Conditioned effects of a ketamine-paired context: implications for its antidepressant mechanism

Abstract

It has been proposed that a context paired with ketamine (KET) can elicit an antidepressant response through principles of Pavlovian conditioning. This raises the question as to whether this conditioned antidepressant response is unique to KET, or whether it can be generalized to other antidepressant drugs with known pharmacological mechanisms like the serotonin reuptake inhibitor, escitalopram (ESC), or the norepinephrine-dopamine reuptake inhibitor, bupropion (BUP). Thus, the current study investigated whether a context paired with KET, ESC, or BUP could influence the immobility response to forced swimming stress (FSS; 10 mins/session, 3 sessions total), which is a preclinical tool used to assess the antidepressant efficacy of drugs. To do this, male Sprague-Dawley rats were injected with 0.9% saline (w/v; SAL) and placed in a vehicle-paired context (CS-) and injected with SAL, KET (10 or 20 mg/kg, IP), ESC (10 mg/kg, IP), or BUP (10 mg/kg, IP) and placed in a drug-paired context (CS+) on alternating days (10 days total, 5 pairings each in the CS- and CS+). One week later, rats were exposed to 3 sessions of FSS over 3 consecutive days (FSS1-3; exposure to CS- and CS+ prior to FSS2 and FSS3, respectively). Exposure to a KET-paired context prior to FSS3 significantly reduced immobility without affecting general locomotor activity in comparison to contexts paired with SAL or BUP, but not ESC. These findings support the notion that a KET-paired context elicits a conditioned antidepressant response, and that this response may partially involve serotonergic mechanisms.