Knockdown of the histone di-methyltransferase G9a in nucleus accumbens shell decreases cocaine self-administration, stress-induced reinstatement, and anxiety

Abstract

Comorbid neuropsychiatric disorders such as addiction and anxiety could involve common underlying mechanisms. One potential mechanism involves epigenetic regulation of histone 3 dimethylation at lysine 9 residues (H3K9me2) by the histone dimethyltransferase G9a. Here we provide evidence that local AAV-RNAi-mediated knockdown of G9a expression in nucleus accumbens shell (NAcSh) of male rats reduces both addictive-related and anxiety-related behaviors. Specifically, G9a knockdown reduces sensitivity to low dose cocaine reinforcement when cocaine is freely available (fixed ratio schedule). Similarly, G9a knockdown reduces motivation for cocaine under higher effort demands (progressive ratio schedule). Following several weeks of forced abstinence, G9a knockdown attenuates extinction responding and reinstatement triggered by either cocaine-priming injections or footshock stress. This decrease in addictive behavior is associated with a long-term reduction in anxiety-like behavior as measured by the elevated plus maze (EPM). G9a knockdown also reduces basal anxiety-like behavior in EPM and marble burying tests in drug-naïve rats. These results complement our previous work showing that increased G9a expression in NAcSh enhances addictive-related and anxiety-related behaviors, indicating that G9a bi-directionally controls these responses. These results also suggest that regulation of G9a-influenced gene expression could be a common epigenetic mechanism for co-morbid anxiety and psychostimulant addiction.

Fetal Programming by Methyl Donors Modulates Central Inflammation and Prevents Food Addiction-Like Behavior in Rats

“…For example, changes in DNA methylation could be responsible for neuroplasticity changes induced by addictive drugs, such as repeated cocaine administration reduced global levels of H3K9 dimethylation in the NAc, which correlates with changes in dendritic spines (Maze et al, 2010). Also, changes of the histone dimethyltransferase G9a in the NAc shell actively affect cocaine self-administration in rats (Anderson et al, 2018(Anderson et al, , 2019. Of importance, DNA methylation in NAc during drug addiction seems to respond to a time-dependent regulation, enhancing DNA methylation in the NAc after 30 days of cocaine withdrawal (Massart et al, 2015), suggesting that an increase in DNA methylation is responsible for cocaine craving.…”

Dopamine Receptor D1 Contributes to Cocaine Epigenetic Reprogramming of Histone Modifications in Male Germ Cells

“…In line with this, we found that cocaine treatment increased KMT1C/G9A and decreased KDM1A/LSD1 enzymes. KMT1C/G9A is a key mediator of the epigenetic effects of cocaine in the mesolimbic system (Maze et al, 2010;Anderson et al, 2019) and has been described as a crucial epigenetic marker of heterochromatin formation during meiosis (Tachibana et al, 2007). KDM1A/LSD1 participates in the demethylation of H3K4/K9 and is required for spermatogonial differentiation and germ cell survival in mice (Myrick et al, 2017).…”

The Paraventricular Nucleus of the Thalamus as an Integrating and Relay Node in the Brain Anxiety Network

“…The NAcSh has been mostly studied for its role in reward and appetitive behaviors ( Nicola, 2007 ; Floresco, 2015 ; Namburi et al, 2016 ). However, there is ample evidence that the NAcSh regulates defensive responses ( Reynolds and Berridge, 2001 , 2002 , 2003 , 2008 ; Newton et al, 2002 ; Barrot et al, 2005 ; Al-Hasani et al, 2015 ; Ramirez et al, 2015 ; Zhu et al, 2016 ; Anderson et al, 2018 ; Lee et al, 2018 ; Piantadosi et al, 2018 ) including anxiety ( Martinez et al, 2002 ; Lopes et al, 2007 , 2012 ; da Cunha et al, 2008 ). It is generally accepted that the striatum including the NAcSh integrates cognitive and affective information from the cortex and thalamus in a way that leads to the selection or promotion of an appropriate behavioral response ( Nicola, 2007 ; Floresco, 2015 ; Namburi et al, 2016 ) especially where the outcome of an action is ambiguous ( Namburi et al, 2016 ).…”