NEUROPEPTIDE-Y AND THE CALCITONIN-GENE-RELATED PEPTIDE ATTENUATE LEARNING IMPAIRMENTS INDUCED BY MK-801 VIA A SIGMA-RECEPTOR-RELATED MECHANISM

It has been shown recently that low doses of sigma (a) receptor ligand s like 1,3-di-(2-tolyl)guanidine (DTG), (+)N-allylnormetazocine [(+)SK F 10 047] and (+)pentazocine can antagonize learning impairments induc ed by dizocilpine (MK-801), a non-competitive antagonist at the NMDA r eceptor channel. This antagonism has been proposed to involve a recept or sites since it is blocked by the administration of purported a anta gonists such as NE-100 and BMY-14802, It has also been demonstrated th at peptides of the neuropeptide Y (NPY) and calcitonin gene-related pe ptide (CGRP) families modulate, in vivo, a labelling and electrophysio logical effects in the hippocampal formation, Accordingly, we investig ated ii NPY-and CGRP-related peptides modulate cognitive processes by interacting with sigma sites in mice, In order to test this hypothesis , a step-down passive avoidance task was used, Interestingly, similarl y to various a agonists, NPY, peptide YY (PYY) and the Y-1 agonist [Le u(31)Pro(34)]NPY (but not NPY13-36, a purported Y-2 agonist), as well as hCGRP alpha and the purported CGRP(2) agonist [Cys(ACM)(2-7)]hCGRP alpha (but not CGRP(8-37), a CGRP(1) receptor antagonist), significant ly attenuated learning impairments induced by MK-801. Furthermore, the effects of NPY, [Leu(31)Pro(34)]NPY, hCGRP alpha and [Cys(ACM)(2-7)]h CGRP alpha were blocked by the administration of the a antagonist, BMY -14802. The present data suggest that NPY-and CGRP-related peptides ca n indirectly interact in vivo with a receptors to modulate cognitive p rocesses associated with NMDA receptor function.