Amino Acids (2002) 23: 153–159 DOI 10.1007/s00726-001-0121-7 Modulation of glutamate receptors: Strategies for the development of novel antidepressants P. Skolnick DOV Pharmaceutical, Inc. Hackensack, New Jersey, U.S.A. Received July 6, 2001 Accepted August 6, 2001 Published online June 17, 2002 © Springer-Verlag 2002 agonist (ACPC) reduce immobility in these behavioral despair procedures. These data have recently been reviewed (Trullas, 1997; Skolnick, 1999; Petrie et al., 2000), and will not be re-described in detail here. Nonetheless, a recent report based on this literature merits additional comment. Harkin et al. (1999) described the ability of nitric oxide (NO) synthase inhibitors to reduce immobility in the FST (with no concomitant change in motor activity, see below). Further, this antidepressant-like effect was blocked by pretreatment with L-arginine, the substrate for NO synthase. Since an increase in NO production (via activation of NO synthase) is one of the principal downstream events associated with NMDA receptor activation, these findings indicate that an antidepres- sant-like action may also be produced by interruption of the signaling cascade as well as at the receptor level, thereby increasing the potential number of targets for novel “glutamate-based” antidepressants. In contrast to a relatively large body of preclinical data, there has been only one report of a study specifi- cally designed to test the hypothesis that NMDA antagonists are antidepressant. Berman et al. (2000) administered either the uncompetitive NMDA an- tagonist ketamine or saline to patients who were un- responsive to conventional antidepressants. Ketamine (0.5 mg/kg, infused over 40 min) significantly reduced Hamilton Depression (HAM-D) scores within 3 h. The reduction in HAM-D scores continued to emerge over time, and persisted for at least 72 h, the planned duration of this study. At the point the study was terminated, HAM-D scores were reduced (X  SD) 14  10 and 0  12 points in the ketamine and saline Summary. On a biochemical level, conventional antidepressants have been shown to modulate synaptic levels of biogenic amines (i.e., serotonin, norepinephrine, and dopamine), most often by interfering with reuptake processes or inhibiting metabolism. Strategies directed at modulating glutamatergic transmission may overcome the principal limitations (i.e., delayed onset and low effi- cacy) that appear to be inherent to these conventional agents. In this brief overview, I summarize two glutamate-based approaches to develop novel antidepressants. These distinct and (on a cellular level) seemingly diametric strategies may converge on intracellular pathways that are also impacted upon by chronic treatment with biogenic amine based agents. Keywords: NMDA antagonists – Depression – Behavioral despair – AMPA – AMPA receptor potentiators Functional NMDA antagonists as antidepressants: Preclinical and clinical evidence For the purpose of this overview, functional NMDA antagonists are compounds that reduce transmission at any of the multiple, allosteric regulatory sites on NMDA receptors. Over the past decade, a body of literature has emerged (reviewed in Trullas, 1997; Skolnick, 1999, Petrie et al., 2000) demonstrating that functional NMDA antagonists are active in “beha- vioral despair” procedures. Behavioral despair proce- dures such as the forced swim (Porsolt et al., 1977a,b) and tail suspension (Steru et al., 1985) tests, whilst not true animal models of depression, are highly predic- tive of antidepressant activity in humans (Borsini and Meli, 1988; Porsolt and Lenegre, 1992). Like clini- cally effective antidepressants, competitive NMDA antagonists (e.g., AP-7, CGP 39551), uncompetitive antagonists (e.g., MK-801, memantine), a polyamine (NR-2B) antagonist (eliprodil), and a glycine partial