Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects.
Nonpeptidic delta-opioid receptor agonists produce antidepressant-like effects in rodents, and compounds that inhibit the breakdown of endogenous opioid peptides have antidepressant-like effects in animal models. In this study, the behavioral effects of the enkephalinase inhibitor, RB101 (N-[(R, S)-2-benzyl-3-[(S)(2-amino-4-methyl-thio)-butyldithio]-1-oxopropyl]-l-phenylalanine benzyl ester), were examined. Specifically, the effects of RB101 on convulsive activity, locomotor activity, and antidepressant-like effects in the forced swim test were studied in Sprague-Dawley rats, and the opioid receptor types mediating these effects were examined by antagonist studies. In addition, the effects of RB101 on brain-derived neurotrophic factor (BDNF) mRNA expression were evaluated in relation to its antidepressant effects. RB101 produced delta-opioid receptor-mediated antidepressant effects (32 mg/kg i.v. and 100 mg/kg i.p.) and increased locomotor activity (32 mg/kg i.v.) in rats. RB101 did not produce convulsions or seizures and did not alter BDNF mRNA expression. In conclusion, RB101 has the potential to produce antidepressant effects without convulsions.
Jutkiewicz
Emily M
EM
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA. ejutkiew@umich.edu
Torregrossa
Mary M
MM
Sobczyk-Kojiro
Katarzyna
K
Mosberg
Henry I
HI
Folk
John E
JE
Rice
Kenner C
KC
Watson
Stanley J
SJ
Woods
James H
JH
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood / Q000235:genetics; D004220:Disulfides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005625:Frontal Lobe / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013550:Swimming
D000928:Antidepressive Agents; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D004220:Disulfides; D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D010879:Piperazines; D012333:RNA, Messenger; C074024:RB 101; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D010649:Phenylalanine; D009271:Naltrexone; D000324:Adrenocorticotropic Hormone; D015260:Neprilysin; C055382:naltrindole