Neuropharmacology 40 (2001) 1028–1033 www.elsevier.com/locate/neuropharm Antidepressant-like actions of an AMPA receptor potentiator (LY392098) Xia Li * , Joseph P. Tizzano, Kelly Griffey, Michael Clay, Terry Lindstrom, Phil Skolnick Eli Lilly and Co., Lilly Research Laboratories, Indianapolis, IN 46285-0510, USA Received 25 September 2000; received in revised form 7 November 2000; accepted 13 November 2000 Abstract LY392098 is a member of a novel class of biarylpropylsulfonamides that potentiates AMPA receptor-mediated responses both in vitro and in vivo. In this study, the effects of LY392098 were evaluated in two “behavioral despair” models (the forced swim and tail suspension tests) commonly used to identify clinically useful antidepressants. LY392098 reduced immobility in the forced swim test in both rats and mice, with a minimum effective dose of 0.5 mg/kg (i.p.) in both species. LY392098 (0.1–10 mg/kg, i.p.) did not affect motor activity of rats, indicating that the ability of this compound to reduce immobility in the forced swim test is unrelated to a motor stimulant action. LY392098 also reduced immobility in the tail suspension test in a dose-dependent manner, with a minimum effective dose of 5 mg/kg (i.p). A non-competitive AMPA antagonist (LY300168) blocked the activity of LY392098 in the forced swim test, but did not affect imipramine-induced reductions in immobility. Thus, AMPA receptor activation appears to be required for the antidepressant-like effect of LY392098, but not imipramine. These findings indicate that biarylpropylsulfonam- ides, exemplified by LY392098, may represent a novel class of antidepressants.  2001 Elsevier Science Ltd. All rights reserved. Keywords: LY392098; Forced swim test; Tail suspension test; Behavioral despair; Antidepressants; AMPA receptors 1. Introduction Most clinically useful antidepressants affect the dispo- sition (i.e. the reuptake and/or metabolism) of biogenic amines (reviewed in Caldecott-Hazard et al., 1991). Nevertheless, in most well-controlled clinical trials, sev- eral weeks of antidepressant treatment are generally required to produce significant symptom remission (Oswald et al., 1972; reviewed in Nelson, 1999). This “therapeutic lag” indicates that an increased synaptic availability of biogenic amines per se is not sufficient to produce an antidepressant action. Instead, an antide- pressant-induced increase in the synaptic availability of biogenic amines may initiate one or more signal trans- duction cascades that ultimately effect a relief of depressive symptomatology (reviewed in Duman et al., 1997a,b; Rossby and Sulser, 1997; Skolnick, 1999). * Corresponding author. Tel.: +1-317-433-0108; fax: +1-317-276- 7600. E-mail address: liFxiaFx1@lilly.com (X. Li). 0028-3908/01/$ - see front matter  2001 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(00)00194-5 During the past five years, converging lines of evi- dence indicate brain-derived neurotrophic factor (BDNF) may be a pivotal downstream mediator of antidepressant action (reviewed in Altar, 1999). Thus, chronic but not acute treatment of rats with a structurally diverse group of first and second generation antidepressants (e.g. tri- cyclics, serotonin specific reuptake inhibitors, monoam- ine oxidase inhibitors), as well as electroconvulsive shock, has been reported to elevate hippocampal levels of mRNA encoding BDNF (Nibuya et al., 1995; Fuji- maki et al., 2000; but see Russo-Neustadt et al., 1999). It has been hypothesized that the trophic and protective properties of BDNF in mature neurons, and in particular monoaminergic neurons (Mamounas et al., 1995; Altar, 1999), may be critical in maintaining appropriate levels of synaptic transmission in the face of stress-induced insults to the central nervous system (McEwen, 1999; Nitta et al., 1999). Furthermore, central infusion of BDNF has been reported (Siuciak et al., 1997) to reduce immobility in the forced swim test. A reduction in immobility is the hallmark of a clinically effective anti- depressant in this model of behavioral despair (Porsolt et al., 1977a,b; Borsini and Meli, 1988).