to dramatically reduce nicotine-induced conditioned place preference (CPP) in zebrafish. Simultaneous treatment with DNMT inhibitor 5-aza-2'-deoxycytidine (AZA) was found to reverse the L-met effect on nicotine-induced CPP as well as nicotine reward-specific effects on genetic expression in zebrafish. Therefore, pharmacological interventions that modulate epigenetic regulation of gene expression should be considered as a potential therapeutic method to treat nicotine addiction.