In a double-blind crossover design, either 30 mg of the noncompetitive NMDA-receptor antagonist memantine or a placebo was administered to 40 healthy male volunteers. Twenty line drawings of objects and 20 photographs of unfamiliar faces were presented on a computer screen. After a retention interval of 80 min, the participants' task was to select the original objects and faces from a set of 80 items. Results were analyzed applying a signal-detection-theory approach. Recognition performance for objects was significantly impaired under memantine as compared to placebo, whereas performance on face recognition was not affected. Findings support the notion of differential effects of NMDA-receptor antagonists on memory functions in humans.Glutamate is one of the main excitatory neurotransmitters in the mammalian brain. The wide distribution of glutamate within the central nervous system suggests that it mediates normal neural transmission (Collingridge and Singer 1990; Scatton 1993) by activating three major classes of subreceptors: NMDA (N-methyl-D-aspartate), AMPA (␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), and kainate (cf. Danysz and Archer 1994). Abnormal excitatory glutamatergic neurotransmission has been suggested as a pathological mechanism in various disorders such as schizophrenia (Tamminga 1998;Duncan et al. 1999), hypoxic-ischemic brain damage (Choi and Rothman 1990;Scatton 1993), and Alzheimer's dementia (Greenamyre et al. 1988;Foster 1990;Lees 1993). Cognitive symptoms associated with ischemia or Alzheimer's disease are considered a consequence of overactivation of NMDA receptors by endogenous glutamate, which causes neurodegeneration caused by excitotoxicity (Meldrum and Garthwaite 1990;Thomas 1995). Several clinical studies showed that NMDA-receptor antagonists improve cognitive disturbances by inhibiting pathological overactivation of NMDA receptors (Ditzler 1991;Pantev et al. 1993;Müller et al. 1995;Winblad and Poritis 1999).Under physiological conditions, however, inhibition of NMDA receptors suppresses long-term potentiation (LTP) and thus impairs learning and memory (Izquierdo 1994). Although a large number of animal studies support the notion that NMDA antagonists negatively affect learning and memory processes (for reviews, see Danysz and Archer 1994;Aigner 1995), investigations on memory functions in humans after NMDA-receptor blockade are exceedingly scant. The very few existing studies provide ambiguous results. As can be seen from Table 1, the effects of NMDA antagonists on immediate and delayed verbal and nonverbal memory performance in humans remain unclear, whereas spatial memory was consistently shown to be unaffected by NMDA-antagonistic pharmacological treatment. This pattern of results suggests differential effects of NMDA-receptor antagonists on memory functions in humans.To date, no human data on the functional relationship between NMDA-receptor activity and other declarative memory functions, such as long-term memory for objects and faces, appear to exist. This is impor...