Substance P antagonists block carbachol-induced "boxing" behavior at a site of coexistence in the rat prefrontal cortex.
A cholinergic projection from the dorsolateral tegmentum to the medial anterior cortex has previously been shown to contain substance P and corticotropin releasing factor. Behavioral analysis of acetylcholine, substance P and corticotropin releasing factor microinjected into the medial anterior cortex revealed a seizure-related "boxing" behavior elicited by carbachol, which was potentiated by coinjection with substance P and antagonized by coinjection with corticotropin releasing factor. We now report that two antagonists of substance P receptors, [D-Pro2, D-Phe7, D-Trp9]-substance P and [D-Pro2, D-Trp7,9]-substance P, attenuate "boxing" behavior when coinjected with carbachol. Neither antagonist produced observable behavioral effects when microinjected alone. An analog of substance P, [pGlu,5, MePhe,8 Sar9]-substance P (5-11) potentiated carbachol-induced "boxing" at doses similar to naturally-occurring substance P. Monoclonal and polyclonal antisera against substance P were not effective antagonists of carbachol-induced "boxing." The ability of substance P antagonists to block carbachol-induced "boxing" has two major implications: (1) endogenous substance P may be modulating endogenous acetylcholine in the tegmental-cortical pathway; and (2) substance P antagonists may provide a new avenue for the development of antiepileptic drugs.
Stivers
J A
JA
Unit on Behavioral Neuropharmacology, National Institute of Mental Health, Bethesda, MD 20892.
Crawley
J N
JN
D000595:Amino Acid Sequence; D000818:Animals; D002217:Carbachol; D008297:Male; D008845:Microinjections; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000032:analysis; D010446:Peptide Fragments / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology
D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D013373:Substance P; C032720:substance P (5-11), pGlu(5)-MePhe(8)-MeGly(9)-; D002217:Carbachol; D011761:Pyrrolidonecarboxylic Acid