Molecular pharmacology
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Molecular pharmacology · Aug 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.
The interaction between 5-hydroxytryptamine(2A) (5-HT(2A)) serotonin receptors and metabotropic glutamate (mGlu) 2/3 receptors underlies the antipsychotic activity of mGlu2/3 receptor agonists in experimental animals and humans. The molecular nature of this interaction is only partially known. We here report for the first time that pharmacological activation of mGlu2/3 receptors attenuates the stimulation of polyphosphoinositide (PI) hydrolysis mediated by 5-HT(2A) receptors in the frontal cortex of living mice. ⋯ Surprisingly, contrasting results were obtained in cortical slice preparations, where LY379268 amplified both DOI- and 3,5-dihydroxyphenylglycine-stimulated PI hydrolysis. Amplification was abrogated by the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine, suggesting that experiments in brain slices are biased by an additional component of receptor-stimulated PI hydrolysis. This highlights the importance of in vivo models for the study of the interaction between 5-HT(2A) and mGlu2/3 receptors.
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Molecular pharmacology · Aug 2009
Augmentation of fear extinction by infusion of glycine transporter blockers into the amygdala.
It is known that fear extinction is blocked by the N-methyl D-aspartate (NMDA) receptor antagonist. In this study, we investigate whether extinction could be facilitated by the enhancement of NMDA response, achieved by the blocking of glycine transporters. In amygdala slices, NMDA at a concentration that normally does not have a long-term effect was found to reduce the cellular levels of postsynaptic density protein 95 and synapse-associated protein 97, in addition to the surface expression of GluR1/2, in the presence of a glycine transporter blocker, N[3-(4-fluorophenil)-3-(4'-phenilphenoxy)] propylsarcosine (NFPS). ⋯ In parallel, NFPS treatment in conjunction with extinction reversed the conditioning-induced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/NMDA ratio. In behavioral tests, Tat-GluR2(3Y), a synthetic peptide that has been shown to block AMPA receptor endocytosis, inhibited only the additional reduction caused by NFPS treatment, rather than returning the fear potentiation levels to those of fear-conditioned animals that did not undergo extinction. These results suggest that NFPS in combination with extinction training reverses GluR1/2 surface expression and thus augments the extinction of conditioned fear.