Tolerance to the discriminative stimulus and reinforcing effects of ketamine.
B.A. Rocha, A.S. Ward, Y. Egilmez, D.A. Lytle, M.W. Emmett-Oglesby
Behavioural Pharmacology March 1, 1996 DOI: 10.1097/00008877-199603000-00007 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal behavioral pharmacology experiment Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | Ketamine |
| Dose | 10 mg/kg (discrimination training), 1.1 mg/kg/injection (self-administration), 32 mg/kg i.p. every 8 hours for 7 days (chronic treatment) |
| Duration | 7 days of chronic ketamine treatment; 2-week rest period; training sessions |
| Topics | Esketamine Ketamine |
| Key findings | Chronic ketamine (32 mg/kg every 8 hours for 7 days) did not shift dose-response curves for ketamine's discriminative stimulus or reinforcing effects. After a 2-week rest, sensitivity increased, shown by a two-fold leftward shift in the dose-response curve, and resuming training shifted the curve back to the right. The authors suggest tolerance to these effects develops during training, supported by decreasing inter-reinforcer time (increased intake) over sessions. |
Abstract
In order to examine whether tolerance develops to the discriminative stimulus and reinforcing effects of ketamine, rats were trained either to discriminate ketamine (10mg/kg) from saline or to self-administer ketamine (1.1mg/kg/injection), and then treated with chronic ketamine (32mg/kg), administered i.p. every 8 hours for 7 days. No shift in the dose-response curve for either paradigm was obtained following this chronic regimen. However, following a 2-week rest period in which animals had no exposure to ketamine, the dose-response curve was shifted two-fold to the left, indicating increased sensitivity to the drug. Reinstatement of training shifted the dose-response curve back to the right in both paradigms. These results suggest that tolerance to the discriminative stimulus and reinforcing effects of ketamine develops during training. Examination of the self-administration training data support this assumption, since inter-reinforcer time decreases, reflecting an increase in ketamine intake over training sessions.
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 13
- Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants The Annual Review of Pharmacology and Toxicology October 9, 2018
- The abuse liability of ketamine: A scoping review of preclinical and clinical studies. Journal of Psychiatric Research May 1, 2022
- Oral ketamine for the treatment of pain and treatment-resistant depression The British Journal of Psychiatry February 1, 2016
- Targeting metaplasticity mechanisms to promote sustained antidepressant actions. Molecular Psychiatry April 1, 2024
- Psychedelic Therapy: A Primer for Primary Care Clinicians-Ketamine. American Journal of Therapeutics
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