The antidepressant-like activity of ketamine in the rat chronic mild stress model requires activation of cortical 5-HT1A receptors

Ketamine displays efficacious rapid-acting antidepressant (RAAD) activity in the rat chronic mild stress (CMS) model. It rapidly reverses anhedonia (CMS-induced sucrose consumption deficit) and attenuates working memory deficit (novel object recognition: NOR) following both systemic (intraperitoneal, i.p.) administration or local administration in the prefrontal cortex (PFC). However, the receptor mechanisms underlying these effects remain to be clarified and may involve activation of serotonin 5-HT1A receptors, as previously found in experiments using the forced swim test. The present study explored the contribution of PFC 5-HT1A receptors in ketamine's RAAD activity in the CMS model. Ketamine (10 mg/kg i.p.) reversed CMS-induced sucrose consumption and working memory (NOR test) deficits. Notably, unilateral PFC microinjections of a 5-HT1A receptor antagonist, WAY-100635 (2 mu g), prevented the antidepressant-like and pro-cognitive activity of systemic ketamine on sucrose consumption and working memory deficits. These data indicate that the RAAD activity of ketamine in the rat CMS model requires activation of PFC 5-HT1A receptors. They also reinforce the notion that drugs that directly activate PFC 5-HT1A receptors could constitute an alternative to ketamine as a promising strategy to achieve RAAD effects, with additional benefits against cognitive deficits in depressed patients, but without ketamine's troublesome side-effects and requirements for in-patient supervision. Behavioural Pharmacology 36: 182-188 Copyright (c) 2024 Wolters Kluwer Health, Inc. All rights reserved.