Ketamine, a dissociative anesthetic agent, appears to have rapid antidepressant effects at sub-anesthetic doses in clinically depressed patients. Although promising, these results need to be replicated in double-blind placebo-controlled studies, a strategy thwarted by the psychoactive effects of ketamine, which are obvious to both patients and clinicians. Alternatively, demonstrations of the psychotherapeutic effects of ketamine in animal models are also complicated by ketamine's side-effects on general activity, which have not been routinely measured or taken into account in experimental studies. In this study we found that ketamine decreased "behavioral despair" in the forced swim test, a widely used rats model of antidepressant drug action. This effect was not confounded by side-effects on general activity, and was comparable to that of a standard antidepressant drug, fluoxetine. Interestingly, ketamine also produced anxiolytic-like effects in the elevated-plus-maze. Importantly, the effective dose of ketamine in the plus-maze did not affect general locomotion measures, in either the plus-maze or in the open field test. While the selective N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 also produced antidepressant-like and anxiolytic-like effects, these were mostly confounded by changes in general activity. Finally, in a neurophysiological model of anxiolytic drug action, ketamine reduced the frequency of reticularly-activated theta oscillations in the hippocampus, similar to the proven anxiolytic drug diazepam. This particular neurophysiological signature is common to all known classes of anxiolytic drugs (i.e. benzodiazepines, 5-HT1A agonists, antidepressants) and provides strong converging evidence for the anxiolytic-like effects of ketamine. Further studies are needed to understand the underlying pharmacological mechanisms of ketamine's effects in these experiments, since it is not clear they were mimicked by the selective NMDA antagonist MK-801.