Abstract
Opioids play a critical role in hippocampally dependent behavior and plasticity. In the hippocampal formation, mu opioid receptors (MOR) are prominent in parvalbumin (PARV) containing interneurons. Previously we found that gonadal hormones modulate the trafficking of MORs in PARV interneurons. Although sex differences in response to stress are well documented, the point at which opioids, sex, and stress interact to influence hippocampal function remains elusive. Thus, we used quantitative immunocytochemistry in combination with light and electron microscopy for the phosphorylated MOR (pMOR) at the SER375 carboxy-terminal residue in male and female rats to assess these interactions. In both sexes, pMOR-immunoreactivity (ir) was prominent in axons and terminals and in a few neuronal somata and dendrites, some of which contained PARV in the mossy fiber pathway region of the dentate gyrus (DG) hilus and CA3 stratum lucidum. In unstressed rats, the levels of pMOR-ir in the DG or CA3 were not affected by sex or estrous cycle stage. However, immediately following 30 min of acute immobilization stress (AIS), males had higher levels of pMOR-ir whereas females at proestrus and estrus (high estrogen stages) had lower levels of pMOR-ir within the DG. In contrast, the number and types of neuronal profiles with pMOR-ir were not altered by AIS in either males or proestrus females. These data demonstrate that although gonadal steroids do not affect pMOR levels at resting conditions, they are differentially activated both pre and postsynaptic MORs following stress. These interactions may contribute to the reported sex differences in hippocampally dependent behaviors in stressed animals.
Highlights
Estrogens influence fundamental processes within the hippocampus
Diffuse phosphorylated mu opioid receptors (MORs) (pMOR)-ir was found in the stratum lucidum of the CA3, in CA3b and c, and the central hilus of the dentate gyrus (DG; Figure 1A)
A two-way ANOVA revealed no significant difference between groups (p > 0.05) when either total number of profiles, or types profiles were compared. This is the first report to demonstrate that pMOR-ir is restricted to the mossy fiber pathway region where it is found primarily in axons and dendrites, some of which arise from PARV-containing interneurons
Summary
Estrogens influence fundamental processes within the hippocampus. When estrogen levels are high (either at the proestrus stage of the estrous cycle or in ovariectomized animals replaced with estradiol), spine density, synaptic proteins, and glutamatergic receptors are elevated in the hippocampus (Gazzaley et al, 1996; Woolley, 1998; McEwen and Milner, 2007; Spencer et al, 2008; Waters et al, 2009). Chronic stress is detrimental to learning processes, decreases in LTP, and results in atrophy of CA3 pyramidal cell dendrites as well as increased packing density of small synaptic vesicles near active zones of mossy fiber terminals (Magariños et al, 1997, and reviewed by McEwen and Milner, 2007). In females, chronic stress either does not effect or slightly increases spatial learning performance, at the proestrus phase of the estrus cycle, and does not result in the dramatic morphological changes seen in the male hippocampus (Shors and Thompson, 1992; Galea et al, 1997; Luine et al, 2007; McEwen and Milner, 2007). The relative preservation of hippocampal morphology and learning processes in females following stress could contribute to accelerated course of addiction seen in females (Robbins et al, 1999; Elman et al, 2001)
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