Modulation of N-methyl-D-aspartate (NMDA) antagonist-induced darting behaviour by the peptidomimetic PAMTA.
The N-Methyl-D-Aspartate (NMDA) receptor has attracted much attention in recent years due to its involvement in both the functions and dysfunctions of CNS neurotransmission. The existence of multiple sites by which NMDA receptor channel function can be pharmacologically modified and the interaction between glutamate and other neurotransmitter systems such as dopamine, provide exciting therapeutic avenues for related CNS disorders. In the present study, a novel synthetic analogue of the endogenous brain peptide L-prolyl-L-leucyl glycinamide (PLG) has demonstrated a significant modulatory action on the NMDA receptor. On the basis of radioligand binding studies, the novel synthetic peptide 5-[1(S)-(2(S)-pyrrolidinylcarbonyl)amino-3-methylbutyl]-2- tetrazolylacetamide (PAMTA) has been suggested to act at a polyamine site on the NMDA receptor complex. Scatchard analysis of [3H]MK-801 binding revealed that in the presence of 100 microM PAMTA, a single binding site was obtained with the Kd being increased from 2.5 +/- 0.2 nM to 6.2 +/- 0.1 nM. The ability of PAMTA to inhibit the binding of [3H]MK-801 was sensitive to the presence of both spermidine (polyamine agonist) and arcaine (polyamine antagonist). Analyses of the binding profiles of various NMDA receptor antagonists support PAMTA's interaction with the polyamine site on this receptor complex. Furthermore, we have investigated the behavioural profile of the peptidomimetic PAMTA, by studying its effect on stereotypic behaviours induced by the NMDA receptor antagonist, CPP (3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid). Male Sprague-Dawley rats cannulated bilaterally into the medial prefrontal cortex were injected with PAMTA, CPP, a CPP/PAMTA combination, or a saline control.(ABSTRACT TRUNCATED AT 250 WORDS)
Savelli
J E
JE
Department of Psychiatry and Biomedical Sciences, McMaster University, Hamilton, Ont., Canada.
Chugh
A
A
Cheng
C
C
Mishra
R K
RK
Johnson
R L
RL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002417:Cattle; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors; D004298:Dopamine / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D009435:Synaptic Transmission / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*
D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D013777:Tetrazoles; C096039:5-(1-(2-pyrrolidinylcarbonyl)amino-3-methylbutyl)-2-tetrazolylacetamide; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D004298:Dopamine