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NEUROPHARMACOLOGY

The Human Immunodeficiency Virus-1 Protein Transactivator of Transcription Up-Regulates N-Methyl-D-aspartate Receptor Function by Acting at Metabotropic Glutamate Receptor 1 Receptors Coexisting on Human and Rat Brain Noradrenergic Neurones

Pharmacology and Toxicology Section, Department of Experimental Medicine, University of Genova, Genova, Italy (F.L., M.F., M.R., A.P.); Division of Neurosurgery, Galliera Hospital, Genova, Italy (G.C., P.F.S.); and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy (M.R., A.P.)

We investigated the effects of the human immunodeficiency virus-1 transactivator of transcription (Tat) on the release of norepinephrine (NE) from human and rat brain synaptosomes. Tat could not evoke directly release of [³H]NE. In the presence of Tat (1 nM), N-methyl-D-aspartate (NMDA) concentrations unable to release (human synaptosomes) or slightly releasing (rat synaptosomes) [³H]NE became very effective. The NMDA/Tat-evoked release depends on NMDA receptors (NMDARs) since it was abolished by MK-801 (dizocilpine). Tat binding at NMDARs was excluded. The NMDA-induced release of [³H]NE in the presence of glycine was further potentiated by Tat. The release evoked by NMDA/glycine/Tat depends on metabotropic glutamate receptor 1 (mGluR1) activation, since it was halved by mGluR1 antagonists. Tat seems to act at the glutamate recognition site of mGluR1. Recently, Tat was shown to release [³H]acetylcholine from human cholinergic terminals; here, we demonstrate that this effect is also mediated by presynaptic mGluR1. The peptide sequence Tat_41–60, but not Tat_61–80, mimicked Tat. Phospholipase C, protein kinase C, and cytosolic tyrosine kinase are involved in the NMDA/glycine/Tat-evoked [³H]NE release. To conclude, Tat can represent a potent pathological agonist at mGlu1 receptors able to release acetylcholine from human cholinergic terminals and up-regulate NMDARs mediating NE release from human and rat noradrenergic terminals.

Address correspondence to: Dr. Anna Pittaluga, Dipartimento di Medicina Sperimentale, Sezione Farmacologia e Tossicologia, Viale Cembrano 4, 16148 Genova, Italy. E-mail: pittalug{at}pharmatox.unige.it

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