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 (sigma) receptor sites and calcitonin gene-related peptides (CGRP) were investigated using receptor subtype-related analogues and fragment in in vivo [3H](+)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]hCGRPalpha modulated sigma systems. In vivo binding experiments demonstrated that CGRP and [Cys(ACM)2,7]hCGRPalpha inhibited 25-40% of specific [3H](+)SKF 10 047 labelling in the mouse hippocampal formation while the purported antagonist hCGRP8-37 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 P1-7. 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 hCGRP8-37 had no effect. Haloperidol, a high-affinity sigma receptor ligand, inhibited by 90% the in vivo [3H](+)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.
Douglas Hospital Research Center, Verdun, Québec, Canada.
P
P
Bouchard
F
F
Monnet
R
R
Bergeron
F
F
Roman
J L
JL
Junien
C
C
de Montigny
G
G
Debonnel
R
R
Quirion
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004594:Electrophysiology; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007478:Iontophoresis; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009294:Narcotics / Q000494:pharmacology; D009478:Neuropeptide Y / Q000494:pharmacology; D010423:Pentazocine / Q000494:pharmacology; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000187:drug effects*
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D009294:Narcotics; D009478:Neuropeptide Y; D017480:Receptors, sigma; C012134:SK&F 10047; D010620:Phenazocine; D006220:Haloperidol; D015740:Calcitonin Gene-Related Peptide; D010423:Pentazocine