Metabotropic glutamate receptor 4 novel agonist LSP1-2111 with anxiolytic, but not antidepressant-like activity, mediated by serotonergic and GABAergic systems.
Our earlier studies have demonstrated that the non-selective group III mGlu receptor agonist, ACPT-I, produced anxiolytic rather than antidepressant-like actions after its peripheral administration. Here, we describe the effects of LSP1-2111 ((2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitro-phenyl)methyl]phosphoryl]butanoic acid), a novel orthosteric, preferential agonist of the mGlu4 receptor, a member of the group III mGlu receptors family, in the stress-induced hyperthermia (SIH) and elevated plus-maze (EPM) tests in mice. In both tests an anxiolytic-like effect was clearly seen in doses of 2 and 5 mg/kg, i.p. The compound did not produce antidepressant-like effects in the tail suspension test (TST) or in the forced swim test (FST) in mice. The potential anxiolytic effect of LSP1-2111 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (given i.p., 10 mg/kg), and by a 5-HT(1A) receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY100635) (0.1 mg/kg, s.c.). At the same time, ritanserin (0.5 mg/kg i.p.), the 5-HT(2A/C) receptor antagonist, did not change the anxiolytic-like effects of LSP1-2111. Moreover, the compound was not effective in 5-HT depleted animals. The results of these studies indicate that the GABAergic and serotonergic systems are involved in the potential anxiolytic action of LSP1-2111.
Wierońska
Joanna M
JM
Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland. wierons@if-pan.krakow.pl
Stachowicz
Katarzyna
K
Pałucha-Poniewiera
Agnieszka
A
Acher
Francine
F
Brański
Piotr
P
Pilc
Andrzej
A
D000613:Aminobutyrates / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D005334:Fever / Q000188:drug therapy / Q000209:etiology; D005442:Flumazenil / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D010721:Phosphinic Acids / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D016713:Ritanserin / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology; D013315:Stress, Psychological / Q000150:complications; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000613:Aminobutyrates; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D058787:GABA-A Receptor Antagonists; C555637:LSP1 2111; D010721:Phosphinic Acids; D010879:Piperazines; D011725:Pyridines; D044402:Receptor, Serotonin, 5-HT2A; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D058829:Serotonin 5-HT1 Receptor Antagonists; D058826:Serotonin 5-HT2 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D016713:Ritanserin; D012701:Serotonin; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D003975:Diazepam; C108823:metabotropic glutamate receptor 4