Chronic treatment with a metabotropic mGlu2/3 receptor agonist diminishes behavioral response to a phenethylamine hallucinogen
- 164 Downloads
There is evidence that mGlu2/3 receptors regulate 5-HT2A signaling, interactions that have been theorized to play a role in the antipsychotic-like effects of mGlu2/3 agonists as well as the hallucinogenic effects of 5-HT2A agonists. One approach to unraveling this interaction is through the chronic administration of agonists at the two receptors, which should influence the functional properties of the targeted receptor due to receptor downregulation or desensitization and thereby alter crosstalk between the two receptors. In this study, we investigated whether chronic treatment with the mGlu2/3 agonist LY379268 would alter the behavioral response to a phenethylamine hallucinogen, 25CN-NBOH, which acts as a selective 5-HT2A agonist.
We first conducted a dose response of 25CN-NBOH (0.1, 0.3, 1, 3, or 10 mg/kg) to confirm the effects on head-twitch response (HTR) and then blockade studies with either the M100907 (0.1 mg/kg) or SB242084 (0.1, 0.3, or 1 mg/kg) to determine the contribution of 5-HT2A and 5-HT2C to 25CN-NBOH-induced HTR, respectively. To determine whether an mGlu2/3 agonist could block 25CN-NBOH-induced HTR, mice were pretreated with vehicle or LY379268 (0.1, 1, or 10 mg/kg) prior to 25CN-NBOH, and HTR was assessed. The effects of chronic LY379268 on 5-HT2A agonist-induced HTR were evaluated by treating mice with either vehicle or LY379268 (10 mg/kg) for 21 days and measuring 25CN-NBOH-induced HTR 48 h after the final LY379268 treatment. The following day (72 h after the final LY379268 treatment), the ability of acute LY379268 to block PCP-induced locomotor activity was assessed.
25CN-NBOH dose-dependently increased the HTR, a 5-HT2A-mediated behavior, in mice. The selective 5-HT2A antagonist M100907 completely blocked the HTR induced by 25CN-NBOH, whereas the selective 5-HT2C antagonist SB242084 had no effect on the HTR. Administration of LY379268 (10 mg/kg SC) attenuated the HTR induced by 1 mg/kg 25CN-NBOH by ~ 50%. Chronic treatment (21 days) with LY379268 also attenuated the HTR response to 25CN-NBOH when tested 48 h after the last dose of LY379268. In locomotor tests, acute LY379268 significantly attenuated PCP-induced locomotor activity in the chronic vehicle treatment group; by contrast, there was only a trend for an overall interaction in the chronic LY379268 group, with LY379268 blocking the locomotor-stimulating effects of PCP only during the last 20 min.
These data are consistent with a functional interaction between mGlu2/3 and 5-HT2A receptors, although the specific mechanism for the interaction is not known. These data support the hypothesis that mGlu2/3 receptors play a prominent role in modulating the behavioral response to 5-HT2A receptor activation.
KeywordsSerotonin 5-HT2A Metabotropic glutamate receptor mGlu2/3 Hallucinogen Head twitch
We would like to thank Landon Klein and Mahalah Buell for the technical assistance. LY379268 was generously supplied by the NIMH Chemical Synthesis and Drug Supply Program (CSDSP). These studies were supported by R01 DA002925, R01 DA041336, K01 MH100644, and Veteran’s Affairs VISN 22 MIRECC.
These studies were supported by R01 DA002925, R01 DA041336, K01 MH100644, and Veteran’s Affairs VISN 22 MIRECC.
Compliance with ethical standards
Conflict of interest
Mark Geyer holds an equity interest in San Diego Instruments.
- Bond A, Jones NM, Hicks CA, Whiffin GM, Ward MA, O’Neill MF, Kingston AE, Monn JA, Ornstein PL, Schoepp DD, Lodge D, O’Neill MJ (2000) Neuroprotective effects of LY379268, a selective mGlu2/3 receptor agonist: investigations into possible mechanism of action in vivo. J Pharmacol Exp Ther 294:800–809Google Scholar
- Cartmell J, Monn JA, Schoepp DD (1999) The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. J Pharmacol Exp Ther 291:161–170Google Scholar
- Cartmell J, Perry KW, Salhoff CR, Monn JA, Schoepp DD (2001) Acute increases in monoamine release in the rat prefrontal cortex by the mGlu2/3 agonist LY379268 are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade. Neuropharmacology 40:847–855CrossRefGoogle Scholar
- Christopoulos A, Grant MK, Ayoubzadeh N, Kim ON, Sauerberg P, Jeppesen L, El-Fakahany EE (2001) Synthesis and pharmacological evaluation of dimeric muscarinic acetylcholine receptor agonists. J Pharmacol Exp Ther 298:1260–1268Google Scholar
- Fantegrossi WE, Gray BW, Bailey JM, Smith DA, Hansen M, Kristensen JL (2015) Hallucinogen-like effects of 2-([2-(4-cyano-2,5-dimethoxyphenyl) ethylamino]methyl)phenol (25CN-NBOH), a novel N-benzylphenethylamine with 100-fold selectivity for 5-HT(2)A receptors, in mice. Psychopharmacology 232:1039–1047CrossRefGoogle Scholar
- Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R, Park G, Adney SK, Hatcher C, Eltit JM, Ruta JD, Albizu L, Li Z, Umali A, Shim J, Fabiato A, MacKerell AD Jr, Brezina V, Sealfon SC, Filizola M, Gonzalez-Maeso J, Logothetis DE (2011) Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell 147:1011–1023CrossRefGoogle Scholar
- Galici R, Echemendia NG, Rodriguez AL, Conn PJ (2005) A selective allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors has effects similar to an orthosteric mGlu2/3 receptor agonist in mouse models predictive of antipsychotic activity. J Pharmacol Exp Ther 315:1181–1187CrossRefGoogle Scholar
- Halberstadt AL, van der Heijden I, Ruderman MA, Risbrough VB, Gingrich JA, Geyer MA, Powell SB (2009) 5-HT(2A) and 5-HT(2C) receptors exert opposing effects on locomotor activity in mice. NeuropsychopharmacologyGoogle Scholar
- Iacovelli L, Molinaro G, Battaglia G, Motolese M, Di Menna L, Alfiero M, Blahos J, Matrisciano F, Corsi M, Corti C, Bruno V, De Blasi A, Nicoletti F (2009) Regulation of group II metabotropic glutamate receptors by G protein-coupled receptor kinases: mGlu2 receptors are resistant to homologous desensitization. Mol Pharmacol 75:991–1003CrossRefGoogle Scholar
- Jensen AA, McCorvy JD, Leth-Petersen S, Bundgaard C, Liebscher G, Kenakin TP, Brauner-Osborne H, Kehler J, Kristensen JL (2017) Detailed characterization of the in vitro pharmacological and pharmacokinetic properties of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH), a highly selective and brain-penetrant 5-HT2A receptor agonist. J Pharmacol Exp Ther 361:441–453CrossRefGoogle Scholar
- Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S, Jackson K, Kryzhanovskaya L, Jarkova N (2011) A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol 31:349–355CrossRefGoogle Scholar
- Klein LM, Cozzi NV, Daley PF, Brandt SD, Halberstadt AL (2018) Receptor binding profiles and behavioral pharmacology of ring-substituted N,N-diallyltryptamine analogs. NeuropharmacologyGoogle Scholar
- Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, Varney MA (2003) Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 117:697–706CrossRefGoogle Scholar
- Marek GJ, Wright RA, Schoepp DD, Monn JA, Aghajanian GK (2000) Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J Pharmacol Exp Ther 292:76–87Google Scholar
- Molinaro G, Traficante A, Riozzi B, Di Menna L, Curto M, Pallottino S, Nicoletti F, Bruno V, Battaglia G (2009) Activation of mGlu2/3 metabotropic glutamate receptors negatively regulates the stimulation of inositol phospholipid hydrolysis mediated by 5-hydroxytryptamine2A serotonin receptors in the frontal cortex of living mice. Mol Pharmacol 76:379–387CrossRefGoogle Scholar
- Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuellar F, Mocci G, Seto J, Callado LF, Neve RL, Milligan G, Sealfon SC, Lopez-Gimenez JF, Meana JJ, Benson DL, Gonzalez-Maeso J (2012) Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A.mGlu2) receptor heteromerization and its psychoactive behavioral function. J Biol Chem 287:44301–44319CrossRefGoogle Scholar
- Nichols DE, Sassano MF, Halberstadt AL, Klein LM, Brandt SD, Elliott SP, Fiedler WJ (2015) N-Benzyl-5-methoxytryptamines as potent serotonin 5-HT receptor family agonists and comparison with a series of phenethylamine analogues. In: ACS Chem NeurosciGoogle Scholar
- Nisenbaum LK, Downing AM, Zhao F, Millen BA, Munsie L, Kinon BJ, Adams DH, Gomez JC, Penny MA (2016) Serotonin 2A receptor SNP rs7330461 association with treatment response to pomaglumetad methionil in patients with schizophrenia. J Pers Med 6Google Scholar
- Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med 13:1102–1107CrossRefGoogle Scholar
- Schoepp DD (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 299:12–20Google Scholar