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

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 μM) indicated that the inhibitory effect of the peptide was noncompetititive, producing a decrease in the maximal number of binding sites (B_max of 62.5 fmol/mg protein as compared with 91.3 fmol/mg protein in control), but no significant change in the affinity (K_d 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.