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 ligands like 1,3-di-(2-tolyl)guanidine (DTG), (+)N-allylnormetazocine [(+)SKF 10 047] and (+)pentazocine can antagonize learning impairments induced by dizocilpine (MK-801), a non-competitive antagonist at the NMDA receptor channel. This antagonism has been proposed to involve a receptor sites since it is blocked by the administration of purported a antagonists such as NE-100 and BMY-14802, It has also been demonstrated that peptides of the neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) families modulate, in vivo, a labelling and electrophysiological effects in the hippocampal formation, Accordingly, we investigated 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, similarly to various a agonists, NPY, peptide YY (PYY) and the Y-1 agonist [Leu(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), significantly attenuated learning impairments induced by MK-801. Furthermore, the effects of NPY, [Leu(31)Pro(34)]NPY, hCGRP alpha and [Cys(ACM)(2-7)]hCGRP alpha were blocked by the administration of the a antagonist, BMY-14802. The present data suggest that NPY-and CGRP-related peptides can indirectly interact in vivo with a receptors to modulate cognitive processes associated with NMDA receptor function.