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

Highlights

• In rats, low doses of memantine and ketamine have similar behavioral effects.

• High doses of these drugs tend to have qualitatively different behavioral effects.

• Delay between drug delivery and behavioral testing has little influence on outcome.

• Divergent behavioral effects cannot be explained by differences in pharmacokinetics.

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.

Introduction

Although N-methyl-d-aspartate (NMDA) receptor inhibitors exhibit therapeutic potential, their clinical use often is limited by their tendency to produce unacceptable side effects. For instance, the NMDA receptor channel blocker ketamine shows great promise in the treatment of both pain (Prommer, 2012) and depression (Duman and Aghajanian, 2012). However, ketamine also reproduces the positive, negative, and cognitive symptoms of schizophrenia in healthy humans, and exacerbates symptoms in schizophrenics (Krystal et al., 2003, Lahti et al., 2001); as a result, ketamine has been critical in furthering understanding of the pathology of schizophrenia and is used widely to generate animal models of schizophrenia (Greene, 2001, Gunduz-Bruce, 2009, Jentsch and Roth, 1999). The channel blocker memantine, which inhibits NMDA receptor activity with affinity and kinetics similar to those of ketamine (Kotermanski and Johnson, 2009, Mealing et al., 1999, Parsons et al., 1995), is far less prone to induce the psychotomimetic side-effects of ketamine and other NMDA receptor channel blockers. Furthermore, memantine, but not ketamine, has been approved by the Food and Drug Administration to treat moderate-to-severe Alzheimer's disease (Parsons et al., 2007). Improved understanding of the bases of these drugs' differential effects could shed light on mechanisms of Alzheimer's disease therapy and the etiology of schizophrenia.

Subanesthetic doses (≤ 100 mg/kg) of ketamine were reported to increase rats' locomotor activity and stereotypic behavior, decrease rearing and lever-pressing for food, and impair attention and spatial and non-spatial memory (Alessandri et al., 1989, Danysz et al., 1994, Dix et al., 2010, Grant et al., 1996, Hetzler and Wautlet, 1985, Koros et al., 2007, Smith et al., 2011, Verma and Moghaddam, 1996). Similar, although generally less pronounced, effects were observed with memantine (Creeley et al., 2006, Danysz et al., 1994, Dix et al., 2010, Gilmour et al., 2009, Grant et al., 1996, Koros et al., 2007, More et al., 2008, Smith et al., 2011). Unlike ketamine, however, low doses of memantine were found by some groups to exert beneficial effects on memory function (Danysz and Parsons, 2003, Wise and Lichtman, 2007, Yuede et al., 2007, Zoladz et al., 2006).

The differential behavioral effects of memantine and ketamine could arise from at least three mechanistic differences between the drugs: differences in pharmacokinetics, differences in actions at targets other than NMDA receptors, or differences in mechanism of inhibition of NMDA receptors (Danysz et al., 1994, Gilmour et al., 2009, Grant et al., 1996, Johnson and Kotermanski, 2006, Jones et al., 2001, Kotermanski et al., 2009, Rogawski and Wenk, 2003). One goal of the current study was to examine the hypothesis that the pharmacokinetic differences between the drugs may explain differences in their behavioral effects. Reported pharmacokinetic differences between memantine and ketamine, which are likely to have multiple causes, including differences in drug metabolism and lipid solubility (Beconi et al., 2011, Cohen et al., 1973, Cohen and Trevor, 1974, White et al., 1982), are substantial. After intraperitoneal (i.p.) administration in rats, memantine peak plasma concentration is reached within 30–60 min, and half-life is ~ 120 min (Hesselink et al., 1999b, Zoladz et al., 2006); the time course in brain is similar or moderately slower (Hesselink et al., 1999a, Spanagel et al., 1994). We could not find time course data on ketamine after i.p. administration in rats; however, after intravenous administration, peak plasma concentration is reached immediately, and half-life is ~ 10 min; the time course in brain is very similar (Cohen et al., 1973, Marietta et al., 1976, White et al., 1976). After intramuscular administration, peak plasma concentration is observed within 5–20 min, and half-life is ~ 30 min (White et al., 1976, Williams et al., 2004). Because ketamine has much faster pharmacokinetics than memantine, the two drugs may inhibit NMDA receptors with different time courses (Jones et al., 2001), which, in turn, may contribute to differential behavioral consequences of the two drugs (Gilmour et al., 2009, Johnson and Kotermanski, 2006).

In previous studies on memantine and ketamine, behavioral testing was conducted at only one time point after drug administration (Danysz et al., 1994, Gilmour et al., 2009, Koros et al., 2007). Here, we compared directly the behavioral effects of memantine and ketamine using two different delays after drug administration chosen to accentuate any differential effects that may result from the drugs' differences in pharmacokinetics. We found that the behavioral consequences of low doses of memantine and ketamine are similar regardless of delay. At higher doses, some divergent effects emerged; however, they too were largely delay-independent. Our findings suggest that the drugs' differential pharmacokinetics do not lead to differences in behavioral outcome.