Sex Differences in Sensitivity to the Depressive-like Effects of the Kappa Opioid Receptor Agonist U-50488 in Rats

Abstract

Background Dynorphin, an endogenous ligand at kappa opioid receptors (KOR), produces depressive-like effects and contributes to addictive behavior in male non-human primates and rodents. Although comorbidity of depression and addiction is greater in women than men, the role of KORs in female motivated behavior is unknown. Methods In adult Sprague Dawley rats, we used intracranial self-stimulation (ICSS) to measure effects of the KOR agonist (±)-trans-U-50488 methanesulfonate salt (U-50488) (0.0 – 10.0 mg/kg) on brain stimulation reward in gonadally intact and castrated males and in females at estrous cycle stages associated with low and high estrogen levels. Pharmacokinetic studies of U-50488 in plasma and brain were conducted. Immunohistochemistry was used to identify sex-dependent expression of U-50488-induced c-Fos in brain. Results U-50488 dose-dependently increased the frequency of stimulation (threshold) required to maintain ICSS responding in male and female rats, a depressive-like effect. However, females were significantly less sensitive than males to the threshold-increasing effects of U-50488, independent of estrous cycle stage in females or gonadectomy in males. Although initial plasma concentrations of U-50488 were higher in females, there were no sex differences in brain concentrations. Sex differences in U-50488-induced c-Fos activation were observed in CRF-containing neurons of the paraventricular nucleus (PVN) of the hypothalamus and primarily in non-CRF-containing neurons of the bed nucleus of the stria terminalis (BNST). Conclusions These data suggest that the role of KORs in motivated behavior of rats is sexdependent, which has important ramifications for the study and treatment of mood-related disorders including depression and drug addiction in people.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…Some data also suggest that morphine serves as a stronger reinforcer in females than males in self-administration procedures (Cicero et al, 2003). Similar to these effects with morphine, the kappa opioid agonist U50,488 was also more potent to depress ICSS in male rats than in females responding under a frequency-rate procedure (Russell et al, 2013).…”

“…Rates of drug abuse are higher in males than females (SAMHSA, 2012), and efforts have been made to examine sex differences in drug effects on ICSS. Males and females do not differ with regard to baseline sensitivity to the reinforcing effects of electrical stimulation of the MFB, and sensitivity in females is also stable across stages of the estrous cycle (Stratmann and Craft, 1997;Russell et al, 2013). However, exogenously administered estradiol facilitates ICSS in ovariectomized female rats (Galankin et al, 2010) and exogenous testosterone facilitates ICSS in castrated male rats (Olds, 1958a).…”

“…Kappa and Delta Opioids. Selective kappa opioid receptor agonists such as U50,488 (5,6-dimethoxy-N, N-dipropyl-2,3-dihydro-1H-inden-2-amine), U69,593 [Nmethyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]acetamide], and salvinorin A produce a dose-dependent depression of ICSS (Todtenkopf et al, 2004;Carlezon et al, 2006;Dinieri et al, 2009;Do Carmo et al, 2009;Negus et al, 2010Negus et al, , 2012aRussell et al, 2013). For example, Fig.…”

“…For example, nearly all ICSS studies have been conducted in male subjects, but the few studies that have been conducted with females have identified intriguing sex differences in effects of some drugs such as opioids (Craft et al, 2001;Russell et al, 2013). Systematic examination of state/trait variables on drug effects in ICSS procedures may help to identify conditions under which selected drugs are most likely to produce an abuse-related effect.…”

Interaction of CRF and kappa opioid systems on GABAergic neurotransmission in the mouse central amygdala

“…Female C57BL/6 mice (60-90 days old; Charles River Laboratories, Raleigh, NC), and homozygous KOR knockout (KO) mice and wild-type (WT) littermate mice (120-180 days old, shipped from the Scripps Research Institute, La Jolla, CA) were used for this study. We exclusively used female mice, as it has been reported that female animals showed a greater or selective sensitivity to KORmediated behaviors such as antinociception, motivation, mood-related disorders, and social interaction (Chang et al, 2000;Chakrabarti et al, 2010;Lawson et al, 2010;Liu et al, 2011;Robles et al, 2014;Russell et al, 2014). The genetic background of KOR KO and WT mice was a hybrid C57BL/6Orl  129/SV strain.…”