Selective activation of metabotropic G-protein-coupled glutamate 7 receptor elicits anxiolytic-like effects in mice by modulating GABAergic neurotransmission.

We describe the anxiolytic-like effects of the first, selective metabotropic G-protein-coupled glutamate 7 (mGlu7) receptor agonist, N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), as measured in the modified stress-induced hyperthermia (SIH) and the four-plate tests. Administration of AMN082 (3-6 mg/kg intraperitoneally) to Swiss mice produced anxiolytic-like effects in the modified SIH and four-plate tests. Moreover, it was ineffective as an anxiolytic in the SIH test in mGlu7 receptor knockout mice as compared with wild-type C57BL/6J littermate controls. In contrast, diazepam (1.25-5 mg/kg) significantly reduced SIH in both the wild-type and knockout animals. The anxiolytic-like effect of AMN082 in the SIH paradigm was abolished by pretreatment with flumazenil (10 mg/kg intraperitoneally). This indicates an involvement of gamma-aminobutyric acid-ergic neurotransmission in AMN's anxiolytic actions. The results indicate that activation of the mGlu7 receptor produces anxiolytic-like effects via the modulation of the gamma-aminobutyric acid system.

Chronic imipramine treatment reduces inhibitory properties of group II mGlu receptors without affecting their density or affinity.

An increasing body of evidence indicates an important role of the glutamatergic system in the pathophysiology of depression. Not only ionotropic but also metabotropic glutamate receptors (mGlu receptors) have been suggested to be involved in the mechanism of action of antidepressant drugs. Moreover, several mGlu receptor ligands possess a great antidepressant potential. Group II mGlu receptor antagonists have been shown to induce antidepressant-like effects in rodents. An influence of chronic antidepressant treatment on group II mGlu receptors has also been suggested. In our studies, we examined an influence of repeated (21-day) imipramine treatment on the density of group II mGlu receptors and affinity of mGlu2 and mGlu3 receptor radioligand [3H]-LY341495 for group II mGlu receptors in the rat brain hippocampus and frontal cortex. Moreover, we analyzed an influence of chronic imipramine administration on the ability of group II mGlu receptor agonist, 2R,4R-APDC, to inhibit forskolin-stimulated cAMP accumulation in the rat brain cortical slices. We found that inhibitory properties of group II mGlu receptors were diminished after chronic, but not acute imipramine administration. However, no changes in the density or affinity of the mGlu2 and mGlu3 receptor ligand for group II mGlu receptors were observed.

Citalopram influences mGlu7, but not mGlu4 receptors' expression in the rat brain hippocampus and cortex.

Earlier studies showed that chronic electroconvulsive shock (ECS) or imipramine treatment induced a sub-sensitivity of group I metabotropic glutamate receptors (mGluRs) in the hippocampus as well as an increase in the receptor protein level in this structure. In the present study, the effects of chronic imipramine (10 mg/kg, 21 days) or citalopram (10 mg/kg, 21 days) treatment on the mGlu4 or mGlu7 receptors' protein levels in the frontal cortex and hippocampus of the rat brain were examined using the Western blot analysis. We also examined the influence of these drugs' administration on forskolin-stimulated cAMP formation. A non-selective agonist of all receptors belonging to the III group of mGluRs, ACPT-1, was used to establish their effects on the cAMP production. It was found that mGluR7-immunoreactivity both in the hippocampus and in the cerebral cortex was decreased after citalopram, but not imipramine treatment. No changes were observed in the mGluR4-immunoreactivity. Prolonged treatment with these two drugs failed to change the action of group III mGluR agonist, ACPT-1, on the forskolin-stimulated cAMP accumulation. Our results suggest that the mGluR7 receptor is influenced by prolonged treatment of the antidepressant drug citalopram in the brain regions that are considered to be implicated in the clinical response to antidepressant therapy whilst the mGlu4 receptor is not.

Activation of the mGlu7 receptor elicits antidepressant-like effects in mice.

RATIONALE: Broad evidence indicates that modulation of the glutamatergic system could be an efficient way to achieve antidepressant activity. Metabotropic glutamate receptor (mGlu receptor) ligands seem to be promising agents to treat several central nervous system disorders, including psychiatric ones. OBJECTIVES: The aim of our study was to investigate potential antidepressant-like activity of the first, selective, and bio-available mGlu7 receptor agonist, AMN082 (N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride), in wild-type (WT) and mGlu7 receptor knock-out (KO) mice. MATERIALS AND METHODS: The forced swim test (FST) and the tail suspension test (TST) in mice were used to assess antidepressant-like activity of AMN082. RESULTS: We found that AMN082, administered IP, induced a dose-dependent decrease in the immobility time of WT animals in the FST and TST, suggesting antidepressant-like potency of an mGlu7 receptor agonist. Moreover, AMN082 did not change the behaviour of mGlu7 receptor KO mice compared to WT littermates in the TST, while imipramine, used as a reference control, significantly reduced their immobility, indicating an mGlu7 receptor-dependent mechanism of the antidepressant-like activity of AMN082. However, at high doses, AMN082 significantly decreased spontaneous locomotor activity of both mGlu7 receptor KO mice and WT control animals, suggesting off-target activity of AMN082 resulting in hypo-locomotion. CONCLUSIONS: These results strongly suggest that activation of the mGlu7 receptor elicits antidepressant-like effects.

Anxiolytic-like effects of group III mGlu receptor ligands in the hippocampus involve GABAA signaling.

Recent literature data and the results of our earlier pharmacological studies, have provided evidence that antagonists of group I metabotropic glutamate receptors (mGluRs) and agonists of group II mGluRs show anxiolytic-like properties in preclinical and clinical studies. Out of all glutamate receptors, the role of group III mGluRs in anxiety-like states is the least investigated because of the lack of specific pharmacological tools, moreover all group III receptor ligands synthesized so far are not systemically active, so they have to be administered centrally. In the present study, we investigated the anxiolytic-like activity of group III mGlu receptor ligands including a nonselective group III mGlu receptor agonist (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I), group III mGlu receptor antagonist, (RS)-alpha -cyclopropyl-4-phosphonophenylglycine (CPPG) and a positive allosteric modulator of mGluR4 (-)-N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC). The Vogel conflict drinking test in rats was used to test the anxiolytic-like effects. The hippocampus was chosen as a site of the injection of drugs, as this brain regions is involved in the regulation of anxiety-related behavior. Intrahippocampal injections (CA1 region of the hippocampus) of PHCCC (12 nmol) but not of CPPG (75 nmol ) produced an anxiolytic-like response, moreover, the effect of PHCCC was totally blocked by CPPG. The anxiolytic-like effects of ACPT-I (7.5 nmol) or PHCCC (12 nmol) were significantly attenuated by flumazenil (10 mg/kg), indicating an involvement of GABAergic system in the anxiolytic-like response.

Lack of the antianxiety-like effect of (S)-3,4-DCPG, an mGlu8 receptor agonist, after central administration in rats.

Substances acting as agonists of group III mGlu receptors were shown to induce an antianxiety-like effect after intrahippocampal administration to rats. The purpose of the present study was to establish whether the selective mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG) induced an anxiolytic-like effect after injection into the basolateral amygdala nuclei or the CA1 region of the hippocampus in the conflict drinking Vogel test in rats. The obtained results indicate that (S)-3,4-DCPG (10, 50 and 100 nmol/rat) produces no anticonflict effect in rats. We conclude that selective stimulation of mGlu8 receptors (a subtype of group III mGluRs) does not evoke anxiolytic-like activity, and that the mGlu8 receptors are of no significance for anxiolytic-like effects of group III mGluR agonists.

Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist.

The involvement of glutamate in the pathophysiology of depression has been suggested by a number of experiments. It was well established that compounds, which decreased glutamatergic transmission via blockade of NMDA receptor, produced antidepressant-like action in animal tests and models. The present study was carried out to investigate whether a selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) induces antidepressant-like effects after intraperitoneal injections in male Wistar rats or male C57BL/6J mice. Potential antidepressant-like activity of MTEP was evaluated using the forced swimming test (FST) in rats, the tail suspension test (TST) in mice and the olfactory bulbectomy (OB) model of depression in rats. The results of our studies showed, that MTEP (0.3-3 mg/kg) produced a significant dose-dependent decrease in the immobility time of mice in the TST, however, at doses of 1 or 10 mg/kg, it did not influence the behavior of rats in the FST in rats. Moreover, the repeated administration of MTEP (1 mg/kg) attenuated the OB-related hyperactivity of rats in the open field test, in the manner similar to that seen following chronic (but not acute) treatment with typical antidepressant drugs. These data suggest that MTEP, which is considered to be a potential therapeutic agent, may play a role in the therapy of depression.

Anxiolytic-like effects of PHCCC, an allosteric modulator of mGlu4 receptors, in rats.

We examined the potential anxiolytic-like activity of (-)-N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide (PHCCC), an allosteric modulator of metabotropic glutamate4 receptors (mGlu4), after administration into the basolateral amygdala, using the conflict drinking Vogel test in rats as a model. The results indicate that PHCCC, but not 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), the selective antagonist of group mGlu1 receptors, showed significant, dose-dependent anticonflict effects without affecting the threshold current or water intake. The results indicate that positive allosteric modulation of mGlu4 receptors may be a useful therapeutic approach to anxiety.

Long-term changes in postnatal susceptibility to pilocarpine-induced seizures in rats exposed to gamma radiation at different stages of prenatal development.

PURPOSE: To determine whether brains irradiated at different stages of prenatal development also have different postnatal susceptibility to seizures evoked by pilocarpine. METHODS: Pregnant Wistar rats were exposed to a single 1.0-Gy dose of gamma rays on gestation days 13, 15, 17, or 19 (E13, E15, E17, and E19, respectively). On postnatal day 60, their offspring received i.p. pilocarpine injections to evoke status epilepticus. Behavior of the animals was observed continuously for 6 h after the injection, and motor manifestations of seizure activity were rated, and survival times recorded. After 7-day survival, the animals were killed, and their brains were weighed. RESULTS: The average brain weight of animals exposed to irradiation at earlier prenatal stages (E13 or E15) was significantly lower than that after irradiation on E17 or E19. However, effects of the irradiation on the susceptibility to pilocarpine-induced seizures were quite opposite. The intensity of status epilepticus evoked in rats irradiated on E13 or E15 was significantly lower than that in nonirradiated controls or in those irradiated on E17 or E19. Moreover, after irradiation on E13 or E15, survival of the animals was significantly higher in relation not only to other irradiated groups but also to the controls. CONCLUSIONS: The results suggest than the extent of neuronal deficit, even if relatively greater, cannot always lead to higher susceptibility of the dysplastic brain to seizures. Functional consequences of the deficit, even if its magnitude is relatively smaller but involving specific brain areas, appear to be critical for the epileptogenesis.