Neuropeptide Y and the Calcitonin Gene‐related Peptide Attenuate Learning Impairments Induced by MK‐801 via a Sigma Receptor‐related mechanism

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Abstract
It has been shown recently that low doses of sigma (σ) 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 σ receptor sites since it is blocked by the administration of purported o 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, é labelling and electrophysiological effects in the hippocampal formation. Accordingly, we investigated if NPY- and CGRP-related peptides modulate cognitive processes by interacting with σ sites in mice. In order to test this hypothesis, a step-down passive avoidance task was used. Interestingly, similarly to various σ agonists, NPY, peptide YY (PYY) and the Y1 agonist [Leu31Pro34]NPY (but not NPY13–36, a purported Y2 agonist), as well as hCGRPα and the purported CGRP2 agonist [CyS(ACM)2–7]hCGRPα (but not CGRP8–37, a CGRP1 receptor antagonist), significantly attenuated learning impairments induced by MK-801. Furthermore, the effects of NPY, [Leu31 Pro34]NPY, hCGRPα and [CYS(ACM)2–7]hCGRPα were blocked by the administration of the σ antagonist, BMY-14802. The present data suggest that NPY- and CGRP-related peptides can indirectly interact in vivo with σ receptors to modulate cognitive processes associated with NMDA receptor function.