Ketamine, a dissociative anesthetic proposed for treatment-resistant depression, produces beneficial clinical effects only after its psychotropic actions fade, suggesting dose-independent mechanisms. This study compared an anesthetic dose of ketamine with a high dose of fluoxetine in Wistar rats 24 hours after administration. Fluoxetine reduced immobility in the forced swim test without affecting locomotor activity, while ketamine strongly decreased locomotor activity and did not change immobility. In separate rats, lateral septal nucleus (LSN) stimulation produced a long-lasting inhibitory afterdischarge in prelimbic and infralimbic cortices. Both ketamine and fluoxetine accentuated this inhibition, indicating that despite different neurotransmission actions, antidepressants may share a common final pathway involving forebrain structures linked to emotional regulation.
A 15-minute forced swim session in male Wistar rats altered the responsiveness of connections between the hippocampal CA3 region and the medial prefrontal cortex (mPFC). Ketamine, given 60 minutes after the stressor, reduced immobility in a later swim test without affecting general locomotion. In the mPFC, CA3 stimulation normally inhibited the prelimbic region and excited the infralimbic region; ketamine reversed the infralimbic response to inhibition. Prior stress amplified the inhibitory response in the infralimbic region, an effect that ketamine abolished. The prelimbic region's response was sensitive to stress but not to ketamine, whereas the infralimbic region's response was sensitive to ketamine only when stress had occurred.