IN-VIVO MODULATION OF SIGMA-RECEPTOR SITES BY CALCITONIN-GENE-RELATED PEPTIDE IN THE MOUSE AND RAT HIPPOCAMPAL-FORMATION - RADIOLIGAND BINDING AND ELECTROPHYSIOLOGICAL STUDIES

Possible interactions between sigma to) receptor sites and calcitonin gene-related peptides (CGRP) were investigated using receptor subtype-related analogues and fragments in in vivo [H-3](+)SKF 10 047/sigma binding in the hippocampus, and electrophysiological recording of the N-methyl-D-aspartate (NMDA)-induced activation of CA3 pyramidal neurons, two well-established sigma assays. In both paradigms, CGRP and the agonist [Cys(ACM)(2,7)]hCGRP alpha modulated sigma systems. In vivo binding experiments demonstrated that CGRP and [Cys(ACM)(2,7)]hCGRP alpha inhibited 25-40% of specific [H-3](+)SKF 10 047 labelling in the mouse hippocampal formation while the purported antagonist hCGRP(8-37) was inactive. The specificity of this modulation was demonstrated further by the lack of effect of other vasoactive peptides, including the atrial natriuretic peptide, substance P, and its N-terminal fragment, substance P-1-7 In the CA3 subfield of the rat dorsal hippocampus, hCGRP alpha decreased (up to 61%) the NMDA-induced activation of the pyramidal neurons. Conversely, the linear analogue [Cys(ACM)(2,7)]hCGRP alpha enhanced (by 85%) the NMDA-induced activation of CA3 pyramidal neurons, while the antagonistic fragment hCGRP(8-37) had no effect. Haloperidol, a high-affinity sigma receptor ligand, inhibited by 90% the in vivo [H-3](+)SKF 10 047 labelling, and prevented the modulation of the NMDA-induced activation by hCGRP alpha and [Cys(ACM)(2,7)]hCGRP alpha. It thus appears that CGRP can modulate sigma-related systems in the hippocampal formation.