| Relapse to drug taking following abstinence is a major impediment to the treatment of addiction. Clinical and preclinical studies indicate that women and men differ in relapse vulnerability during abstinence periods, particularly in response to stress. As relapse is frequently triggered by exposure of the recovered addict to objects previously associated with drug use and the formation of these associations requires memory systems engaged by the hippocampal formation (HF), studies exploring ovarian hormone modulation of hippocampal function are warranted. The present studies provide new insights on the interaction of opioid receptors, specifically delta opioid receptors (DORs), with the corticotropin releasing factor (CRF) system not only in males but also in females. They provide new anatomical evidence of hormonal regulation of DORs in the HF, adding to the growing body of literature supporting cooperative interaction between opioid systems and estrogens in modulating hippocampal excitability. Moreover, these studies reveal CRF receptor colocalization with DORs in CA1 pyramidal neurons and CRF peptide colocalization with DORs in interneurons, supporting and extending reports investigating the interaction between endogenous opioid and CRF systems to the HF. In particular, they suggest that DORs are well positioned and capable of influencing CRF peptide release and CRF receptor signaling, but that their ability to do so may be compromised in females when estrogen levels are high. Hence, these studies (1) characterize the DOR and CRF system in the hippocampus of drug naive, unstressed normal cycling females in comparison to males; (2) describe ovarian steroid induced alterations that reduce DOR ability to modulate CRF release and CRF receptor activity in the HF and may contribute to observed sex differences in relapse proclivity given the essential role of the hippocampus in context-induced relapse; (3) highlight the need for further research focusing on the impact of circulating hormones and DOR-CRF system activation in animal models of relapse; and (4) emphasize the importance of studying unique mechanisms in females, particularly related to stress, that may be targeted by novel treatments for addiction. |
