1. Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism
- Author
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Sinead M. Gibney, Andrew Harkin, Sheena Casey, Danielle Egan, Grainne O’Dowd, and Valentina Gigliucci
- Subjects
Male ,Serotonin ,Time Factors ,Pharmacology toxicology ,Pharmacology ,Antidepressant like ,Rats, Sprague-Dawley ,medicine ,Animals ,Ketamine ,Swimming ,Mechanism (biology) ,Depression ,Antidepressive Agents ,Rats ,Disease Models, Animal ,NMDA receptor ,Antidepressant ,Psychology ,human activities ,Excitatory Amino Acid Antagonists ,Stress, Psychological ,medicine.drug ,Behavioural despair test - Abstract
Behavioural antidepressant-like effects of ketamine have been reported in the forced swimming test (FST). The mechanisms mediating such effects are unknown.As serotonin (5-HT) is an important transmitter mediating antidepressant responsiveness in the FST, the influence of 5-HT depletion on the antidepressant-like effect of ketamine was assessed.The effect of ketamine (25 mg/kg, i.p., 1 or 24 h prior to test) was assessed in the FST in naive rats or animals subjected to 5-HT depletion, repeated stress or following a combination of 5-HT depletion and stress. Endogenous 5-HT was depleted using the tryptophan hydroxylase inhibitor para-chlorophenylalanine (3 × 150 mg/kg, i.p.). Stress was induced by physical restraint (2 h/day for 10 days).In naive rats, ketamine administered 24 or 1 h prior to test produced a characteristic antidepressant-like reduction in immobility time in the FST. Depletion of 5-HT blocked this reduction in immobility when ketamine was administered 24 h prior FST, indicative of 5-HT dependency. The increase in immobility provoked by repeated restraint stress (2 h/day for 10 days) was blocked by ketamine when administered 24 h prior to FST, but this effect dissipated when animals were subjected to 5-HT depletion.These observations are consistent with a role for 5-HT in mediating sustained antidepressant activity of ketamine in the FST. Molecular and cellular changes induced by ketamine may produce a rapid adaptation of 5-HT transmission which underlies the antidepressant response.
- Published
- 2012