Stress interacts with addictive processes to increase drug use, drug seeking, and relapse. While the underlying mechanism involves many brain areas traditionally associated with drug reward circuitry, the hippocampal formation (HF) also plays a critical role in the interaction between stress and drug addiction. The HF is an important site at which stress circuits and endogenous opioid systems intersect. Studies in male rats suggest that the stress-related neuropeptide corticotropin-releasing factor (CRF), the CRF receptor, and the 6-opioid receptor (DOR) are localized to similar neuronal populations and subcompartments within HF lamina. As both opioids and the CRF receptor have demonstrated roles in regulating dendritic differentiation, spine plasticity, and long-term potentiation, the anatomical relationship between DORs and the CRF system in the HF merits direct study. Such investigation is particularly relevant in light of studies showing heightened stress sensitivity and increased vulnerability to drug abuse and relapse in females. Ovarian hormones modulate the distribution of opioid receptors in the HF with regional specificity and may therefore complicate opioid interaction with stress factors, like CRF. Hence, this proposal will test the central hypothesis that ovarian hormone modulation of DORs restricts DOR ability to influence CRF release and CRF receptor activity in the hippocampus. Dual label confocal and immunoelectron microscopy will assess whether DORs are contained in CRF- (and CRF receptor-) labeled neurons in the CA1 of male and normal cycling female rats and, if so, whether the subcellular distribution of DORs varies by sex or hormonal status. Immunocytochemical and biochemical in vitro approaches will determine whether DORs colocalize and heterodimerize with CRF receptors. These studies will establish potential mechanisms through which ovarian hormones, by regulating DOR trafficking and expression, may influence CRF peptide release and CRF receptor activity and, thereby, hippocampal morphology, plasticity, and function. Relapse to drug taking following abstinence is a major impediment to the treatment of addiction. Both clinical and preclinical studies demonstrate an important role for the hippocampus in reinstatement of drug seeking behavior. As stress has been shown to increase relapse probability, the proposed studies will provide new insights on opioid-stress system interaction in the hippocampus of both males and females and, thereby, improve our understanding of gender differences in hippocampal processes relevant to drug abuse and relapse.
