LY354740, an mGlu2/3 Receptor Agonist as a Novel Approach to Treat Anxiety/Stress

Abstract

Metabotropic glutamate (mGlu) receptors, which include mGlu1-8 receptors, are a heterogeneous family of G-protein coupled receptors (GPCRs) that function to modulate neuronal excitation and plasticity via pre-synaptic, post-synaptic and glial mechanisms. Agonists for group II mGlu receptors (mGlu2 and mGlu3), such as LY354740, have been shown to suppress enhanced glutamatergic excitations in brain synapses known to be involved in the expression of fear/anxiety in animals and humans. Systemic administration of LY354740 increases open-arm time in the elevated plus maze in mice under conditions of moderate to severe stress, blocks the expression but not development of fear-potentiated startle in rats, prevents lactate-induced panic-like responses in panic-prone rats, and attenuates certain physiological, behavioral, and neurochemical consequences of acute stress in rodents. In these preclinical models, LY354740 does not produce the side-effects (e.g. sedation) that are associated with other anxiolytic agents such as benzodiazepines. Early clinical results with LY354740 have demonstrated safety and efficacy in a human anxiety model (panic provocation induced by CO2 challenge). Collectively, these data indicate mGlu2/3 receptor agonists such as LY354740 represent a promising new approach for treatment of anxiety and stress-related disorders in humans.

Anxiolytic Activity of the MGLU2/3 Receptor Agonist LY354740 on the Elevated Plus Maze is Associated with the Suppression of Stress-Induced c-Fos in the Hippocampus and Increases in c-Fos Induction in Several Other Stress-Sensitive Brain Regions

“…c-Fos expression was induced by LY354740 in stress-related brain regions such as the amygdala, EW, and LC, and also in the thalamic and midbrain structures that process sensory information. It has been shown that systemically administered LY354740 reaches the brain at pharmacologically relevant concentrations (see Schoepp et al, 2003). However, we cannot rule out the possibility that , and LY354740-treated EPM-exposed (d) mice.…”

“…Based on animal and early human data, modulation of excitatory neurotransmission via mGlu2/3 receptors is a novel approach to treat anxiety, as well as other psychiatric disorders (Schoepp, 2001;Schoepp and Marek, 2002;Schoepp et al, 2003). (1S,2S,5R,6S)-2-aminobicyclo [3.1.0]hexane-2,6-dicarboxylic acid (LY354740) is a selective and potent agonist for mGlu2 and mGlu3 receptors (Monn et al, 1997).…”

“…LY354740 is also active in an animal model of panic disorder (Shekhar and Keim, 2000). In humans, LY354740 reduced CO 2 -induced panic anxiety (Levine et al, 2001;Schoepp et al, 2003) and produced anxiolytic effects in the fear-potentiated startle paradigm (Grillon et al, 2003).…”

“…LY354740 binds to mGlu2/3 receptors primarily throughout the forebrain of rats (Schaffhauser et al, 1998;Wright et al, 2001;Schoepp et al, 2003). In brain synapses such as the central nucleus of the amygdala (Neugebauer et al, 2000), hippocampal perforant path (Kilbride et al, 1998(Kilbride et al, , 2001, medial prefrontal cortex (mPFC) (Marek et al, 2000), nucleus accumbens (Robbe et al, 2002), and substantia nigra (Bradley et al, 2000), LY354740 has been shown to suppress evoked glutamate excitatory synaptic potentials/ currents (reviewed by Schoepp et al, 2003).…”

“…In brain synapses such as the central nucleus of the amygdala (Neugebauer et al, 2000), hippocampal perforant path (Kilbride et al, 1998(Kilbride et al, , 2001, medial prefrontal cortex (mPFC) (Marek et al, 2000), nucleus accumbens (Robbe et al, 2002), and substantia nigra (Bradley et al, 2000), LY354740 has been shown to suppress evoked glutamate excitatory synaptic potentials/ currents (reviewed by Schoepp et al, 2003). In particular, the intra-amygdalar injection of LY354740 disrupted fearpotentiated startle (Walker et al, 2002), and intrahippocampal injection of LY354740 produced an anticonflict effect in the Vogel drinking test (Tatarczynska et al, 2001), suggesting that these regions may be involved in the anxiolytic actions of LY354740 when it is administered systemically.…”