Transgenerational attenuation of opioid self-administration as a consequence of adolescent morphine exposure

Abstract

The United States is in the midst of an opiate epidemic, with abuse of prescription and illegal opioids increasing steadily over the past decade. While it is clear that there is a genetic component to opioid addiction, there is a significant portion of heritability that cannot be explained by genetics alone. The current study was designed to test the hypothesis that maternal exposure to opioids prior to pregnancy alters abuse liability in subsequent generations. Female adolescent Sprague Dawley rats were administered morphine at increasing doses (5–25 mg/kg, s.c.) or saline for 10 days (P30–39). During adulthood, animals were bred with drug-naïve colony males. Male and female adult offspring (F1 animals) were tested for morphine self-administration acquisition, progressive ratio, extinction, and reinstatement at three doses of morphine (0.25, 0.75, 1.25 mg/kg/infusion). Grandoffspring (F2 animals, from the maternal line) were also examined. Additionally, gene expression changes within the nucleus accumbens were examined with RNA deep sequencing (PacBio) and qPCR. There were dose- and sex-dependent effects on all phases of the self-administration paradigm that indicate decreased morphine reinforcement and attenuated relapse-like behavior. Additionally, genes related to synaptic plasticity, as well as myelin basic protein (MBP), were dysregulated. Some, but not all, effects persisted into the subsequent (F2) generation. The results demonstrate that even limited opioid exposure during adolescence can have lasting effects across multiple generations, which has implications for mechanisms of the transmission of drug abuse liability in humans.

Sex differences in neural mechanisms mediating reward and addiction

“…Finally, some effects of maternal opioid exposure were transgenerational, as they were found in the F2 generation. For example, F2 females of F0 dams exposed to morphine during adolescence showed reduced morphine self-administrationsimilar to effects observed in the F1 generation [137]. Expression levels of a number of synaptic plasticity genes were examined in the nucleus accumbens of F1 and F2 males and females.…”

“…Although there are numerous studies, particularly from the Byrnes lab [136,137], that explored multigenerational effects of parental opioid exposure, sex differences in direct effects on dopamine systems were not specifically reported. As such, this represents a gap in knowledge open to investigation.…”

“…Organizational influences: epigenetics Parental (F0) opioid exposure has sex-dependent effects on offspring: A series of studies from the Byrnes lab [137,[151][152][153][154][155] examined the impact of adolescent morphine exposure in female rats (F0) on behavioral and molecular measures in the F1 offspring at different developmental times.…”

Multigenerational and transgenerational effects of paternal exposure to drugs of abuse on behavioral and neural function

“…The majority of multigenerational and transgenerational opioid exposure studies have involved maternal opioid exposure (Byrnes, 2005;Byrnes et al, 2011Byrnes et al, , 2013Johnson et al, 2011;Vassoler et al, , 2016Vassoler et al, , 2017Vassoler et al, , 2018. However, a few studies have investigated behavioral and neurobiological differences in the offspring of opioid-exposed sires (Table 3).…”

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

“…A growing body of evidence indicates that ancestral exposure to all of the major classes of abused drugs influences the physiology and behavior of descendants (Finegersh, Rompala, Martin, & Homanics, 2015;Finegersh, Ferguson et al, 2015;Szutorisz et al, 2014;Vassoler, White, Schmidt, Sadri-Vakili, & Pierce, 2013;Vassoler, Wright, & Byrnes, 2016;Vassoler et al, 2017;White, Vassoler, Schmidt, Pierce, & Wimmer, 2015;Yohn, Bartolomei, & Blendy, 2015). Several reports have consistently shown that sire exposure to cocaine influences cocaine-associated behaviors in the next generation.…”