Sex- and dose-dependent abuse liability of repeated subanesthetic ketamine in rats

Schoepfer, Kristin; Strong, Caroline E.; Saland, Samantha K.; Wright, Katherine N.; Kabbaj, Mohamed

doi:10.1016/j.physbeh.2017.10.021

Cited by 30 publications

(44 citation statements)

References 92 publications

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“…Locomotor sensitization after repeated exposure to drugs of abuse is indicative of plasticity in the reward circuitry that may underlie the transition to addiction. Interestingly in these studies, the same rats that displayed sensitization did not form a CPP to ketamine at any dose tested [62,63]; in fact, females displayed a conditioned place aversion to 5.0 mg/kg. Together, these findings suggest that divergent mechanisms may underlie the locomotor activating effects and the associative rewarding effects of ketamine.…”

Section: Sex Differences In the Anti-depressant Activity Of Ketaminementioning

confidence: 88%

“…Female rats show increased locomotor sensitization to intermittent (weekly and every other day, respectively) repeated ketamine at depression-relevant doses (2.5-10.0 mg/kg intraperitoneally, i.p.) [62,63]. Locomotor sensitization after repeated exposure to drugs of abuse is indicative of plasticity in the reward circuitry that may underlie the transition to addiction.…”

Section: Sex Differences In the Anti-depressant Activity Of Ketaminementioning

confidence: 99%

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Sex Differences in the Antidepressant Effects of Ketamine in Animal Models of Depression

Adu-Nti¹,

Ghartey‐Kwansah²,

Aboagye³

2019

Int J Depress Anxiety

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Major depressive disorder (MDD) is the most common psychiatric disease and it affects millions of people across the world. Patients suffering from MDD consistently complain about cognitive disturbances, significantly worsening the burden of this illness. The second most frequent mental illness in Europe is mood disorders and they are dominated by MDD, a-ecting 7% of the population. The recent discovery that the N-methyl-D-aspartate receptor (NMDAR) antagonist; ketamine; a revolutionary novel antidepressant, rapidly relieves depressive symptoms and suicidal imaginations, particularly amongst those with treatment-resistant depression have generated a new wave of excitement. This article discusses the sex differences that exist in depressive patients, summarizes the antidepressant activity of ketamine and reviews the mechanisms underlying the rapid antidepressant effects of ketamine. It further discusses the sexual differences in the antidepressant activity of ketamine in preclinical studies.

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Section: Sex Differences In the Anti-depressant Activity Of Ketaminementioning

confidence: 88%

Section: Sex Differences In the Anti-depressant Activity Of Ketaminementioning

confidence: 99%

Sex Differences in the Antidepressant Effects of Ketamine in Animal Models of Depression

Adu-Nti¹,

Ghartey‐Kwansah²,

Aboagye³

2019

Int J Depress Anxiety

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“…Additionally, depression is twice as prevalent in women as compared to men ( Whiteford et al, 2013 ), is highly comorbid with addiction ( Ng et al, 2017 ), and women who recreationally abuse ketamine report more severe symptoms during withdrawal from ketamine, concomitant substance use, and more cognitive impairments when compared to men ( Chen et al, 2014 ). As we will discuss later, animal studies have also reported a heightened sensitivity to antidepressant and addictive effects of ketamine in females compared to males ( Carrier and Kabbaj, 2013 ; Franceschelli et al, 2015 ; Schoepfer et al, 2017 ; Strong et al, 2017 ; Zanos et al, 2016 ). The meta-analysis mentioned above analyzed gender and age as factors across the 11 studies and found no effect of either ( Cho et al, 2005 ), and a recent report found no evidence of gender nor age being significant predictors of ketamine's antidepressant efficacy ( Niciu et al, 2014 ).…”

Section: The Addictive Potential Of Repeated Low-dose Ketamine Infusimentioning

confidence: 97%

“…when compared to males (5 mg/kg, i.p.) ( Schoepfer et al, 2017 ). Interestingly, behavioral sensitization in both sexes was positively correlated with ΔfosB –a marker of long-term plasticity-expression in the NAc ( Schoepfer et al, 2017 ).…”

Section: The Addictive Potential Of Repeated Low-dose Ketamine Infusimentioning

confidence: 99%

On the safety of repeated ketamine infusions for the treatment of depression: Effects of sex and developmental periods

Strong

Kabbaj

2018

Neurobiology of Stress

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In this review, we will discuss the safety of repeated treatments with ketamine for patients with treatment-resistant depression (TRD), a condition in which patients with major depression do not show any clinical improvements following treatments with at least two antidepressant drugs. We will discuss the effects of these treatments in both sexes at different developmental periods. Numerous small clinical studies have shown that a single, low-dose ketamine infusion can rapidly alleviate depressive symptoms and thoughts of suicidality in patients with TRD, and these effects can last for about one week. Interestingly, the antidepressant effects of ketamine can be prolonged with intermittent, repeated infusion regimens and produce more robust therapeutic effects when compared to a single infusion. The safety of such repeated treatments with ketamine has not been thoroughly investigated. Although more studies are needed, some clinical and preclinical reports indicated that repeated infusions of low doses of ketamine may have addictive properties, and suggested that adolescent and adult female subjects may be more sensitive to ketamine's addictive effects. Additionally, during ketamine infusions, many TRD patients report hallucinations and feelings of dissociation and depersonalization, and therefore the effects of repeated treatments of ketamine on cognition must be further examined. Some clinical reports indicated that, compared to women, men are more sensitive to the psychomimetic effects of ketamine. Preclinical studies extended these findings to both adolescent and adult male rodents and showed that male rodents at both developmental periods are more sensitive to ketamine's cognitive-altering effects. Accordingly, in this review we shall focus our discussion on the potential addictive and cognitive-impairing effects of repeated ketamine infusions in both sexes at two important developmental periods: adolescence and adulthood. Although more work about the safety of ketamine is warranted, we hope this review will bring some answers about the safety of treating TRD with repeated ketamine infusions.

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“…However, chronic ketamine (20 mg/kg, twice a day) in the adolescent rat was also reported to endure resilience and presumed useful as an antidepressant [23]. Of note, repeated administration of 10 mg/kg dose was recently shown to elicit condition place preference in male rats [24]. In previous studies, behavioral evaluation was usually focused on domains related to attention, working memory, problem solving and social deficits [17], while anxiety-like symptoms were mostly neglected [3].…”

Section: Introductionmentioning

confidence: 99%

Repeated Exposure to Ketamine in Adolescent Rats Results in Persistent Anxiety in the Adulthood

Amorim¹,

Bravo²,

Silva³

et al. 2018

jdar

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Background. Adolescent development of the prefrontal cortex (PFC) is accompanied by important changes in glutamatergic, GABAergic and dopaminergic circuitries, susceptible to modulation by N-methyl-D-aspartate receptors (NMDAR) antagonists. Repeated ketamine was associated with social and memory deficits, but other relevant factors, such as anxiety, were not sufficiently addressed. The present study aimed to examine the behavioral and molecular consequences of repeated exposure to ketamine with a particular focus in anxiety. Methods. We treated male adolescent Wistar rats, starting postnatal day (PND) 35, with ketamine (30 mg/kg, i.p, 7 days). Behavioral evaluation was conducted in the adulthood (PND 60). The elevated plus maze (EPM) and open field tests were used to evaluate anxiety and locomotion, while sociability and novelty recognition were assessed through the novel object recognition (NOR) and the sociability and social novelty tests. At the end of the behavioral evaluation, brains were dissected and the prefrontal cortex used for biochemical evaluation. Results. Analysis of the elevated plus maze (EPM) data revealed a ketamine-induced anxiety-like profile, corroborated by the open field data. Ketaminetreated rats also failed to increase contact time with a conspecific in the social affiliation test and with an unknown rat in the novelty preference test. At the molecular level, frontal expression levels of tyrosine hydroxylase were found decreased. Conclusion. Altogether, these results show that repeated ketamine-exposure in the adolescent may result in long-term anxiety.

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Sex- and dose-dependent abuse liability of repeated subanesthetic ketamine in rats

Cited by 30 publications

References 92 publications

Sex Differences in the Antidepressant Effects of Ketamine in Animal Models of Depression

Sex Differences in the Antidepressant Effects of Ketamine in Animal Models of Depression

On the safety of repeated ketamine infusions for the treatment of depression: Effects of sex and developmental periods

Repeated Exposure to Ketamine in Adolescent Rats Results in Persistent Anxiety in the Adulthood

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