Elsevier

Biological Psychiatry

Volume 80, Issue 6, 15 September 2016, Pages 448-456
Biological Psychiatry

Archival Report
Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats

https://doi.org/10.1016/j.biopsych.2015.12.025Get rights and content

Abstract

Background

The mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examined the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine density, and synaptic proteins in male and female rats.

Methods

We used a chronic social IS paradigm to test the effects of ketamine (0, 2.5 mg/kg, and 5 mg/kg) on behavior and levels of synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 in male rats and female rats in diestrus. Medial prefrontal cortex spine density was also examined in male rats and female rats that received ketamine during either the diestrus or the proestrus phase of their estrous cycle.

Results

Male rats showed anhedonia and depression-like behavior after 8 weeks of IS, concomitant with decreases in spine density and levels of synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 in the medial prefrontal cortex; these changes were reversed by a single injection of ketamine (5 mg/kg). After 11 weeks of IS, female rats showed depression-like behavior but no signs of anhedonia. Although both doses of ketamine rescued depression-like behavior in female rats, the decline observed in synaptic proteins and spine density in IS and in diestrus female rats could not be reversed by ketamine. Spine density was higher in female rats during proestrus than in diestrus.

Conclusions

Our findings implicate a role for synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 and medial prefrontal cortex spine density in the antidepressant effects of ketamine in male rats subjected to IS but not in female rats subjected to IS, suggesting dissimilar underlying mechanisms for efficacy of ketamine in the two sexes.

Section snippets

Animals

Adult male (250–270 g) and female (200–225 g) Sprague Dawley rats (Charles River, Wilmington, MA) were maintained either under pair-housed (PH) condition or in solitary cages under IS on a 12-hour light/dark cycle (lights on at 5:00 am) with ad libitum access to food and water. All animal protocols were carried out in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of Florida State

Effect of Ketamine on Anhedonia and Depression-like Behavior in Male and Female Rats Subjected to IS

Male rats subjected to IS started showing a significant decline in sucrose preference from week 7 onward, which was stable across week 8 (effect of housing condition: F1,46 = 50.1, p < .05) (Figure 1B). In male rats, the IS-evoked decline in sucrose preference (housing: F1,42 = 7.76, p < .05) was completely rescued by an acute injection of ketamine (5 mg/kg) on day 1 of the SPT (effect of treatment: F2,42 = 3.24, p < .05) but not on day 2 (Figure 1C). In the FST in male rats, IS also elicited

Discussion

The consequences of social isolation are distinct and different, based on the time and duration of administration (33). Studies have investigated the effect of early-life (34, 35, 36, 37) and adolescent (38, 39) social isolation of varying durations on behavior and underlying mechanisms. In the present study, we show, to our knowledge for the first time, the effect of chronic social isolation (8–12 weeks) during adulthood on behavior, spine density, and synaptic molecules in the mPFC in male

Acknowledgments and Disclosures

This work was supported by the National Institutes of Health Grant Nos. R01-MH087583 and RO1-MH099085 (to MK).

The authors report no biomedical financial interests or potential conflicts of interest.

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