Female adolescent exposure to cannabinoids causes transgenerational effects on morphine sensitization in female offspring in the absence of in utero exposure

Abstract

Female adolescent marijuana use is increasing, yet the effect on future offspring is unknown. Here, adolescent female Sprague Dawley rats (postnatal-day 30; PN30) were given subcutaneous (s.c.) injections with the cannabinoid agonist WIN-55,212 (WIN) or its vehicle (VEH) for three consecutive days using a twice-daily, increasing dosage regimen (1 mg/kg day 1; 2 mg/kg day 2; 4 mg/kg day 3). As adults (PN60), females were mated with drug-naïve males. Their adult female offspring (VEH-F1 or WIN-F1) were tested for behavioral sensitization by administering morphine (0 or 7.5 mg/kg s.c.) every other day for a total of five administrations. Following five days of abstinence, all animals received a morphine challenge (7.5 mg/kg s.c.) and locomotor activity was monitored. At completion of behavioral testing, mu opioid receptor (OPRM1), FosB, cFos, and dopamine receptor mRNA expression was measured in the nucleus accumbens as well as OPRM1 and corticotropin-releasing hormone mRNA in the paraventricular nucleus. In addition, plasma corticosterone levels were examined. On the day of challenge, morphine-pretreated WIN-F1 animals demonstrated a significantly enhanced response to morphine compared to morphine-pretreated VEH-F1 animals. Also following the morphine challenge, significantly higher levels of OPRM1 in the nucleus accumbens were observed in WIN-F1 animals. Together, these findings demonstrate transgenerational effects of adolescent exposure to cannabinoids in the absence of any in utero exposure.