MODULATION OF N-METHYL-D-ASPARTATE (NMDA) ANTAGONIST-INDUCED DARTING BEHAVIOR 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 dysfu nctions of CNS neurotransmission. The existence of multiple sites by w hich NMDA receptor channel function can be pharmacologically modified and the interaction between glutamate and other neurotransmitter syste ms 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 demo nstrated a significant modulatory action on the NMDA receptor. On the basis of radioligand binding studies, the novel synthetic peptide arbo nyl)amino-3-methylbutyl]-2-tetrazolylacetamide (PAMTA) has been sugges ted to act at a polyamine site on the NMDA receptor complex. Scatchard analysis of [H-3]MK-801 binding revealed that in the presence of 100 mu M PAMTA, a single binding site was obtained with the K-d, being inc reased from 2.5 +/- 0.2 nM to 6.2 +/- 0.1 nM. The ability of PAMTA to inhibit the binding of [H-3]MK-801 was sensitive to the presence of bo th 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 c omplex. Furthermore, we have investigated the behavioural profile of t he peptidomimetic PAMTA, by studying its effect on stereotypic behavio urs 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 microinjecti on of CPP (2 mu g) resulted in a significant increase in locomotion, o bserved as an increase in the distance travelled by the animal. This s tereotypic increase in locomotor activity induced by CPP was augmented significantly (2-fold) when given in combination with PAMTA (20 mu g) . We evaluated general hyperactivity by measuring rearing, grooming be haviour and distance travelled in an open field. No significant increa ses were observed for the CPP/PAMTA combination on grooming or rearing behaviours when these parameters were observed individually. PAMTA (2 0 mu g) given alone had no significant effect on total activity as com pared to animals receiving the saline control. We also studied the eff ect of PAMTA on a unique behavioural paradigm, known as darting, elici ted 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 attenu ate this behavioural profile, the behavioural results presented here i n accordance with the radioligand binding studies, provide support tha t PAMTA may be interacting as an antagonist at the polyamine binding s ite. If so, drugs designed specifically to act at the polyamine site o r other sites on the NMDA receptor may prove to be useful for modulati ng 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.