Increased cocaine reward in offspring of females exposed to morphine during adolescence

  • Fair M. VassolerEmail author
  • Anika M. Toorie
  • Elizabeth M. Byrnes
Original Investigation



A growing body of evidence demonstrates that environmental exposures can impact the physiology and behavior of subsequent generations. We have previously demonstrated reduced morphine self-administration in the F1 and F2 offspring of female rats exposed to morphine during adolescence.


The current study was designed to determine whether attenuated self-administration for a substance not in the opioid class is also observed in the F1 progeny of adolescent morphine exposed females.


Female adolescent rats were administered morphine at increasing doses for 10 days (P30–39). Females then remained drug free for at least 3 weeks prior to mating with drug-naïve males. As adults, male and female offspring (F1 animals) were tested for cocaine self-administration acquisition, progressive ratio, extinction, and reinstatement. In addition, β-endorphin peptide levels were measured in the nucleus accumbens (NAc) of behaviorally experienced animals following reinstatement and in behaviorally naïve littermates after acute cocaine (0 or 10 mg/kg, i.p.). Proopiomelanocortin, the polypeptide that is cleaved to produce β-endorphin, as well as β-endorphin, was examined in the arcuate nucleus of the hypothalamus and the nucleus accumbens, respectively. Finally, corticosterone was measured following acute cocaine.


While no differences were observed during the cocaine acquisition phase (FR-1 and FR-5 schedules), under a PR schedule, Mor-F1 animals (both males and females) had increased motivated responding for cocaine. In addition, Mor-F1 males demonstrated enhanced reinstatement compared to Sal-F1 males. In Mor-F1 males, an acute injection of cocaine (10 mg/kg, i.p.) decreased β-endorphin levels in the NAc compared to a saline injection while acute cocaine increased β-endorphin in the NAc in Sal-F1 males compared to saline injection. Following acute cocaine, Mor-F1 males had significantly lower levels of β-endorphin in the Nac compared to Sal-F1 males. Additionally, β-endorphin levels in the nucleus accumbens were negatively correlated with reinstatement behavior only in Mor-F1 males. Levels of POMC in the arcuate nucleus were elevated in Mor-F1 males compared to Sal-F1 males, a main effect driven primarily by POMC levels in the acute cocaine condition. These changes were not observed in Mor-F1 females. Finally, plasma corticosterone was increased in Mor-F1 males regardless of acute injection while Mor-F1 females displayed increased corticosterone in response to acute cocaine.


These data indicate that morphine prior to conception increases the rewarding effects of cocaine in male and female offspring. In addition, sex-specific alterations in endogenous opioids and hypothalamic physiology were observed.


Multigenerational Transgenerational Epigenetic Cocaine Self-administration Morphine Abuse liability 


Funding information

This work was funded by National Institute of Health, National Institute of Drug Abuse (NIDA) grant R01DA025674.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Tufts University Cummings School of Veterinary MedicineNorth GraftonUSA

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