Hormonal regulation of delta opioid receptor immunoreactivity in interneurons and pyramidal cells in the rat hippocampus

Abstract

Clinical and preclinical studies indicate that women and men differ in relapse vulnerability to drug-seeking behavior during abstinence periods. 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. Previous studies revealed that ovarian steroids alter endogenous opioid peptide levels and trafficking of mu opioid receptors in the HF, suggesting cooperative interaction between opioids and estrogens in modulating hippocampal excitability. However, whether ovarian steroids affect the levels or trafficking of delta opioid receptors (DORs) in the HF is unknown. Here, hippocampal sections of adult male and normal cycling female Sprague-Dawley rats were processed for quantitative immunoperoxidase light microscopy and dual label fluorescence or immunoelectron microscopy using antisera directed against the DOR and neuropeptide Y (NPY). Consistent with previous studies in males, DOR-immunoreactivity (-ir) localized to select interneurons and principal cells in the female HF. In comparison to males, females, regardless of estrous cycle phase, show reduced DOR-ir in the granule cell layer of the dentate gyrus and proestrus (high estrogen) females, in particular, display reduced DOR-ir in the CA1 pyramidal cell layer. Ultrastructural analysis of DOR-labeled profiles in CA1 revealed that while females generally show fewer DORs in the distal apical dendrites of pyramidal cells, proestrus females, in particular, exhibit DOR internalization and trafficking towards the soma. Dual label studies revealed that DORs are found in NPY-labeled interneurons in the hilus, CA3, and CA1. While DOR colocalization frequency in NPY-labeled neuron somata was similar between animals in the hilus, proestrus females had fewer NPY-labeled neurons that co-labeled with DOR in stratum oriens of CA1 and CA3 when compared to males. Ultrastructural analysis of NPY-labeled axon terminals within stratum radiatum of CA1 revealed that NPY-labeled axon terminals contain DORs that are frequently found at or near the plasma membrane. As no differences were noted by sex or estrous cycle phase, DOR activation on NPY-

Hippocampal mossy fiber leu-enkephalin immunoreactivity in female rats is significantly altered following both acute and chronic stress

“…These alterations in peptidergic transmitter levels occur in parallel with known stress-induced changes in their associated receptors, MORs and DORs. As discussed, MORs are found most frequently on PARV-containing basket cells, while DORs are located both on granule and pyramidal cell dendrites, and on interneurons that contain somatostatin or neuropeptide Y (Drake et al, 2007; Williams et al, 2011). AIS significantly reduces MOR levels within dentate gyrus PARV-containing interneurons in females, while comparable values in males were unaffected (Milner et al, 2013).…”

“…In female rats, estrogen influences LENK expression: levels of LENK within the MF system, particularly CA3b, vary significantly across the estrous cycle, with high levels being observed in proestrus and estrus, when estrogen levels are highest (Torres-Reveron et al, 2008). These cyclic elevations in LENK levels occur concurrently with changes in the subcellular distributions of MORs and DORs in select neuronal populations (Torres-Reveron et al, 2009; Williams et al, 2011). …”

Estrogen receptor α and G-protein coupled estrogen receptor 1 are localized to GABAergic neurons in the dorsal striatum

“…Tissue for this experiment was taken from rats in the diestrus phase of the estrous cycle. Estrous phase was verified by measuring uterine weights and plasma estradiol levels from blood samples [15]. All procedures were in accordance with the National Institutes of Health guidelines and approved by the Weill Cornell Medicine Institutional Animal Care and Use Committee.…”

Enkephalin levels and the number of neuropeptide Y-containing interneurons in the hippocampus are decreased in female cannabinoid-receptor 1 knock-out mice

“…These differences could indicate that the effects of CB1 −/− are regionally selective. However, the lack of effect of CB1 receptor gene deletion on parvalbumin immunoreactive interneurons in the dentate gyrus of female mice used in the present study may also be the result of sexual dimorphism that is known to be influential in both the cannabinoid and opioid systems [26;34;46]. Alternatively, we cannot rule out the possibility of non-specific developmental changes in the CB1 −/− mice.…”

“…NPY-containing neurons in the hilus of the dentate gyrus express enkephalin-activating DORs, but do not express CB1 receptors in their cell bodies [46][16]. Thus, the decrease in the number of NPY-immunoreactive neurons seen in the hilus of CB1−/− may be an indirect reflection of the reduced L-ENK in mossy fibers in these mutant mice.…”