Chronic ketamine impairs fear conditioning and produces long-lasting reductions in auditory evoked potentials

Abstract

Ketamine is an NMDA receptor antagonist with a variety of uses, ranging from recreational drug to pediatric anesthetic and chronic pain reliever. Despite its value in the clinical setting, little is known about the immediate and long-lasting effects of repeated ketamine treatment. We assessed the effects of chronic administration of a subanesthetic dose of ketamine on contextual fear conditioning, detection of pitch deviants and auditory gating. After four, but not two, weeks of daily ketamine injections, mice exhibited decreased freezing in the fear conditioning paradigm. Gating of the P80 component of auditory evoked potentials was also significantly altered by treatment condition, as ketamine caused a significant decrease in S1 amplitude. Additionally, P20 latency was significantly increased as a result of ketamine treatment. Though no interactions were found involving test week, stimulus and treatment condition, these results suggest that repeated ketamine administration impairs fear memory and has lasting effects on encoding of sensory stimuli.

Figure 1

Schedule of injections and experimental testing.

Figure 2

Freezing ratios of mice chronically treated with either saline (gray) or 5.0 mg/kg ketamine (black) in contextual fear conditioning. Pre- and post-shock data represent baseline and immediate, unconditioned responses before and after footshock, respectively. Freezing behavior in the conditioned context during the first test session (following 2 weeks of ketamine) and second test session (17 days after training) are also shown. Error bars represent standard error of the mean (±SEM). Ketamine resulted in a significant impairment of contextual fear conditioning during the second test session (asterisk) but not the first.

Figure 3

Grand average AEP readings for each treatment, test session and stimulus condition in the gating task are shown. Grand averages of (A) 0.09% saline and (B) 5.0 mg/kg ketamine treated mice, 3 weeks after the cessation of the 4-week, daily administration schedule. (C) Saline- and (D) ketamine-treated grand averages, 5 weeks after the cessation of treatment. S1 represents the response to the first of two white-noise bursts, while S2 represents the response to the second.

Figure 4

S1 latencies of the P20, N40 and P80 components of the auditory ERP following chronic saline (gray) or 5.0 mg/kg ketamine (black) treatment. Asterisk indicates either a significant ketamine-induced increase in P20 latency across both test weeks, or a decrease in P80 latency between weeks 3 and 5. Overall, ketamine increased the S1 latency of all components at both time points. Data are presented as mean ± SEM.

Figure 5

Gating data for the P20, N40 and P80 AEP components three and five weeks after cessation of chronic saline (gray) or 5.0 mg/kg ketamine (black) treatment. Asterisk indicates either a significant interaction between N40 gating and test week, or P80 gating and treatment condition. Post hoc analyses revealed that both of these results were mediated by effects on S1 amplitude, which increased between weeks 3 and 5, and was decreased by ketamine. Data are presented as mean ± SEM.