Metabotropic Glutamate Receptors Play a Key Role in Modulating Head Twitches Induced by a Serotonergic Hallucinogen in Mice.

There is substantial evidence that glutamate can modulate the effects of 5-hydroxytryptamine (5-HT) receptor activation through stimulation of metabotropic glutamate (mGlu) receptors in the prefrontal cortex. Here we show that constitutive deletion of the mGlu gene profoundly attenuates an effect of 5-HT receptor activation using the mouse head twitch response (HTR). MGlu and mGlu receptor knockout (KO) as well as age-matched ICR (CD-1) wild type (WT) mice were administered (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and observed for head twitch activity.

mGlu5 receptor deletion reduces relapse to food-seeking and prevents the anti-relapse effects of mGlu5 receptor blockade in mice.

Aims: Convergent data suggest that there is a hyperglutamatergic state that arises during relapse to drug seeking. Blockade of mGlu5 receptors provides one approach to dampening glutamate tone. However, the role of mGlu5 receptors in relapse to food seeking behavior has not been explored extensively and has not been scrutinized using receptor null mice.

mGlu5 receptor deletion does not confer seizure protection to mice.

Metabotropic glutamate mGlu5 receptors have been implicated in the regulation of seizures and have been suggested as a target against which discovery of novel anticonvulsants may be possible. However, the experimental literature is not consistent in reporting anticonvulsant efficacy of mGlu5 receptor antagonists. Additional assessment of this target was approached in the present study by comparing convulsions in wild-type (WT) and mGlu5 receptor null (knockout or KO) mice.

Constitutive deletion of the serotonin-7 (5-HT(7)) receptor decreases electrical and chemical seizure thresholds.

The localization of serotonin-7 (5-HT(7)) receptors and the biological activity of ligands have suggested that 5-HT(7) receptors might be involved in pain, migraine, epilepsy, anxiety, depression, memory, and sleep. In the present study, the potential involvement of 5-HT(7) receptors in epilepsy and other seizure disorders was assessed by comparing the seizures produced by three types of electrical stimulation and three chemical convulsants in 5-HT(7) receptor-deficient (knockout, KO) mice to those seizures observed in wild-type (WT) mice. Thresholds for producing electroshock-induced clonic seizures did not differ between KO versus WT mice.

Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice.

Antidepressant-like effects of metabotropic glutamate (mGlu)5 receptor antagonists have been reported previously. We now provide definitive identification of mGlu5 receptors as a target for these effects through the combined use of selective antagonists and mice with targeted deletion of the mGlu5 protein. In these experiments, the mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the more selective and metabolically stable analog 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) decreased immobility in the mouse forced swim test, a test predictive of antidepressant efficacy in humans.

Neurotensin negatively modulates Akt activity in neurotensin receptor-1-transfected AV12 cells.

Neurotensin (NT) regulates a variety of biological processes primarily through interaction with neurotensin receptor-1 (NTR1), a heterotrimeric G-protein-coupled receptor (GPCR). Stimulation of NTR1 has been linked to activation of multiple signaling transduction pathways via specific coupling to G(q), G(i/o), or G(s), in various cell systems. However, the function of NT/NTR1 in the regulation of the Akt pathway remains unknown.

Systemic administration of the potent mGlu8 receptor agonist (S)-3,4-DCPG induces c-Fos in stress-related brain regions in wild-type, but not mGlu8 receptor knockout mice.

The effect of a novel and potent metabotropic glutamate 8 (mGlu8) receptor agonist, (S)-3,4-dicarboxyphenylglycine (DCPG), was studied in vivo in mouse brain. c-Fos expression was used as a marker of neuronal activity in specific brain regions 2 h after systemic (S)-3,4-DCPG (3-100 mg/kg, i.p.

Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2- trifluoroethylsulfonyl)pyrid-3-ylmethylamine.

This report describes recently discovered novel allosteric modulators of metabotropic glutamate2 (mGlu2) receptors. These pyridylmethylsulfonamides (e.g.

Modulation of lateral perforant path excitatory responses by metabotropic glutamate 8 (mGlu8) receptors.

The contribution of metabotropic glutamate 8 (mGlu8) receptors to modulation of medial and lateral perforant path (MPP and LPP) inputs to the dentate gyrus was investigated using electrophysiological recording of field excitatory postsynaptic potentials (fEPSPs) from hippocampal slices taken from wild-type and mGlu8 receptor knockout animals. Application of the selective group III mGlu receptor agonist, L-AP4 (1-100 microM), reduced fEPSPs evoked by LPP, but not MPP stimulation in wild-type slices in a concentration-dependent manner (EC(50) = 4.7 microM).