Ketamine and fluoxetine exert similar actions on prelimbic and infralimbic responsivity to lateral septal nucleus stimulation in Wistar rats.

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.

Study at a glance

Abstract

Ketamine is a dissociative anesthetic that has been proposed to be a useful alternative in cases of a poor response to other treatments in patients with depression. Remarkably, beneficial clinical actions of ketamine are detected once its psychotropic actions disappear. Therefore, clinical actions may occur independently of dose. Most current studies focus on actions of ketamine on neurotrophic factors, but few studies have investigated actions of ketamine on neural structures for which actions of antidepressants have been previously explored. Lateral septal nucleus (LSN) stimulation reduces neural activity in the prelimbic cortex (PL) and infralimbic cortex (IL) subregions of the medial prefrontal cortex (mPFC). Fluoxetine increases inhibitory responsivity of the LSN-IL connection. In the present study, actions of an anesthetic dose of ketamine were compared with a high dose of fluoxetine on behavior and neural responsivity 24 h after drug administration. Fluoxetine reduced immobility in the forced swim test without changing locomotor activity in the open field test. Ketamine strongly decreased locomotor activity and did not produce changes in immobility. In another set of Wistar rats that received similar drug treatment regimens, the results indicated that LSN stimulation in saline-treated animals produced a long-lasting inhibitory afterdischarge in these mPFC subregions. Actions of ketamine on the LSN-mPFC connection reproduced actions of fluoxetine, consisting of accentuated inhibition of the LSN action on the mPFC. These findings suggest that independent of different actions on neurotransmission, the common final pathway of antidepressants lies in their actions on forebrain structures that are related to emotional regulation.