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N-methyl-D-aspartate receptor antagonist activity and phencyclidine-like behavioral effects of the pentadecapeptide, [Ser1]histogranin



N-methyl-D-aspartate receptor antagonist activity and phencyclidine-like behavioral effects of the pentadecapeptide, [Ser1]histogranin



Pharmacology Biochemistry and Behavior 50(1): 49-54



The behavioral and pharmacologic profiles of [Ser1]histogranin ([Ser1]HN) were assessed by monitoring its ability to displace the binding of the specific N-methyl-D-aspartate (NMDA) receptor ligand, [3H]CGP 39653, to block the convulsant effects of NMDA and other excitatory agents in mice, and to produce phencyclidine (PCP)-like behavioral effects in rats. The peptide potently inhibited [3H]CGP 39653 binding to membrane preparations of rat brain with an IC50 of 198 nM and a maximal inhibition of 34% of the specific binding activity. Saturation binding experiments with [3H]CGP 39653 in the absence and presence of [Ser1]HN (2 microM) indicated that the inhibitory effect of the peptide was noncompetititive, producing a decrease in the maximal number of binding sites (Bmax of 62.5 fmol/mg protein as compared with 91.3 fmol/mg protein in control), but no significant change in the affinity (Kd of 4.5 nM as compared with 5.1 nM in control). Intracerebroventricular (ICV) injection of [Ser1]HN (10-100 nmol) in mice evoked a dose-dependent and selective blockade of NMDA-induced convulsions. In rats, [Ser1]HN (2.5-100 nmol, ICV) produced dose-dependent stereotypy, ataxia, and locomotion similar to those observed with PCP, at doses ranging between 50 and 400 nmol. The data indicate that [Ser1]HN noncompetitively interacts with the NMDA receptor, an action that goes along with its in vivo NMDA receptor antagonist activity and PCP-like behavioral effects.

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Accession: 043712488

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PMID: 7700954

DOI: 10.1016/0091-3057(94)00247-g


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