PET imaging of kappa opioid receptors and receptor expression quantified in neuron-derived extracellular vesicles in socially housed female and male cynomolgus macaques

Abstract

Recent positron emission tomography (PET) studies of kappa opioid receptors (KOR) in humans reported significant relationships between KOR availability and social status, as well as cocaine choice. In monkey models, social status influences physiology, receptor pharmacology and behavior; these variables have been associated vulnerability to cocaine abuse. The present study utilized PET imaging to examine KOR availability in socially housed, cocaine-naïve female and male monkeys, and peripheral measures of KORs with neuron-derived extracellular vesicles (NDE). KOR availability was assessed in dominant and subordinate female and male cynomolgus macaques (N = 4/rank/sex), using PET imaging with the KOR selective agonist [¹¹C]EKAP. In addition, NDE from the plasma of socially housed monkeys (N = 13/sex; N = 6-7/rank) were isolated by immunocapture method and analyzed for OPRK1 protein expression by ELISA. We found significant interactions between sex and social rank in KOR availability across 12 of 15 brain regions. This was driven by female data, in which KOR availability was significantly higher in subordinate monkeys compared with dominant monkeys; the opposite relationship was observed among males, but not statistically significant. No sex or rank differences were observed for NDE OPRK1 concentrations. In summary, the relationship between brain KOR availability and social rank was different in female and male monkeys. This was particularly true in female monkeys. We hypothesize that lower [¹¹C]EKAP binding potentials were due to higher concentrations of circulating dynorphin, which is consistent with greater vulnerability in dominant compared with subordinate females. These findings suggest that the KOR is an important target for understanding the neurobiology associated with vulnerability to abused drugs and sex differences, and detectable in peripheral circulation.

Fig. 1. Representative PET/CT brain images with the KOR selective agonist [¹¹C]EKAP in dominant (left) and subordinate (right), female (top) and male (bottom) cynomolgus monkeys.

Subordinate females and dominant males have the higher KOR availability compared with dominant females and subordinate males (see also Table 2). Illustrated images are of slice 134, frame 17. The lower right image includes co-registered regions of interest labeled a–f. a Temporal cortex. b Hippocampus. c Insula and claustrum. d Globus pallidus. e Thalamus. f Cingulate cortex.

Fig. 2. Relationship between social rank and NDE OPRK1 concentration in dominant (Dom) and subordinate (Sub) female (left) and male (right) cynomolgus monkeys (N = 13/sex).

OPRK1 expression in NDE was anlayzed by ELISA and presented as ng/ml per 100 ug of NDE. Each bar represents mean and 95% confidence intervals for 26 monkeys (N = 13/sex).