-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT Receptor Dependent Mechanism in a Genetic Rat Model of Depression.

The mechanisms responsible for the unique antidepressant properties of ketamine have only been partly resolved. Recent preclinical reports implicate the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] in the antidepressant-like response of ketamine, and modulation of 5-HT receptors has been hypothesized to attain an important role. To evaluate the role of endogenous stimulation of 5-HT heteroreceptors in the antidepressant-like activity of -ketamine. Flinders sensitive line (FSL) rats, a genetic model of depression, were depleted of endogenous 5-HT by 4-chloro-DL-phenylalanine methyl ester HCl administration (pCPA; 86 mg/kg/day for 3 days). In pCPA-pretreated and control FSL rats, the acute and sustained effects of a single dose of -ketamine (15 mg/kg) and the selective 5-HT receptor agonist CP94253 (1-6 mg/kg) alone and in combination with -ketamine were studied in the forced swim test (FST), a commonly used assay that detects antidepressant activity. pCPA pretreatment decreased cortical 5-HT levels to ∼6% but did not affect the baseline behavioral phenotype of FSL rats. -ketamine demonstrated acute and sustained antidepressant-like activity, both of which were abolished by 5-HT depletion. Combining -ketamine with a sub-effective dose of CP94253 (1 mg/kg) rescued -ketamine's acute and sustained antidepressant-like effects, when CP94253 was administered 2 h prior to the FST. Co-administration of -ketamine and CP94253 did not affect the plasma level of either compound, suggesting that the observed behavioral interaction could not be ascribed to a kinetic drug-drug interaction. 5-HT receptor activation during testing appears to be critical for -ketamine's antidepressant-like potentials in this model.