Metabotropic glutamate 2/3 (mGlu2/3) receptors have emerged as potential therapeutic targets due to the ability of mGlu2/3 receptor agonists to modulate excitatory transmission at specific synapses. LY354740 and LY379268 are selective and potent mGlu2/3 receptor agonists that show both anxiolytic- and antipsychotic-like effects in animal models. We compared the efficacy of LY354740 and LY379268 in attenuating restraint-stress-induced expression of the immediate early gene c-Fos in the rat prelimbic (PrL) and infralimbic (IL) cortex. LY354740 (10 and 30？mg/kg, i.p.) showed statistically significant and dose-related attenuation of stress-induced increase in c-Fos expression, in the rat cortex. By contrast, LY379268 had no effect on restraint-stress-induced c-Fos upregulation (0.3–10？mg/kg, i.p.). Because both compounds inhibit serotonin 2A receptor ( )-induced c-Fos expression, we hypothesize that LY354740 and LY379268 have different in vivo properties and that activation and restraint stress induce c-Fos through distinct mechanisms. 1. Introduction Preclinical and clinical studies indicate that modulation of glutamatergic activity in the brain may have therapeutic value for the treatment of schizophrenia and anxiety-related disorders [1, 2]. Glutamate acts through ligand-gated ion channels and G-protein-coupled metabotropic glutamate (mGlu) receptors. The mGlu receptors can be subdivided into three groups (Group I: mGlu1, 5; Group II: mGlu2, 3; Group III: mGlu4, 6, 7, 8) based on the sequence homology, signal transduction pathways, and pharmacology [3, 4]. Activation of presynaptic mGlu2 receptors with mGlu2/3 agonists negatively modulates the release of glutamate providing a feedback that prevents excessive glutamate release [5, 6]. Presynaptic mGlu2/3 receptors also regulate the release of other neurotransmitters [7], and postsynaptic mGlu2/3 receptors can regulate neuronal excitability via the modulation of ion channel functions [5]. The actions of multiple mGlu2/3 agonists and mGlu2 positive allosteric modulators (PAMs) have been explored in animal models predictive of antipsychotic and anxiolytic activity. Of these, the two orthosteric mGlu2/3 agonists, LY354740 and the structurally related compound LY379268, have been widely studied. LY354740 and LY379268 block PCP- and amphetamine-induced hyperlocomotion [8], two commonly used models of the positive symptoms of schizophrenia. Both compounds also show efficacy in alleviating cognitive deficits induced by PCP. For example, LY354740 improved the detrimental effects of PCP on the performance in a
References
[1]
G. J. Marek, “Metabotropic glutamate2/3 (mGlu2/3) receptors, schizophrenia and cognition,” European Journal of Pharmacology, vol. 639, no. 1–3, pp. 81–90, 2010.
[2]
C. J. Swanson, M. Bures, M. P. Johnson, A.-M. Linden, J. A. Monn, and D. D. Schoepp, “Metabotropic glutamate receptors as novel targets for anxiety and stress disorders,” Nature Reviews Drug Discovery, vol. 4, no. 2, pp. 131–144, 2005.
[3]
P. J. Conn and J.-P. Pin, “Pharmacology and functions of metabotropic glutamate receptors,” Annual Review of Pharmacology and Toxicology, vol. 37, pp. 205–237, 1997.
[4]
D. D. Schoepp, D. E. Jane, and J. A. Monn, “Pharmacological agents acting at subtypes of metabotropic glutamate receptors,” Neuropharmacology, vol. 38, no. 10, pp. 1431–1476, 1999.
[5]
R. Anwyl, “Metabotropic glutamate receptors: electrophysiological properties and role in plasticity,” Brain Research Reviews, vol. 29, no. 1, pp. 83–120, 1999.
[6]
M. Scanziani, P. A. Salin, K. E. Vogt, R. C. Malenka, and R. A. Nicoll, “Use-dependent increases in glutamate concentration activate presynaptic metabotropic glutamate receptors,” Nature, vol. 385, no. 6617, pp. 630–634, 1997.
[7]
J. Cartmell and D. D. Schoepp, “Regulation of neurotransmitter release by metabotropic glutamate receptors,” Journal of Neurochemistry, vol. 75, no. 3, pp. 889–907, 2000.
[8]
J. Cartmell, J. A. Monn, and D. D. Schoepp, “The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats,” Journal of Pharmacology and Experimental Therapeutics, vol. 291, no. 1, pp. 161–170, 1999.
[9]
B. Moghaddam and B. W. Adams, “Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats,” Science, vol. 281, no. 5381, pp. 1349–1352, 1998.
[10]
B. Greco, R. W. Invernizzi, and M. Carli, “Phencyclidine-induced impairment in attention and response control depends on the background genotype of mice: reversal by the mGLU2/3 receptor agonist LY379268,” Psychopharmacology, vol. 179, no. 1, pp. 68–76, 2005.
[11]
D. R. Helton, J. P. Tizzano, J. A. Monn, D. D. Schoepp, and M. J. Kallman, “Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors,” Journal of Pharmacology and Experimental Therapeutics, vol. 284, no. 2, pp. 651–660, 1998.
[12]
J. A. Monn, M. J. Valli, S. M. Massey et al., “Design, synthesis, and pharmacological characterization of (+)-2- aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties,” Journal of Medicinal Chemistry, vol. 40, no. 4, pp. 528–537, 1997.
[13]
E. Dunayevich, J. Erickson, L. Levine, R. Landbloom, D. D. Schoepp, and G. D. Tollefson, “Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder,” Neuropsychopharmacology, vol. 33, no. 7, pp. 1603–1610, 2008.
[14]
A. Satow, S. Maehara, S. Ise et al., “Pharmacological effects of the metabotropic glutamate receptor 1 antagonist compared with those of the metabotropic glutamate receptor 5 antagonist and metabotropic glutamate receptor 2/3 agonist in rodents: detailed investigations with a selective allosteric metabotropic glutamate receptor 1 antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methy l-3,6-dihydropyridine-1(2H)-carboxamide],” Journal of Pharmacology and Experimental Therapeutics, vol. 326, no. 2, pp. 577–586, 2008.
[15]
M. P. Johnson and M. Chamberlain, “Modulation of stress-induced and stimulated hyperprolactinemia with the group II metabotropic glutamate receptor selective agonist, LY379268,” Neuropharmacology, vol. 43, no. 5, pp. 799–808, 2002.
[16]
G. Imre, A. Salomons, M. Jongsma, D. S. Fokkema, J. A. den Boer, and G. J. Ter Horst, “Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat,” Pharmacology Biochemistry and Behavior, vol. 84, no. 3, pp. 392–399, 2006.
[17]
V. Grivas, A. Markou, and N. Pitsikas, “The metabotropic glutamate 2/3 agonist LY379268 induces anxiety-like behavior at the highest dose tested in two rat models of anxiety,” European Journal of Pharmacology, vol. 715, pp. 105–110, 2013.
[18]
W. E. Cullinan, J. P. Herman, D. F. Battaglia, H. Akil, and S. J. Watson, “Pattern and time course of immediate early gene expression in rat brain following acute stress,” Neuroscience, vol. 64, no. 2, pp. 477–505, 1995.
[19]
M. Girotti, T. W. W. Pace, R. I. Gaylord, B. A. Rubin, J. P. Herman, and R. L. Spencer, “Habituation to repeated restraint stress is associated with lack of stress-induced c-fos expression in primary sensory processing areas of the rat brain,” Neuroscience, vol. 138, no. 4, pp. 1067–1081, 2006.
[20]
T. Imaki, T. Shibasaki, M. Hotta, and H. Demura, “Intracerebroventricular administration of corticotropin-releasing factor induces c-fos mRNA expression in brain regions related to stress responses: comparison with pattern of c-fos mRNA induction after stress,” Brain Research, vol. 616, no. 1-2, pp. 114–125, 1993.
[21]
M. S. Weinberg, M. Girotti, and R. L. Spencer, “Restraint-induced fra-2 and c-fos expression in the rat forebrain: relationship to stress duration,” Neuroscience, vol. 150, no. 2, pp. 478–486, 2007.
[22]
C. H. M. Beck and H. C. Fibiger, “Conditioned fear-induced changes in behavior and in the expression of the immediate early gene c-fos: with and without diazepam pretreatment,” The Journal of Neuroscience, vol. 15, no. 1, pp. 709–720, 1995.
[23]
J. González-Maeso, R. L. Ang, T. Yuen et al., “Identification of a serotonin/glutamate receptor complex implicated in psychosis,” Nature, vol. 452, no. 7183, pp. 93–97, 2008.
[24]
J. C. Gewirtz and G. J. Marek, “Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors,” Neuropsychopharmacology, vol. 23, no. 5, pp. 569–576, 2000.
[25]
R. A. Leslie, J. M. Moorman, and D. G. Grahame-Smith, “Lithium enhances 5-HT2A receptor-mediated c-fos expression in rat cerebral cortex,” NeuroReport, vol. 5, no. 3, pp. 241–244, 1993.
[26]
L. Wischhof and M. Koch, “Pre-treatment with the mGlu2/3 receptor agonist LY379268 attenuates DOI-induced impulsive responding and regional c-Fos protein expression,” Psychopharmacology, vol. 219, no. 2, pp. 387–400, 2012.
[27]
G. Paxinos and C. Watson, The Rat Brain in Stereotaxic Coordinates, 4th edition, 1998.
[28]
J.-C. Bé？que, M. Imad, L. Mladenovic, J. A. Gingrich, and R. Andrade, “Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 23, pp. 9870–9875, 2007.
[29]
B. Moghaddam, “Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia,” Journal of Neurochemistry, vol. 60, no. 5, pp. 1650–1657, 1993.
[30]
M. A. de Medeiros, L. Carlos Reis, and L. Eugenio Mello, “Stress-induced c-Fos expression is differentially modulated by dexamethasone, diazepam and imipramine,” Neuropsychopharmacology, vol. 30, no. 7, pp. 1246–1256, 2005.
[31]
T. Izumi, T. Inoue, Y. Kitaichi, S. Nakagawa, and T. Koyama, “Target brain sites of the anxiolytic effect of citalopram, a selective serotonin reuptake inhibitor,” European Journal of Pharmacology, vol. 534, no. 1–3, pp. 129–132, 2006.
[32]
L. Kargieman, N. Santana, G. Mengod, P. Celada, and F. Artigas, “Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 37, pp. 14843–14848, 2007.
[33]
S. C. Heinrichs, F. Menzaghi, E. M. Pich et al., “Anti-stress action of a corticotropin-releasing factor antagonist on behavioral reactivity to stressors of varying type and intensity,” Neuropsychopharmacology, vol. 11, no. 3, pp. 179–186, 1994.
[34]
J. D. Mikkelsen and M. H. Larsen, “Effects of stress and adrenalectomy on activity-regulated cytoskeleton protein (Arc) gene expression,” Neuroscience Letters, vol. 403, no. 3, pp. 239–243, 2006.
[35]
L. Trne？ková, A. Armario, S. Hynie, P. ？ída, and V. Klenerová, “Differences in the brain expression of c-fos mRNA after restraint stress in Lewis compared to Sprague-Dawley rats,” Brain Research, vol. 1077, no. 1, pp. 7–15, 2006.
[36]
W. P. J. M. Spooren, P. Schoeffter, F. Gasparini, R. Kuhn, and C. Gentsch, “Pharmacological and endocrinological characterisation of stress-induced hyperthermia in singly housed mice using classical and candidate anxiolytics (LY314582, MPEP and NKP608),” European Journal of Pharmacology, vol. 435, no. 2-3, pp. 161–170, 2002.
[37]
B. A. Morrow, J. D. Elsworth, E. J. Lee, and R. H. Roth, “Divergent effects of putative anxiolytics on stress-induced fos expression in the mesoprefrontal system of the rat,” Synapse, vol. 36, no. 2, pp. 143–154, 2000.
[38]
A.-M. Linden, S. J. Greene, M. Bergeron, and D. D. Schoepp, “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,” Neuropsychopharmacology, vol. 29, no. 3, pp. 502–513, 2004.
[39]
J. A. Monn, M. J. Valli, S. M. Massey et al., “Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0]hexane-2,6- dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors,” Journal of Medicinal Chemistry, vol. 42, no. 6, pp. 1027–1040, 1999.
[40]
A. G. M. Lam, J. A. Monn, D. D. Schoepp, D. Lodge, and J. McCulloch, “Group II selective metabotropic glutamate receptor agonists and local cerebral glucose use in the rat,” Journal of Cerebral Blood Flow and Metabolism, vol. 19, no. 10, pp. 1083–1091, 1999.
[41]
J. A. Meyer, J. Peters, J. Horn et al., “The selective mGlu2/3 receptor agonist LY379268 produces divergent basal and ketamine-evoked local cerebral glucose utilization in rats,” in Proceedings of the Annual Meeting Society for Neuroscience, Washington, DC, USA, November 2011.
[42]
M. Fribourg, J. L. Moreno, T. Holloway et al., “Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs,” Cell, vol. 147, no. 5, pp. 1011–1023, 2011.
[43]
M. A. Benneyworth, Z. Xiang, R. L. Smith, E. E. Garcia, P. J. Conn, and E. Sanders-Bush, “A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis,” Molecular Pharmacology, vol. 72, no. 2, pp. 477–484, 2007.
[44]
K. F. Croom, C. M. Perry, and G. L. Plosker, “Mirtazapine: a review of its use in major depression and other psychiatric disorders,” CNS Drugs, vol. 23, no. 5, pp. 427–452, 2009.
[45]
N. V. Weisstaub, M. Zhou, A. Lira et al., “Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice,” Science, vol. 313, no. 5786, pp. 536–540, 2006.
[46]
A. Klodzinska, M. Bijak, K. Tokarski, and A. Pilc, “Group II mGlu receptor agonists inhibit behavioural and electrophysiological effects of DOI in mice,” Pharmacology Biochemistry and Behavior, vol. 73, no. 2, pp. 327–332, 2002.
[47]
B. H. Harvey and M. Shahid, “Metabotropic and ionotropic glutamate receptors as neurobiological targets in anxiety and stress-related disorders: focus on pharmacology and preclinical translational models,” Pharmacology Biochemistry and Behavior, vol. 100, no. 4, pp. 775–800, 2012.
[48]
J. H. Krystal, D. C. D'Souza, I. L. Petrakis et al., “NMDA agonists and as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders,” Harvard Review of Psychiatry, vol. 7, no. 3, pp. 125–143, 1999.
