Ketamine administration during a critical period after forced ethanol abstinence inhibits the development of time-dependent affective disturbances.
Oliver Vranjkovic, Garrett Winkler, Danny G Winder
Neuropsychopharmacology May 24, 2018 DOI: 10.1038/s41386-018-0102-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study in mice Peer reviewed |
|---|---|
| Population | Female C57BL/6J mice with a history of chronic two-bottle-choice ethanol drinking |
| Intervention | Ketamine |
| Dose | 3 mg/kg i.p. |
| Duration | Ketamine administered at onset, two, or six days post-abstinence; synaptic plasticity assessed two to three weeks into abstinence |
| Measures | Elevated Plus Maze (EPM), Novelty Suppressed Feeding Test (NSFT), Forced Swim Test (FST), field potential electrophysiology for long-term potentiation (LTP) in the bed nucleus of the stria terminalis (BNST) |
| Topics | Ketamine Esketamine |
| Keywords | Septal nuclei Animals Mice, inbred c57bl Alcohol-related disorders Substance withdrawal syndrome Disease models, animal Psychotropic drugs Tissue culture techniques Affect Mood disorders Long-term potentiation Female |
| Key findings | Ketamine (3 mg/kg) given at the onset of forced abstinence prevented early elevated plus maze deficits and later Novelty Suppressed Feeding Test and Forced Swim Test deficits, while doses given two or six days after abstinence onset did not. Ketamine at abstinence onset also persistently increased long-term potentiation capacity in the bed nucleus of the stria terminalis. The authors suggest a critical period at abstinence onset for ketamine to prevent affective disturbances, partly through enhanced plasticity in this region. |
Abstract
Forced abstinence from chronic two bottle-choice ethanol drinking produces the development of negative affective states in female C57BL/6J mice. We previously reported that this disrupted behavior is acutely reversed by administration of ketamine 30 min-prior to testing. Here we assessed whether ketamine can be used as an inoculant against the development of abstinence- dependent affective disturbances. In parallel, we examined the impact of ketamine administration on long-term potentiation (LTP) in the bed nucleus of the stria terminalis (BNST), a region implicated in affective disturbances. We administered ketamine (3 mg/kg i.p.) to female C57BL/6J mice with a history of chronic ethanol drinking at either the onset, two, or 6 days- post-abstinence and observed its impact on affective behavior in the elevated plus maze (EPM), the Novelty Suppressed Feeding Test (NSFT), and the Forced Swim Test (FST). In addition, we assessed BNST synaptic plasticity with field potential electrophysiology two to 3 weeks into abstinence. We found that early abstinence was associated with disrupted behavior on the EPM. Ketamine administered at the onset of forced abstinence prevented both the deficit in early EPM behavior, and the delayed deficits in NSFT and FST. However, ketamine administered either two or 6 days post-abstinence failed to prevent the abstinence-induced affective disturbances. To begin to explore potential alterations in neural circuit activity that accompanies these actions of ketamine, we assessed the impact of ketamine administration at the onset of forced abstinence and measured LTP induction in the BNST. We find that early ketamine administration persistently increased the capacity for LTP within the BNST. These findings suggest a critical period at the onset of forced abstinence in which ketamine inoculation can prevent the development of affective disturbances, in part by enhancing plasticity within the BNST.
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
Cites 8
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Therapeutic Modulation of Glutamate Receptors in Major Depressive Disorder Current Neuropharmacology March 25, 2016
- Convergent Mechanisms Underlying Rapid Antidepressant Action. CNS Drugs March 2018
- Ketamine as a prophylactic against stress-induced depressive-like behavior Biological Psychiatry May 4, 2015
and 3 more in the library