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Effects of LY354740, a Novel Glutamatergic Metabotropic Agonist, on Nonhuman Primate Hypothalamic-Pituitary-Adrenal Axis and Noradrenergic Function

Published online by Cambridge University Press:  07 November 2014


The search for novel anxiolytics and antidepressants has focused on compounds with the potential to reduce excessive hypothalamic-pituitary-adrenal (HPA) axis activity. L-glutamate, an excitatory neurotransmitter ubiquitously present within the central nervous system, conceivably plays an important role in activating the neural sites involved in stress modulation. Deactivation of the HPA axis by glutamatergic neurotransmission modulation may represent a novel therapeutic approach. Accordingly, the acute intravenous effects of the novel metabotropic (mGlu2/3) agonist LY354740 were tested on bonnet macaques (Macaca radiata) undergoing acute infusions of yohimbine, a noradrenergic stimulant. Dependent measures were the magnitude of the increase of plasma cortisol and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) customarily elicited by yohimbine. Next, the effects of 6 weeks of chronic oral administration of LY354740 on baseline (postcapture) plasma cortisol and MHPG levels in comparison to the identical measure in untreated controls were assessed. Subjects chronically treated with LY354740 received yohimbine infusions which were compared to yohimbine infusions and saline infusions in non-LY354740-treated subjects. Preliminary evidence supports the view that acute LY354740 infusion resulted in a marked diminution of yohimbine-induced stress response, as manifest by a substantial attenuation of cortisol and MHPG response observed in comparison to the saline-treated yohimbine condition. Chronic oral administration of LY354740 led to postcapture baseline cortisol levels which were markedly reduced (∼50%) in comparison to untreated control subjects; however, there were no significant parallel differences in MHPG levels. Yohimbine infusions elicited an increase in cortisol and MHPG levels in both LY354740-treated and non-LY354740-treated subjects, in comparison to declines in cortisol values observed following vehicle infusions (group X time interaction; P<.0001). Chronic LY354740-treated subjects failed to achieve cortisol levels comparable in range to those of untreated subjects primarily because of their low baseline cortisol levels. In contrast, despite equivalent baselines, yohimbine-induced MHPG values were increased overall in the chronically treated group compared to the saline and yohimbine-alone groups. Thus, LY354740 markedly reduced the acute corticoid and noradrenergic response elicited by yohimbine infusion. Chronic administration of LY354740 appears to present a safe and effective mechanism to markedly down-modulate the HPA axis while retaining noradrenergic responsivity.

Original Research
Copyright © Cambridge University Press 2001

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1. Nakanishi, S. Molecular diversity of glutamate receptors and implications for brain function. Science. 1992;258:597603.CrossRefGoogle ScholarPubMed
2. Cotman, CW, Kahle, JS, Miller, SE, et al. Excitatory amino acid neurotransmission. In: Bloom, FE, Kupfer, DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995:7586.Google Scholar
3. Conn, PJ, Pin, JP. Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol. 1997;37:205237.CrossRefGoogle ScholarPubMed
4. Schoepp, DD. Novel functions for subtypes of metabotropic glutamate receptors. Neurochem Int. 1994;24:439449.CrossRefGoogle ScholarPubMed
5. Forsythe, ID, Barnes-Davies, M. Synaptic transmission: well-placed modulators. Curr Biol. 1997;7:R362–R365.CrossRefGoogle ScholarPubMed
6. Schoepp, DD, Johnson, BG, Wright, RA, et al. LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors. Neuropharmacology. 1997;36:111.CrossRefGoogle ScholarPubMed
7. Schoepp, DD, Johnson, BG, Wright, RA, et al. Potent, stereoselective, and brain region selective modulation of second messengers in the rat brain by (+)LY354740, a novel group II metabotropic glutamate receptor agonist. Naunyn Schmiedebergs Arch Pharmacol. 1998;358:175180.Google Scholar
8. Kilbride, J, Huang, LQ, Rowan, MJ, et al. Presynaptic inhibitory action of the group II metabotropic glutamate receptor agonists, LY354740 and DCG-IV. Eur J Pharmacol. 1998;356:149157.Google Scholar
9. Battaglia, G, Monn, JA, Schoepp, DD. In vivo inhibition of veratridine-evoked release of striatal excitatory amino acids by the group II metabotropic glutamate receptor agonist LY354740. Neurosci Lett. 1997;229:161164.CrossRefGoogle Scholar
10. Helton, DR, Tizzano, JP, Monn, JA, et al. Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors. J Pharmacol Exp Ther. 1998;284:651660.Google ScholarPubMed
11. Helton, DR, Schoepp, DD, Monn, JA, et al. A role for metabotropic glutamate receptors in drug withdrawal states. In: Moroni, F, Nicoletti, F, Pellegrini-Giampietro, DE, eds. Metabotropic Glutamate Receptors and Brain Function. London, England: Portland Press Ltd; 1998:305314.Google Scholar
12. Vandergriff, J, Rasmussen, K. The selective mGlu2/3 receptor agonist LY354740 attenuates morphine-withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal. Neuropharmacology. 1999;38:217222.CrossRefGoogle ScholarPubMed
13. Moghaddam, B, Adams, BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science. 1998;81:13491352.CrossRefGoogle Scholar
14. Coplan, JD, Andrews, MW, Rosenblum, LA, et al. Increased cerebrospinal fluid CRF concentrations in adult non-human primates previously exposed to adverse experiences as infants. Proc Natl Acad Sci U S A. 1996;93:16191623.CrossRefGoogle Scholar
15. Helton, DR, Tizzano, JP, Monn, JA, et al. LY354740: a metabotropic glutamate receptor agonist which ameliorates symptoms of nicotine withdrawal in rats. Neuropharmacology. 1997;36:15111516.CrossRefGoogle ScholarPubMed
16. Anis, NA, Berry, SC, Burton, NR, et al. The dissociative anesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurons by N-methyl-aspartate. Br J Pharmacol. 1983;79:565575.CrossRefGoogle ScholarPubMed
17. Charney, DS, Deutch, AY, Krystal, JH, et al. Psychobiologic mechanisms of posttraumatic stress disorder. Arch Gen Psychiatry. 1993;50:294305.CrossRefGoogle ScholarPubMed
18. Krystal, JH, McDougle, CJ, Woods, SW, et al. Dose-response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine. Psychopharmacology (Berl). 1992;108:313319.CrossRefGoogle ScholarPubMed
19. Price, LH, Charney, DS, Rubin, AL, et al. Alpha-2 adrenergic receptor function in depression: the cortisol response to yohimbine. Arch Gen Psychiatry. 1986;43:849858.CrossRefGoogle ScholarPubMed
20. van den Pol, A, Hermans-Borgmeyer, I, Hofer, M, et al. Ionotropic glutamate-receptor gene expression in hypothalamus: localization of AMPA, kainate, and NMDA receptor RNA with in situ hybridization. J Comp Neurol. 1994;15;343:428444.CrossRefGoogle Scholar
21. Kocsis, K, Kiss, J, Gores, T, et al. Metabotropic glutamate receptor in vaspressin, CRF and VIP hypothalamic neurones. Neuroreport. 1998;21;9:40294033.CrossRefGoogle Scholar
22. Coplan, JD, Pine, D, Papp, L, et al. Uncoupling of the noradrenergic-hythalamic-pituitary-adrenal axis in panic disorder patients. Neuropsychopharmacology. 1995;13:6573.CrossRefGoogle ScholarPubMed