title: 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.
authors.affiliation: Cummings School at Tufts University, 200 Westboro Road, North Grafton, MA 01536, USA. Electronic address: fair.vassoler@gmail.com.
authors.forename: Fair M
authors.initials: FM
authors.lastname: Vassoler
authors.affiliation: University of South Carolina College of Pharmacy, 773 Sumter St, Columbia, SC 29208, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Oliver
authors.affiliation: Cummings School at Tufts University, 200 Westboro Road, North Grafton, MA 01536, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Wyse
authors.affiliation: Cummings School at Tufts University, 200 Westboro Road, North Grafton, MA 01536, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Blau
authors.affiliation: University of South Carolina College of Pharmacy, 773 Sumter St, Columbia, SC 29208, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Shtutman
authors.affiliation: University of South Carolina College of Pharmacy, 773 Sumter St, Columbia, SC 29208, USA.
authors.forename: Jill R
authors.initials: JR
authors.lastname: Turner
authors.affiliation: Cummings School at Tufts University, 200 Westboro Road, North Grafton, MA 01536, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Byrnes
mesh_terms: D000367:Age Factors; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics* / Q000517:prevention & control* / Q000523:psychology; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D005260:Female; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D009020:Morphine / Q000008:administration & dosage*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine
keywords: Epigenetic; Myelin basic protein; Opiate; RNA sequencing; Self-administration; Transgenerational