N-methyl-D-aspartate receptor antagonist activity and phencyclidine-like behavioral effects of the pentadecapeptide, [Ser1]histogranin.
V K Shukla, S Lemaire, M Dumont, Z Merali
Pharmacology, biochemistry, and behavior January 1995 DOI: 10.1016/0091-3057(94)00247-g (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Peer reviewed |
|---|---|
| Population | Rats and mice |
| Intervention | [Ser1]histogranin ([Ser1]HN) |
| Dose | 10-100 nmol (mice, ICV); 2.5-100 nmol (rats, ICV); 2 microM (binding experiments) |
| Measures | [3H]CGP 39653 binding, NMDA-induced convulsions, stereotypy, ataxia, locomotion |
| Key points | The authors report that [Ser1]histogranin noncompetitively inhibits NMDA receptor binding in rat brain membranes (IC50 198 nM; maximal inhibition 34%; reduced Bmax without affinity change), blocks NMDA-induced convulsions in mice, and produces phencyclidine-like stereotypy, ataxia, and locomotion in rats, indicating NMDA receptor antagonist activity. |
Abstract
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.