Blockade of tachykinin NK1 receptors by CP-96345 enhances dopamine release and the striatal dopamine effects of methamphetamine in rats.
The nonpeptide, tachykinin NK1 receptor antagonist, CP-96345, permits the study of the physiological role of extrapyramidal substance P systems. Using microdialysis, we observed that locally applied CP-96345 (200 nM) caused a significant increase in dopamine release in the striatum as well as substantially enhancing striatal dopamine release caused by a low dose of methamphetamine (0.5 mg/kg s.c.). In addition, multiple systemic administrations of CP-96345 almost doubled the dopamine-mediated responses of the striatal neurotensin and dynorphin systems to high doses of methamphetamine (10 mg/kg/dose s.c.). Our findings suggest that the physiological role of substance P released in the striatum is to decrease the activity of the nigrostriatal dopamine pathway.
Gygi
S P
SP
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112.
Gibb
J W
JW
Johnson
M
M
Hanson
G R
GR
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004399:Dynorphins / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D017551:Microdialysis; D064729:Neurokinin-1 Receptor Antagonists; D009496:Neurotensin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
D001713:Biphenyl Compounds; D064729:Neurokinin-1 Receptor Antagonists; D013373:Substance P; D009496:Neurotensin; D008694:Methamphetamine; D004399:Dynorphins; D004298:Dopamine; C066892:CP 96345