Cross-generational THC exposure alters the developmental sensitivity of ventral and dorsal striatal gene expression in male and female offspring

Abstract

Cannabis (Cannabis sativa, Cannabis indica) is the illicit drug most frequently abused by young men and women. The growing use of the drug has raised attention not only on the impact of direct exposure on the developing brain and behavior later in life, but also on potential cross-generational consequences. Our previous work demonstrated that adolescent exposure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, affects reward-related behavior and striatal gene expression in male offspring that were unexposed to the drug during their own lifespan. The significant sex differences documented for most addiction and psychiatric disorders suggest that understanding the perturbation of the brain in the two sexes due to cannabis could provide insights about neuronal systems underpinning vulnerability to psychiatric illnesses. In the current study, we expanded our previous observations in males by analyzing the female brain for specific aberrations associated with cross-generational THC exposure. Based on the impact of adolescent development on subsequent adult behavioral pathology, we examined molecular patterns during both adolescence and adulthood. The results revealed a switch from the ventral striatum during adolescence to the dorsal striatum in adulthood in alterations of gene expression related to synaptic plasticity in both sexes. Females, however, exhibited stronger correlation patterns between genes and also showed locomotor disturbances not evident in males. Overall, the findings demonstrate cross-generational consequences of parental THC exposure in both male and female offspring.

New vistas on cannabis use disorder

“…Nonetheless, the observations that many aberrant effects extend into subsequent generations of offspring whose parents were exposed to cannabinoids before mating (Szutorisz et al 2014; Byrnes et al 2012; Vassoler et al 2013; Watson et al 2015) substantiate the hypothesis that alterations at system level (e.g. glutamatergic, dopaminergic, opioidergic systems) and in synaptic transmission in THC offspring might have trans-generational effects (Szutorisz et al 2016; Szutorisz and Hurd, 2016). Particularly, epigenetic aberrations influencing the risk and conferring an endophenotype to SUDs can also be inherited through parental germline (Vassoler and Sadri-Vakili 2014, Watson et al 2015).…”

Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis

“…RNA expression differences have also been demonstrated in the NAc of adult male and female C57BL/6J mice following binge ethanol drinking sessions that was strongly influenced by sex . Parental germline cannabinoid exposures caused stronger alterations in mRNA co‐expression patterns for synaptic plasticity genes in the dorsal striatum of female Long‐Evans rats . Identifying the molecular changes brought about by drug exposure can help identify the neurobiological substrates that are impacted in both sexes and define sex‐specific risk factors.…”

Impaired cocaine‐induced behavioral plasticity in the male offspring of cocaine‐experienced sires

“…Chromatin remodeling is associated with stable and persistent changes to the transcriptome that may contribute to the development of addiction and other psychiatric diseases (Maze et al., ; Renthal & Nestler, ). Paternal drug exposure produces broad changes in gene expression in the brain reward pathway of the next generation (Rompala, Finegersh, Slater, & Homanics, ; Szutorisz, Egervari, Sperry, Carter, & Hurd, ; Vassoler et al., ), which may be driven by remodeling of histone modifications (Vassoler et al., ). Therefore, we also examined histone PTMs in the nucleus accumbens, a region important for regulating forms of cocaine‐induced behavioral plasticity including cocaine self‐administration and behavioral sensitization.…”