Not all stimulant drugs are the same: insights from histone acetylation and deacetylation

V. BISAGNO

Simposio; ASN 2021 Virtual Meeting; 2021

ASN

Psychostimulants produce different behavioral and neurobiological profiles. For example, some stimulants cause neuroplastic changes leading to addiction and cognitive deficits while others enhance cognition. Epigenetic mechanisms are known contributory factors to drug-induced neuroadaptations. These epigenetic changes include dysregulation of histone deacetylases (HDACs) proposed to participate in maintaining aberrant transcriptional programs associated with altered cognitive functions and behaviors. We have previously reported that the psychostimulant drugs modafinil and methamphetamine differentially influence the acetylation status of histones 3 and 4 at promoters of HDACs in the mouse prefrontal cortex. HDACs are divided into zinc-dependent [class I (HDAC1,2,3,8), class IIa (HDAC4,5,7,9), class IIb (HDAC6,10), and class IV (HDAC11)] and NAD-dependent [class III (sirtuins1-7)] enzymes. Interestingly, class IIa (4, 5, 7, 9) HDACs get phosphorylated and exported from the nucleus to cytoplasm after various stimuli. The phosphorylation state of Class IIa HDACs can impact their enzymatic activity. In this talk, we will present evidence that psychostimulants (modafinil, methamphetamine and caffeine) differently influence the expression of Class IIa HDAC in vivo (mouse prefrontal cortex and dorsal striatum) and in vitro (N2a cell line). The differential impact of these psychostimulant drugs on these HDACs might offer a partial explanation for some of their divergent behavioral effects and therapeutic profiles. Continued under¬standing of how psychostimulants drugs alter epigenetic regulators is essential for iden¬ti¬fying transcriptional changes that occur after exposure to these drugs.