Elsevier

Neuropharmacology

Volume 70, July 2013, Pages 27-34
Neuropharmacology

Sex differences in the antidepressant-like effects of ketamine

https://doi.org/10.1016/j.neuropharm.2012.12.009Get rights and content

Abstract

Current medications for major depression suffer from numerous limitations. Once the right drug for treatment has been determined, it still takes several weeks for it to take effect and improve mood. This time lag is a serious concern for the healthcare community when dealing with patients with suicidal thoughts. However, recent clinical studies have shown that a single low-dose injection of ketamine, an N-methyl d-aspartate receptor (NMDAR) antagonist, has rapid antidepressant effects that are observed within hours and are long lasting. Although major depression affects twice as many women as men, all studies examining the rapid antidepressant effects of ketamine have focused on male subjects. Thus, we have investigated the behavioral and molecular effects of ketamine in both male and female rats and demonstrated greater sensitivity in female rats at a low dose of ketamine, a dose does not have antidepressant-like effects in male rats. The antidepressant-like effects of this low dose of ketamine were completely abolished when female rats were ovariectomized (OVX), and restored when physiological levels of estrogen and progesterone were supplemented, suggesting a critical role for gonadal hormones in enhancing the antidepressant-like effects of ketamine in female rats. In preclinical studies, the mammalian target of rapamycin (mTOR) in the medial prefrontal cortex and the eukaryotic elongation factor (eEF2) in the hippocampus have been proposed as critical mediators of ketamine's rapid antidepressant actions. In our hands, the increased sensitivity of female rats to a low dose of ketamine was not mediated through phosphorylation of mTOR or eEF2.

Highlights

► Females are more sensitive to the antidepressant effects of ketamine than male rats. ► Estrogen and progesterone mediate greater sensitivity to ketamine in female rats. ► The mechanisms of ketamine's antidepressant effects are sexually dimorphic.

Introduction

In any given year, more women than men are diagnosed with depression (Holden, 2005; Kessler et al., 2005; Steiner et al., 2005). This has been attributed to the pronounced sex differences that exist in both the anatomy and function of the brain, as well as to the sexually dimorphic hormonal environment (Cosgrove et al., 2008; Kessler, 2003). In particular, women are more likely to suffer from depression and anxiety during periods of when levels of estrogen and progesterone are at their lowest during the premenstrual, postpartum and perimenopausal periods (Douma et al., 2005). In both sexes, the current available antidepressants have serious limitations in that they require weeks to months to ameliorate symptoms, and only one third of patients respond to the first prescribed antidepressant (Trivedi, 2006; Trivedi et al., 2006). Recent clinical studies have shown that acute treatment with ketamine produces rapid antidepressant effects that last for up to 7 days (Berman et al., 2000; Zarate et al., 2006a), and ketamine infusion has been applied by practitioners in off-label use for treatment resistant major depressive disorder (Covvey et al., 2012).

Ketamine is a non-competitive antagonist acting at the NMDA glutamate receptor. Since its discovery more than 50 years ago, ketamine has been used very efficiently in anesthesia and in pain management and is showing great promises for its antidepressant effects. Indeed, unlike classical antidepressants whose therapeutic effects take weeks to be observed, an acute intravenous injection of ketamine is sufficient to induce quick and long-lasting antidepressant effects (Berman et al., 2000; Zarate et al., 2006a, 2006b). The rapid antidepressant effect of ketamine is of utmost interest when dealing with depressed patients who have suicidal thoughts. In this population, a single injection of small dose of ketamine induced a rapid resolution of suicidal ideation (DiazGranados et al., 2010; Price et al., 2009).

In preclinical studies, two independent research groups have identified mTOR in the mPFC and eEF2 in the HPC for mediating the antidepressant effects of ketamine (Autry et al., 2011; Li et al., 2010). Since these studies were carried out only in male subjects, we aimed to determine if ketamine also has antidepressant-like effects in female rats. Our findings clearly show that female rats are much more sensitive to ketamine when compared to male rats, as they respond to a low dose of ketamine (2.5 mg/kg), a dose that is clearly not antidepressant in male rats, and that the gonadal hormones estrogen and progesterone mediate this high sensitivity to ketamine in female rats. Understanding the behavioral and molecular basis of sex differences in NMDAR function and responses to estrogen and progesterone are vitally important for designing novel therapeutic agents that have optimal effectiveness in men and women. Due to the multimodal mechanism of action of NMDAR antagonists and estrogen, the rapidity and the breadth of action spectrum, and their combination could lead to more rapid effects – in both men and women – as compared to current antidepressant therapy.

In male rats, administration of low doses of ketamine reportedly leads to rapid phosphorylation of synaptoneurosomal mTOR and other associated proteins (PSD-95, GluR1, and synapsin) in the prefrontal cortex which are responsible for increased formation of dendritic spines (Li et al., 2010). Alternatively, increased BDNF translation mediated by reduced activity of eEF2 kinase within the hippocampus has also been implicated in mediating the antidepressant-like effects of ketamine (Autry et al., 2011). To understand the molecular mechanisms underlying sex differences in the antidepressant-like response to ketamine, we investigated the role of mTOR activation within total protein extracts and synaptoneurosomal fractions of the medial prefrontal cortex as well as hippocampal eEF2 kinase phosphorylation in male and female rats following acute exposure to various doses of ketamine.

Section snippets

Experiment 1. Sex differences in the antidepressant and anxiolytic-like effects of ketamine

Male and female rats (n = 6 per group) were exposed to a single intraperitoneal (i.p.) injection of 0, 2.5, 5.0, or 10.0 mg/kg of ketamine hydrochloride (Butler Schein Animal Health, Inc.), or 20 mg/kg imipramine hydrochloride (Sigma–Aldrich, Co.), and their behaviors tested 30 min later in the forced swim test, novelty suppressed feeding test, or light–dark box. Twenty-four and 48 h later, behaviors were tested in the elevated plus maze and sucrose preference, respectively (Supplementary Fig.

Sex differences in the antidepressant and anxiolytic-like effects of ketamine

On day 1 of the forced swim test, during the first 5 min of the 15 min pretest, female rats spent less time immobile compared to male rats indicating greater activity (Fig. 1A; F(1,38) = 29.765; p < 0.0001). There was no main effect. During the 5 min test, we again observed a sex effect (Fig. 1B; F(1,40) = 28.148; p < 0.0001) where females spent less total time immobile and a treatment effect (F(3,40) = 7.448; p < 0.001). Male rats injected with 5.0 or 10.0 mg/kg ketamine spent less time

Discussion

Our findings clearly show that female rats are more sensitive to ketamine when compared to male rats, as they respond to a low dose of ketamine (2.5 mg/kg), a dose that clearly does not have antidepressant-like effects in male rats, and that the gonadal hormones estrogen and progesterone mediate this high sensitivity to ketamine in female rats. Ketamine did not affect the phosphorylation status of mTOR in total protein preparations from the medial prefrontal cortex of either female or male

Conclusions

We have demonstrated that female rats exhibit an antidepressant-like response following injection of 2.5 mg/kg ketamine and that this response at the same dose is absent in male rats. The greater sensitivity to 2.5 mg/kg ketamine is completely abolished in OVX female rats and restored with physiological levels of both estrogen and progesterone administered in a cyclic manner to mimic the four-day estrous cycle in intact female rats. Injection of 5.0 mg/kg ketamine resulted in increased

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