The antidepressant-like activity of ketamine in the rat chronic mild stress model requires activation of cortical 5-HT 1A receptors.

Ketamine rapidly reverses depression-like symptoms in rats exposed to chronic mild stress, including loss of pleasure and working memory deficits, when given systemically or directly into the prefrontal cortex. Blocking serotonin 5-HT1A receptors in the prefrontal cortex with WAY-100635 prevents these effects, showing that ketamine's rapid antidepressant and pro-cognitive actions require activation of these receptors. The findings suggest that drugs directly targeting prefrontal cortex 5-HT1A receptors could provide rapid antidepressant effects and improve cognitive deficits without ketamine's side effects or need for clinical supervision.

Study at a glance

Abstract

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-HT 1A receptors, as previously found in experiments using the forced swim test. The present study explored the contribution of PFC 5-HT 1A 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-HT 1A receptor antagonist, WAY-100635 (2 µg), 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-HT 1A receptors. They also reinforce the notion that drugs that directly activate PFC 5-HT 1A 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.