ly-379268 and 3-4-dihydroxyphenylglycol

mGlu5 receptors are involved in mechanisms of activity-dependent synaptic plasticity, and are targeted by drugs developed for the treatment of CNS disorders. We report that mGlu3 receptors, which are traditionally linked to the control of neurotransmitter release, support mGlu5 receptor signaling in neurons and largely contribute to the robust mGlu5 receptor-mediated polyphosphoinositide hydrolysis in the early postnatal life. In cortical pyramidal neurons, mGlu3 receptor activation potentiated mGlu5 receptor-mediated somatic Ca

Topics: Amino Acids; Animals; Animals, Newborn; Astrocytes; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Central Nervous System; Embryo, Mammalian; Excitatory Amino Acid Agents; Female; Gene Expression Regulation, Developmental; Humans; Hydrolysis; Long-Term Potentiation; Male; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; N-Methylaspartate; Neurons; Phosphatidylinositol Phosphates; Rats; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate

Spontaneously depressed flinders sensitive line (FSL) rats showed a reduced expression of mGlu2/3 metabotropic glutamate receptors in the hippocampus, as compared to "non-depressed" flinders resistant line (FRL) rats. No changes in mGlu2/3 receptor protein levels were found in other brain regions, including the amygdala, hypothalamus, and cerebral cortex. Biochemical analysis of receptor signalling supported the reduction of mGlu2/3 receptors in the hippocampus of FSL rats. Accordingly, the selective mGlu2/3 receptor agonist, LY379268 (1microM) reduced forskolin-stimulated cAMP formation by 56% and 32% in hippocampal slices from FRL and FSL rats, respectively. In addition, LY379268 enhanced 3,5-dihydroxyphenylglycine-stimulated inositol phospholipid hydrolysis from 65% to 215% in hippocampal slices from FRL rats, whereas it was inactive in slices from FRL rats. We also examined the behavioural response of FSL rats to systemic injection of LY379268 (0.5mg/kg, i.p., once a day for 1-21 days) by measuring the immobility time in the forced swim test, which is known to be increased in these rats. LY379268 was administered alone or combined with the classical antidepressant, chlorimipramine (10mg/kg, i.p.). LY379268 alone had no effect at any of the selected time-points, whereas chlorimipramine alone reduced the immobility time only after 21 days of treatment. In contrast, when combined with LY379268, chlorimipramine reduced the immobility time during the first 14 days of treatment. These data support the view that mGlu2/3 receptors might be involved in the pathophysiology of depressive disorders, and that pharmacological activation of these receptors may shorten the latency of antidepressant medication.

Topics: Amino Acids; Animals; Antidepressive Agents, Tricyclic; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; Clomipramine; Colforsin; Cyclic AMP; Depression; Disease Models, Animal; Drug Interactions; Gene Expression Regulation; Hippocampus; In Vitro Techniques; Methoxyhydroxyphenylglycol; Rats; Receptors, Metabotropic Glutamate; RNA, Messenger; Swimming