Sex- and dose-dependent abuse liability of repeated subanesthetic ketamine in rats.
Kristofer J Schoepfer, Caroline E. Strong, Samantha K Saland, Katherine N Wright, Mohamed Kabbaj
Physiology & Behavior May 1, 2019 DOI: 10.1016/j.physbeh.2017.10.021 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical rodent experimental study Peer reviewed |
|---|---|
| Population | Adult male and female rats |
| Interventions | Ketamine rAAV-ΔJunD |
| Dose | 2.5, 5.0, or 10 mg/kg, i.p. |
| Duration | Six treatments on alternating days |
| Measures | Conditioned place preference, locomotor sensitization, ΔFosB protein expression |
| Topics | Ketamine Esketamine |
| Keywords | Conditioned place preference Deltafosb Locomotor sensitization Nucleus accumbens Sex differences |
| Key findings | Six alternating-day ketamine treatments at 2.5 mg/kg produced no clear behavioral signs of abuse liability in rats despite accumbens ΔFosB accumulation; conditioned place preference appeared only in males at 10 mg/kg. Locomotor sensitization occurred at 5.0 and 10 mg/kg in both sexes, was greater in females at 5.0 mg/kg, and correlated with accumbens ΔFosB. The authors report that rAAV-ΔJunD inhibition of ΔFosB-mediated transcription did not block sensitization to 10 mg/kg. |
Abstract
Subanesthetic ketamine (KET) elicits rapid, robust, but transient antidepressant effects. KET's antidepressant actions can be augmented and maintained for a longer duration when repeatedly delivered. However, KET is recreationally abused, raising long-term treatment safety concerns. Women are more likely than men to seek treatment for depression, escalate from casual to compulsive drug use, and are more sensitive to antidepressants. Similarly, female rodents are more sensitive than males to KET's rapid antidepressant-like behavioral effects; dose-response thresholds in these assays equal 2.5 and 5.0mg/kg (i.p.), respectively. This suggests the utility of preclinical rodent models in optimizing sex-differential KET therapy protocols and minimizing adverse drug reactions. Here, we assessed behavioral and biochemical correlates of abuse liability following six serial KET treatments on alternating days at three subanesthetic, antidepressant-like doses (2.5, 5.0, or 10mg/kg, i.p.) in adult male and female rats. A potential role for ΔFosB-mediated transcription in the nucleus accumbens is outlined in the context of KET-mediated locomotor sensitization. Antidepressant-like threshold doses (2.5, 5.0mg/kg KET) failed to evoke a conditioned place preference in all animals, but only males positively responded to a higher dose (10mg/kg). Behavioral sensitization to 5.0 or 10mg/kg KET's locomotor-activating effects was established in both sexes, and females' sensitized response to 5.0mg/kg was greater than males'. KET-induced hyperlocomotion positively correlated with ΔFosB protein expression in the nucleus accumbens. rAAV-ΔJunD inhibition of ΔFosB-mediated transcription in the accumbens failed to block locomotor sensitization to 10mg/kg KET. These data suggest that in rats, six alternating-day treatments with 2.5mg/kg KET do not induce apparent behavioral signatures of abuse liability despite accumulation of ΔFosB protein in the accumbens. Additionally, females are more sensitive than males to KET's locomotor-stimulant properties, both acutely and after repeated treatments. More studies are needed to determine brain regions and neural mechanisms responsible for KET-induced behavioral adaptations and to extrapolate these data to inform sex-dependent strategies for long-term KET therapy protocols for depression.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 16
- The abuse liability of ketamine: A scoping review of preclinical and clinical studies. Journal of Psychiatric Research May 1, 2022
- Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice Nature Communications May 12, 2022
- On the safety of repeated ketamine infusions for the treatment of depression: Effects of sex and developmental periods Neurobiology of Stress September 21, 2018
- Use and abuse of dissociative and psychedelic drugs in adolescence Pharmacology, Biochemistry, and Behavior January 27, 2021
- Ketamine's rapid and sustained antidepressant effects are driven by distinct mechanisms. Cellular and Molecular Life Sciences February 27, 2024
and 11 more in the library
Cites 17
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine use: a review Addiction July 21, 2011
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
and 12 more in the library