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

RATIONALE: 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.

OBJECTIVES: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.