Maternal Methamphetamine Exposure Influences Behavioral Sensitization and Nucleus Accumbens DNA Methylation in Subsequent Generation

Abstract

The deleterious effects of methamphetamine (METH) exposure extend beyond abusers, and may potentially impact the vulnerability of their offspring in developing addictive behaviors. Epigenetic signatures have been implicated in addiction, yet the characteristics to identify prenatal METH abuse to offspring addiction risk remains elusive. Here, we used escalating doses of METH-exposed mouse model in F0 female mice before and during pregnancy to simulate the human pattern of drug abuse and generated METH-induced behavioral sensitization to investigate the addictive behavior in offspring mice. We then utilized whole genome-bisulfite sequencing (WGBS) to investigate the methylation signature of nucleus accumbens (NAc) in male METH-sensitized mice. Interestingly, male but not female offspring exhibited an enhanced response to METH-induced behavioral sensitization. Additionally, the METH-exposed group of male mice underwent a more comprehensive wave of epigenome remodeling over all genomic elements compared with unexposed groups due to drug exposure history. 104,219 DMCs (METH-SAL vs. SAL-SAL) induced by prenatal METH-exposure were positively correlated with that of postnatal METH-exposure (38,570, SAL-METH vs. SAL-SAL). Moreover, 4,983 DMCs induced by pre- and postnatal METH exposure (METH-METH vs. SAL-METH) were negatively correlated with that of postnatal METH exposure, and 371 commonly changed DMCs between the two comparison groups also showed a significantly negative correlation and 86 annotated genes functionally enriched in the pathways of neurodevelopment and addiction. Key annotated genes included Kirrel3, Lrpprc, and Peg3, implicated in neurodevelopmental processes, were down-regulated in METH-METH group mice compared with the SAL-METH group. Taken together, we render novel insights into the epigenetic correlation of drug exposure and provide evidence for epigenetic characteristics that link maternal METH exposure to the intensity of the same drug-induced behavioral sensitization in adult offspring.

Prenatal and postnatal methamphetamine exposure alters prefrontal cortical gene expression and behavior in mice

“…The NOR results suggest methamphetamine exposure during both prenatal and postnatal periods may negatively and selectively impact only certain aspects of memory behavior in mice. The decline in NOR behavior, especially in the MM group, suggests an impact of methamphetamine on the mesocorticolimbic pathway, with methamphetamine exposure leading to impairment of recognition memory as a result of normal maturation of these regions, especially during adolescence ( Joca et al, 2014 ; Itzhak et al, 2015 ; Buck et al, 2017 ; Groman et al, 2018 ; Yan et al, 2019 ; Dong et al, 2022 ). The complexity of the methamphetamine biochemical interaction on the behavioral deficits may be an interplay of several factors including pharmacological and genetically related impacts on the dopaminergic system ( Bubenikova-Valesova et al, 2009 ; Groman et al, 2012 ; Buck and Siegel, 2015 ).…”

“…Although this study focused on the impact of prenatal and postnatal exposure to methamphetamine on prefrontal cortical genes, we note that other regions are likely also affected and interface with the PFC through the meso-corticolimbic pathway, such as the hippocampus, and ventral tegmental area (VTA), as well as others ( Theyel et al, 2010 ; Itzhak et al, 2015 ; Lacy et al, 2016 ; Dong et al, 2018 , 2022 ; Sanjari Moghaddam et al, 2021 ). Future work will focus on the interplay with these other regions to better understand the drivers of cognitive activities due to methamphetamine exposure.…”

“…Methamphetamine hydrochloride purchased from Sigma (St. Louis, MO) was dissolved in 0.9% saline, and sterilized to prepare the injectable solution. Methamphetamine solutions (2.0 mg/kg) were administered subsequently at 10 mL/kg body weight during the experimental epochs ( Figure 1 ), which was the optimum average dose identified from prior studies ( Itzhak et al, 2015 ; Dong et al, 2022 ).…”