Comparison of behavioral effects of the NMDA receptor channel blockers memantine and ketamine in rats

Abstract

Memantine and ketamine block N-methyl-D-aspartate (NMDA) receptors with similar affinity and kinetics, yet their behavioral consequences differ: e.g., memantine is used to alleviate symptoms of Alzheimer's disease, whereas ketamine reproduces symptoms of schizophrenia. The two drugs exhibit different pharmacokinetics, which may play a principal role in their differential behavioral effects. To gain insight into the drugs' behavioral consequences, we treated adult male rats acutely with varying doses (0-40 mg/kg i.p.) of memantine or ketamine and assessed exploratory behavior and spatial working memory. To examine the importance of pharmacokinetics, we assessed behavior either 15 or 45 min after drug administration. Both drugs decreased ambulation, fine movements, and rearing at the beginning of the exploratory activity test; however, at the end of the test, high doses of only memantine increased ambulation and fine movements. High doses of both drugs disrupted spontaneous alternation, a measure of working memory, but high doses of only memantine elicited perseverative behavior. Surprisingly, ketamine's effects were influenced by the delay between drug administration and testing no more frequently than were memantine's. Our findings show that, regardless of test delay, memantine and ketamine evoke similar behavioral effects at lower doses, consistent with NMDA receptors being both drugs' principal site of action, but can have divergent effects at higher doses. Our results suggest that the divergence of memantine's and ketamine's behavioral consequences is likely to result from differences in mechanisms of NMDA receptor antagonism or actions at other targets.

Fig. 1

Effect of memantine on ambulatory distance (a, b), fine movements (c, d), and rearing (e, f) during the first 5 min (a, c, e) and the last 5 min (b, d, f) of the 30-min exploratory activity test, and on spontaneous alternation (g) and perseverative behavior (h) in the spontaneous alternation task. Displayed are group means ± SEM for rats that received either saline (2 ml/kg, i.p.; n=9; open/diagonal-line bars) or memantine (5, 10, 20, or 40 mg/kg, i.p.; n=8 per dose; filled/cross-hatched bars). **, significant difference from saline control (p<0.01); ^&&, significant difference between test delays (p<0.01).

Fig. 2

Effect of ketamine on ambulatory distance (a, b), fine movements (c, d), and rearing (e, f) during the first 5 min (a, c, e) and the last 5 min (b, d, f) of the 30-min exploratory activity test, and on spontaneous alternation (g) and perseverative behavior (h) in the spontaneous alternation task. Displayed are group means ± SEM for rats that received either saline (2 ml/kg, i.p.; n=9; open/diagonal-line bars) or ketamine (5, 10, 20, or 40 mg/kg, i.p.; n=8 per dose; filled/cross-hatched bars). * or **, significant difference from saline control (p<0.05 or p<0.01, respectively); ^&&, significant difference between test delays (p<0.01).

Fig. 3

Comparison between the effect of memantine and of ketamine on ambulatory distance in the exploratory activity test. Memantine (black symbols) or ketamine (grey symbols) was administered either 15 min (a, c) or 45 min (b, d) before testing. Ambulatory distance is shown separately for the first 5 min (a, b) and the last 5 min (c, d) of the 30-min test. To facilitate comparison between the dose-response relations, difference scores from the average performance of saline controls examined at the same test delay were calculated (see Material & Methods for further details) and are displayed in here as group means ± S.E.M. of 18 (saline) or 8 (per drug dose) rats. ^##, significant difference between drugs at a given dose (p<0.01).

Fig. 4

Comparison between the effect of memantine and of ketamine on fine movements in the exploratory activity test. Memantine (black symbols) or ketamine (grey symbols) was administered either 15 min (a, c) or 45 min (b, d) before testing. Frequency of fine movements is shown separately for the first 5 min (a, b) and the last 5 min (c, d) of the 30-min test period. Difference scores (see Fig. 3 legend) are displayed here as group means ± S.E.M. of 18 (saline) or 8 (per drug dose) rats. ^##, significant difference between drugs at a given dose (p ≤ 0.01).

Fig. 5

Comparison between the effect of memantine and of ketamine on rearing in the exploratory activity test. Memantine (black symbols) or ketamine (grey symbols) was administered either 15 min (a, c) or 45 min (b, d) before testing. Counts of rearing is shown separately for the first 5 min (a, b) and the last 5 min (c, d ) of the 30-min test period. Difference scores (see Fig. 3 legend) are displayed here as group means ± S.E.M. of 18 (saline) or 8 (per drug dose) rats. ^##, significant difference between drugs at a given dose (p<0.01).

Fig. 6

Comparison between the effect of memantine and of ketamine on behavior in the spontaneous alternation task. (a, b) Spontaneous alternation; (c, d) Perseveration. Memantine (black symbols) or ketamine (grey symbols) was administered either 15 min (a, c) or 45 min (b, d) before testing. Difference scores (see Fig. 3 legend) are displayed here as group means ± S.E.M. of 18 (saline) or 8 (per drug dose) rats. ^##, significant difference between drugs at a given dose (p<0.01, respectively).