Role of oestrous cycle and orbitofrontal cortex in oxycodone seeking after 15-day abstinence in female rats.

Relapse to oxycodone seeking progressively increases after abstinence in rats, a phenomenon termed incubation of oxycodone craving. We have previously shown that the orbitofrontal cortex (OFC) plays a critical role in incubation of oxycodone craving in male rats. Here, we examined the effect of oestrous cycle on incubated oxycodone seeking in female rats, and whether the critical role of OFC in incubated oxycodone seeking generalizes to female rats. We first assessed oxycodone self-administration and incubated oxycodone seeking on abstinence day 15 across the oestrous cycle. Next, we determined the effect of chemogenetic inactivation of OFC by JHU37160 (J60), a novel agonist for Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), on incubated oxycodone seeking on abstinence day 15. Finally, we determined the effect of J60 alone on incubated oxycodone seeking on abstinence day 15. We found no difference in oxycodone intake across oestrus, pro-oestrus, and metoestrus stages during oxycodone self-administration training. Incubated oxycodone seeking was also similar between nonoestrus and oestrus female rats. Moreover, chemogenetic inactivation of OFC by J60 decreased incubated oxycodone seeking on abstinence day 15, while J60 alone had no effect on incubated oxycodone seeking in no-DREADD control rats. Taken together, results here show that the oestrous cycle has no effect on oxycodone intake and incubated oxycodone seeking in female rats under our experimental conditions. Furthermore, consistent with our previous findings in male rats, results here show that OFC also plays a critical role in incubated oxycodone seeking in female rats.

The estrous cycle has no effect on incubation of methamphetamine craving and associated Fos expression in dorsomedial striatum and anterior intralaminar nucleus of thalamus.

Relapse is a major challenge in treating drug addiction, and drug seeking progressively increases after abstinence, a phenomenon termed "incubation of drug craving". Previous studies demonstrated both sex differences and an effect of estrous cycle in female rats in incubation of cocaine craving. In contrast, while incubation of methamphetamine craving is similar across sexes, whether estrous cycle plays a role in this incubation has yet to be fully addressed. Moreover, whether neural mechanisms underlying incubation of methamphetamine craving differ across estrous cycles is largely unknown. To address these gaps, we first compared methamphetamine self-administration, and methamphetamine seeking on both abstinence days 1 and 28 between male rats and female rats across the estrous cycle. Next, we examined neuronal activation associated with incubated methamphetamine seeking in dorsomedial striatum (DMS) and lateral portion of the anterior intralaminar nucleus of thalamus (AIT-L), two brain areas previously implicated in incubation of methamphetamine craving. We found no effect of sex or estrous cycle on methamphetamine self-administration and methamphetamine seeking on abstinence days 1 and 28. We also found no effect of sex or estrous cycle on the number of Fos-expressing cells in DMS or AIT-L following methamphetamine seeking test. Taken together, our results showed that methamphetamine self-administration and incubation of methamphetamine craving was not dependent on sex or estrous cycles under our experimental condition, and the role of DMS and AIT-L in incubation of methamphetamine craving may be similar across sexes and across estrous cycles in female rats.