Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner

Saland, Samantha K.; Schoepfer, Kristin; Kabbaj, Mohamed

doi:10.1038/srep21322

Cited by 40 publications

(62 citation statements)

References 43 publications

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“…When challenged with 5 mg/kg ketamine, females previously exposed to repeated treatments with both 2.5 and 5 mg/kg ketamine displayed a significant increase in locomotor movements compared to those previously treated with saline (Sidak’s multiple comparison, p= 0.029 and p=0.013, respectively). Interestingly, females sensitized to both 2.5 and 5 mg/kg, whereas males only sensitized to 5 mg/kg, which could reflect greater sensitivity of females to the drug than males, a result supported by previous reports from our lab (Carrier and Kabbaj, 2013; Saland et al , 2016). …”

Section: Resultssupporting

confidence: 88%

“…Vaginal cytology was examined via vaginal lavage on a daily basis during the first 3-hr of the light cycle in order to track female rats’ estrous cycles as previously described (Becker et al , 2005; Saland et al , 2016). All female rats were tested in diestrous 1 (D1), when both progesterone and estrogen levels are low to ensure that fluctuating hormones are not interfering with behavioral data.…”

Section: Methodsmentioning

confidence: 99%

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Locomotor sensitization to intermittent ketamine administration is associated with nucleus accumbens plasticity in male and female rats

et al. 2017

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Clinical evidence suggests superior antidepressant response over time with a repeated, intermittent ketamine treatment regimen as compared to a single infusion. However, the club drug ketamine is commonly abused. Therefore, the abuse potential of repeated ketamine injections at low doses needs to be investigated. In this study, we investigated the abuse potential of repeated exposure to either 0, 2.5, or 5 mg/kg ketamine administered once weekly for seven weeks. Locomotor activity and conditioned place preference (CPP) were assayed to evaluate behavioral sensitization to the locomotor activating effects of ketamine and its rewarding properties, respectively. Our results show that while neither males nor females developed CPP, males treated with 5 mg/kg and females treated with either 2.5 or 5 mg/kg ketamine behaviorally sensitized. Furthermore, dendritic spine density was increased in the NAc of both males and females administered 5 mg/kg ketamine, an effect specific to the NAc shell (NAcSh) in males but to both the NAc core (NAcC) and NAcSh in females. Additionally, males administered 5 mg/kg ketamine displayed increased protein expression of ΔfosB, calcium calmodulin kinase II alpha (CaMKIIα), and brain-derived neurotrophic factor (BDNF), an effect not observed in females administered either dose of ketamine. However, males and females administered 5 mg/kg ketamine displayed increased protein expression of AMPA receptors (GluA1). Taken together, low-dose ketamine, when administered intermittently, induces behavioral sensitization at a lower dose in females than males, accompanied by an increase in spine density in the NAc and protein expression changes in pathways commonly implicated in addiction.

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Section: Resultssupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Locomotor sensitization to intermittent ketamine administration is associated with nucleus accumbens plasticity in male and female rats

et al. 2017

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“…Because our pharmacological and behavioral manipulations occurred over a long period of time, we did not track the estrous cycle in our study in order to minimize handling stress. However, ovarian hormones can significantly impact neuronal morphology, rodent behavior, and (R,S)-ketamine efficacy (51)(52)(53). Our results support the hypothesis that ovarian hormones induce changes at the neuronal level to causally mediate (R,S)ketamine and (2R,6R)-HNK's effects, whether antidepressant or prophylactic, and thus, impact behavior in females.…”

Section: Discussionsupporting

confidence: 73%

Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

et al. 2019

Preprint

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Number of words in the abstract: 227 (250 max)Number of words in the text: 3812 (4000 max) ABSTRACT BACKGROUND: Females are more likely than males to develop major depressive disorder (MDD) after exposure to stress. We previously reported that the administration of (R,S)-ketamine before stress can prevent stress-induced depressive-like behavior in male mice but have yet to assess efficacy in female mice or for other compounds, such as the metabolites of (R,S)-ketamine. METHODS:We administered (R,S)-ketamine or its metabolites (2R,6R)hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-HNK at various doses 1 week before one of a number of stressors, including contextual fear conditioning (CFC), learned helplessness (LH), and chronic immobilization stress (CIS), in male and female 129S6/SvEv mice. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy surgery (OVX) and a hormone replacement protocol prior to drug administration. RESULTS: (R,S)-ketamine and (2S,6S)-HNK, but not (2R,6R)-HNK, attenuated learned fear in male mice. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, significantly reduced stress-induced depressive-like behavior in male and female mice. (R,S)ketamine and (2R,6R)-HNK) were prophylactically effective at a lower dose (10 mg/kg and 0.025 mg/kg, respectively) in female mice than in male mice (30 mg/kg and 0.075 mg/kg, respectively). Moreover, ovarian-derived hormones were necessary and sufficient for prophylaxis in female mice. CONCLUSIONS:Our results suggest that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and that ovarian hormones mediate prophylactic efficacy in females. To our knowledge, this is the first

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“…Upon arrival, rats were double-housed in 43 × 21.5 × 25.5-cm Plexiglas cages on a 12/12-h reverse light/dark cycle, and food and water were provided ad libitum except during behavioral testing. After a period of 5–6 days of acclimation, females underwent daily vaginal lavage to determine stage of estrous cycle, for two complete cycles before behavioral testing (Becker et al 2005; Saland et al 2016). Once cyclicity was established, lavage was carried out every day, no more than 2 h before behavioral testing.…”

Section: Methodsmentioning

confidence: 99%

“…Once cyclicity was established, lavage was carried out every day, no more than 2 h before behavioral testing. Stage of cycle was based on microscopic observation of cell morphology and abundance, as we have previously described (Saland et al 2016; Stack et al 2010). Males were handled daily.…”

Section: Methodsmentioning

confidence: 99%

Reinforcing properties of an intermittent, low dose of ketamine in rats: effects of sex and cycle

et al. 2016

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Rationale Repeated intermittent exposure to ketamine has rapid and long-lasting antidepressant effects, but the abuse potential has only been assessed at high doses. Furthermore, while females are more susceptible to depression and more sensitive to ketamine’s antidepressant-like effects, the abuse potential for ketamine in females is unknown. Objectives The objectives of this study are to determine the reinforcing properties of low-dose intermittent ketamine in adult rats of both sexes and determine whether cycling gonadal hormones influence females’ response to ketamine. In male rats, we also aimed to determine whether reinstatement to intermittent ketamine is comparable to intermittent cocaine. Methods Male rats intravenously self-administered cocaine (0.75 mg/kg/infusion) or ketamine (0.1 mg/kg/infusion) once every fourth day, while intact cycling female rats self-administered ketamine only during preidentified stages of their 4-day estrus cycle, when gonadal hormones are either high (proestrus) or low (diestrus). After acquiring self-administration, rats underwent daily extinction training followed by cue-primed and drug-primed reinstatement to assess drug-seeking behavior. Results Diestrus-trained females fail to maintain ketamine self-administration and did not display reinstatement to ketamine-paired cues. Males and proestrus-trained females reinstated to ketamine-paired cues. Ketamine-primed reinstatement was dependent on simultaneous cue presentation. Male rats reinstated to cocaine priming independent of cue presentation. Conclusion These findings indicate that females’s responsivity to this dose of ketamine depends on stage of cycle, as only proestrus-trained females and males respond to ketamine’s reinforcing effects under this treatment paradigm.

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Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner

Cited by 40 publications

References 43 publications

Locomotor sensitization to intermittent ketamine administration is associated with nucleus accumbens plasticity in male and female rats

Locomotor sensitization to intermittent ketamine administration is associated with nucleus accumbens plasticity in male and female rats

Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

Reinforcing properties of an intermittent, low dose of ketamine in rats: effects of sex and cycle

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