Stress differentially alters mu opioid receptor density and trafficking in parvalbumin‐containing interneurons in the female and male rat hippocampus

Abstract

Stress differentially affects hippocampal dependent learning relevant to addiction and morphology in male and female rats. Mu opioid receptors (MORs), which are located in parvalbumin (PARV)-containing GABAergic interneurons and are trafficked in response to changes in the hormonal environment, play a critical role in promoting principal cell excitability and long-term potentiation. Here, we compared the effects of acute and chronic immobilization stress (AIS and CIS) on MOR trafficking in PARV-containing neurons in the hilus of the dentate gyrus in female and male rats using dual label immuno-electron microscopy. Following AIS, the density of MOR silver-intensified gold particles (SIGs) in the cytoplasm of PARV-labeled dendrites was significantly reduced in females (estrus stage). Conversely, AIS significantly increased the proportion of cytoplasmic MOR SIGs in PARV-labeled dendrites in male rats. CIS significantly reduced the number of PARV-labeled neurons in the dentate hilus of males but not females. However, MOR/PARV-labeled dendrites and terminals were significantly smaller in CIS females, but not males, compared to controls. Following CIS, the density of cytoplasmic MOR SIGs increased in PARV-labeled dendrites and terminals in females. Moreover, the proportion of near-plasmalemmal MOR SIGs relative to total decreased in large PARV-labeled dendrites in females. After CIS, no changes in the density or trafficking of MOR SIGs were seen in PARV-labeled dendrites or terminals in males. These data show that AIS and CIS differentially affect available MOR pools in PARV-containing interneurons in female and male rats. Furthermore, they suggest that CIS could affect principal cell excitability in a manner that maintains learning processes in females but not males.

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

“…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). AIS also reduces DOR levels in CA3 in proestrus females (Hall, Van Kempen and Milner, unpublished data).…”

“…Diestrus 2 rats rather than metestrus (diestrus I) were chosen to insure that rats were completely out of the estrus stage. The tissue used in this study was obtained from rats used in our previous studies (Burstein et al, 2013; Gonzales et al, 2011; Milner et al, 2013). …”

“…During the stress paradigm, CIS rats were housed in a separate room, and were killed 1 day after the last AIS period. Rats in the CIS group had normal estrous cycles (Milner et al, 2013). …”

“…Chronic stress induces drastically differing, sex-specific effects on both learning and memory tasks, and on the structure of the hippocampal formation (HF), an essential region for such processes. While males display impaired cognitive performance, a pronounced remodeling of CA3 pyramidal cell dendrites, particularly CA3b, and a loss of parvalbumin (PARV)-labeled interneurons (Luine et al, 1998; McEwen, 1999; Sousa et al, 2000), females exhibit enhanced performance on the same memory tasks, no apparent dendritic remodeling or loss of PARV interneurons (Conrad et al, 2003; Galea et al, 1997; Milner et al, 2013). Estrogen probably plays an important role in these distinct stress responses.…”

Comparison of operant escape and reflex tests of nociceptive sensitivity

“…However, attempts to understand mechanisms of opioid hypoalgesia have been misdirected by the prevalent methods of antinoceptive testing of humans and laboratory animals. Primary considerations are that: (A) reflexes do not reveal opioid actions at sites throughout the neuraxis known to contain opioid receptors (Becerra et al, 2013;Hagelberg et al, 2012;Maarrawi et al, 2007;Martikainen et al, 2013;Milner et al, 2013;Zubieta et al, 2001Zubieta et al, , 2003; (B) operant responding and human psychophysics have determined that methods of stimulation which are most effective for reflex elicitation are highly insensitive to opioid inhibition, and (C) -opioid agents have sedative properties and can powerfully suppress behavioral performance, giving the impression pain has been inhibited.…”