Cocaine regulates TRH-related peptides in rat brain.
Cocaine administration has previously been reported to alter the levels of prepro-TRH mRNA and TRH (pGlu-His-Pro-NH(2)) in the limbic system of rats (J. Neurochem. 60 (1993) 1151). We have now demonstrated that a previously unrecognized family of TRH-like peptides is involved in the actions of cocaine. We treated young adult male Sprague-Dawley rats (five per group, 250g body weight at sacrifice) for 2 weeks with either twice daily injections of saline (control group), twice daily injections of 15mg/kg cocaine until sacrifice (chronic group), single injection of 15mg/kg cocaine 2h prior to sacrifice (acute group) or chronic cocaine injections replaced by saline injections 72h prior to sacrifice (withdrawal group (WD)). Twelve different brain regions were dissected and immunoreactivity for TRH (TRH-IR), EEP (pGlu-Glu-Pro-NH(2); EEP-IR) and related peptides were measured by radioimmunoassay (RIA). High pressure liquid chromatography (HPLC) revealed that in many brain regions EEP-IR and TRH-IR consisted of a mixture of TRH, and other TRH-like peptides including EEP, pGlu-Val-Pro-NH(2) (Val(2)-TRH), pGlu-Tyr-Pro-NH(2) (Tyr(2)-TRH), pGlu-Leu-Pro-NH(2) (Leu(2)-TRH), and pGlu-Phe-Pro-NH(2) (Phe(2)-TRH). Following i.p. injection, these TRH-like peptides readily crossed the blood-brain barrier but cleared very slowly from brain tissues. Acute cocaine produced a 4.1-fold increase in Val(2)-TRH level in medulla while Val(2)-TRH and Tyr(2)-TRH, increased 6.2- and 2.9-fold, respectively in pyriform cortex PYR. TRH and Leu(2)-TRH, decreased 47 and 93%, respectively in the nucleus accumbens (AM) while other EEP-IR peaks decreased 50-100% consistent with the significant decrease in total EEP-IR in the AMs following acute cocaine treatment. Because 2h is too short a time to alter levels of neuropeptides via changes in the rate of biosynthesis, the acute cocaine-induced elevation or reduction in TRH and related peptides is most likely due to suppression or stimulation, respectively, of the corresponding peptide secretion rate. Because TRH and TRH-like peptides have antidepressant, analeptic and euphorigenic properties, we conclude that these endogenous substances are potential mediators of both the cocaine "high" and withdrawal symptoms.
Eugene Pekary
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Research Services, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. epekary@ucla.edu
Senanayake
Shayani
S
Sattin
Albert
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D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D017207:Rats, Sprague-Dawley; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000378:metabolism*; D013997:Time Factors
D010446:Peptide Fragments; C467689:pyroglutamyl-tyrosyl-prolylamide; D013973:Thyrotropin-Releasing Hormone; C059697:pyroglutamyl-glutamyl-proline amide; D003042:Cocaine; D011761:Pyrrolidonecarboxylic Acid