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 (sigma) 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 sigma receptor sites since it is blocked by the administration of purported sigma 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, sigma labelling and electrophysiological effects in the hippocampal formation. Accordingly, we investigated if 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 sigma agonists, NPY, peptide YY (PYY) and the Y1 agonist [Leu31Pro34]NPY (but not NPY[13-36], a purported Y2 agonist), as well as hCGRPalpha and the purported CGRP2 agonist [Cys(ACM)2-7]hCGRPalpha (but not CGRP[8-37], a CGRP1 receptor antagonist), significantly attenuated learning impairments induced by MK-801. Furthermore, the effects of NPY, [Leu31Pro34]NPY, hCGRPalpha and [Cys(ACM)2-7]hCGRPalpha were blocked by the administration of the sigma antagonist, BMY-14802. The present data suggest that NPY- and CGRP-related peptides can indirectly interact in vivo with sigma receptors to modulate cognitive processes associated with NMDA receptor function.