Modulation ofN-methyl-d-aspartate (NMDA) antagonist-induced darting behaviour by the peptidomimetic PAMTA

J. E. Savelli, A. Chugh, C. Cheng, R. K. Mishra, R. L. Johnson

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

TheN-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 peptidel-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 μM PAMTA, a single binding site was obtained with theKd 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. Drug effects were evaluated in an open field and changes in behaviour were assessed by measuring general hyperactivity and locomotion. Bilateral microinjection of CPP (2 μg) resulted in a significant increase in locomotion, observed as an increase in the distance travelled by the animal. This stereotypic increase in locomotor activity induced by CPP was augmented significantly (2-fold) when given in combination with PAMTA (20 μg). We evaluated general hyperactivity by measuring rearing, grooming behaviour and distance travelled in an open field. No significant increases were observed for the CPP/PAMTA combination on grooming or rearing behaviours when these parameters were observed individually. PAMTA (20 μg) given alone had no significant effect on total activity as compared to animals receiving the saline control. We also studied the effect of PAMTA on a unique behavioural paradigm, known as darting, elicited by CPP microinjection into the medial prefrontal cortex. PAMTA, in combination with CPP, also augmented CPP-induced darting in the rat. Since the polyamines spermine and spermidine have been shown to attenuate this behavioural profile, the behavioural results presented with the accordance with the radioligand binding studies, provide support that PAMTA may be interacting as an antagonist at the polyamine binding site. If so, drugs designed specifically to act at the polyamine site or other sites on the NMDA receptor may prove to be useful for modulating behaviours mediated or influenced by NMDA receptor activity. PAMTA and similiar compounds may also prove to be useful therapeutic agents for CNS disorders involving glutamate and other neurotransmitters, as neuroprotective agents or as pharmacological tools in drug evaluation.

Original languageEnglish (US)
Pages (from-to)41-49
Number of pages9
JournalBrain Research
Volume682
Issue number1-2
DOIs
StatePublished - Jun 5 1995

Keywords

  • Darting behavior
  • NMDA receptor
  • Neuromodulator
  • Polyamine
  • Radioligand binding
  • Rat prefrontal cortex
  • [H]MK-801

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