L-prolyl-l-leucyl-glycinamide and its peptidomimetic analog 3(R)-[(2(S)-pyrrolidylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA) attenuate haloperidol-induced c-fos expression in the striatum.
Acute treatment of rats with haloperidol results in a rapid and transient increase in striatal c-fos mRNA and Fos immunoreactivity. The induction of immediate early genes by haloperidol may be involved in the development of extrapyramidal side effects. L-Prolyl-L-leucyl-glycinamide (PLG, or MIF-1) has been observed to antagonize the development of haloperidol-induced D(2) receptor supersensitivity in rats. We investigated the modulatory effects of PLG on haloperidol-induced c-fos and Fos protein expression in the rat striatum. We report that coadministration of either PLG or the potent analog of PLG, 3(R)-[(2(S)-pyrrolidylcarbonyl)amino]-2-oxo-1-pyrrolidineacetam ide (PAOPA), attenuated haloperidol-induced c-fos and Fos expression. Haloperidol induced [2 mg/kg, intraperitoneally (i.p.)] c-fos and Fos expression by 500% and 100%, respectively. These responses were attenuated by 170% and 75%, respectively, when coadministered with PLG (20 mg/kg, i.p.) or by 79% by PAOPA (10 microg/kg, i.p.).
Ott
M C
MC
Department of Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, Ontario, Canada. mishrar@fhs.mcmaster.ca
Costain
W J
WJ
Mishra
R K
RK
Johnson
R L
RL
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006220:Haloperidol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology*; D009075:MSH Release-Inhibiting Hormone / Q000031:analogs & derivatives / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D010455:Peptides / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D006727:Hormone Antagonists; D010455:Peptides; D016760:Proto-Oncogene Proteins c-fos; D011760:Pyrrolidinones; D012333:RNA, Messenger; C067487:3-(N-prolylamine)-2-oxo-1-pyrrolidineacetamide; D009075:MSH Release-Inhibiting Hormone; D006220:Haloperidol