Opioid receptor-dependent sex differences in synaptic plasticity in the hippocampal mossy fiber pathway of the adult rat

J Neurosci. 2015 Jan 28;35(4):1723-38. doi: 10.1523/JNEUROSCI.0820-14.2015.


The mossy fiber (MF) pathway is critical to hippocampal function and influenced by gonadal hormones. Physiological data are limited, so we asked whether basal transmission and long-term potentiation (LTP) differed in slices of adult male and female rats. The results showed small sex differences in basal transmission but striking sex differences in opioid receptor sensitivity and LTP. When slices were made from females on proestrous morning, when serum levels of 17β-estradiol peak, the nonspecific opioid receptor antagonist naloxone (1 μm) enhanced MF transmission but there was no effect in males, suggesting preferential opioid receptor-dependent inhibition in females when 17β-estradiol levels are elevated. The μ-opioid receptor (MOR) antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP; 300 nm) had a similar effect but the δ-opioid receptor (DOR) antagonist naltrindole (NTI; 1 μm) did not, implicating MORs in female MF transmission. The GABAB receptor antagonist saclofen (200 μm) occluded effects of CTOP but the GABAA receptor antagonist bicuculline (10 μm) did not. For LTP, a low-frequency (LF) protocol was used because higher frequencies elicited hyperexcitability in females. Proestrous females exhibited LF-LTP but males did not, suggesting a lower threshold for synaptic plasticity when 17β-estradiol is elevated. NTI blocked LF-LTP in proestrous females, but CTOP did not. Electron microscopy revealed more DOR-labeled spines of pyramidal cells in proestrous females than males. Therefore, we suggest that increased postsynaptic DORs mediate LF-LTP in proestrous females. The results show strong MOR regulation of MF transmission only in females and identify a novel DOR-dependent form of MF LTP specific to proestrus.

Keywords: area CA3; estrous cycle; hippocampus; long-term potentiation; opiate; sex differences.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Baclofen / analogs & derivatives
  • Baclofen / pharmacology
  • Bicuculline / analogs & derivatives
  • Bicuculline / pharmacology
  • Dendritic Spines / metabolism
  • Dendritic Spines / ultrastructure
  • Estrous Cycle / drug effects
  • Female
  • GABA-A Receptor Antagonists / pharmacology
  • Hippocampus / cytology*
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Male
  • Mossy Fibers, Hippocampal / physiology*
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time / drug effects
  • Receptors, Opioid / metabolism*
  • Sex Characteristics*
  • Somatostatin / analogs & derivatives
  • Somatostatin / pharmacology
  • Synapses / physiology*


  • GABA-A Receptor Antagonists
  • Narcotic Antagonists
  • Receptors, Opioid
  • phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide
  • Naloxone
  • bicuculline methiodide
  • Somatostatin
  • Baclofen
  • saclofen
  • Bicuculline