Effects of TRK-820, a selective kappa opioid receptor agonist, on rat schizophrenia models.
Abnormalities in dopaminergic and serotonergic neurotransmission in the forebrain are believed to be involved in the underlying mechanism of schizophrenia; therefore, the direct blockade of the receptors associated with these systems is a central strategy for schizophrenia treatment, even though this strategy concurrently produces adverse effects like extrapyramidal effects. Kappa opioid receptors exist extensively in the brain and recent reports have suggested that these receptors are involved in modulating the release of several neurotransmitters including dopamine and serotonin. In the present study, we investigated the effect of TRK-820, (E)-N-[17-(cyclopropylmethyl)-4,5alpha-epoxy-3,14-dihydroxymorphinan-6beta-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride, a selective kappa opioid receptor agonist, on phencyclidine-induced rat behavioral changes and on biochemical changes in the prefrontal cortex. First, TRK-820 dose-dependently inhibited phencyclidine-induced rat hyperlocomotion, which is one of the abnormal behaviors recognized as a rodent schizophrenia model. The inhibitory effect was completely antagonized with nor-BNI (nor-binaltorphimine hydrochloride), a selective kappa opioid receptor antagonist. Second, TRK-820 dose-dependently inhibited phencyclidine-induced stereotyped behaviors including head-weaving, which is considered a behavioral syndrome based on the impairment of the serotonergic system. Third, in an in vivo microdialysis study, TRK-820 dose-dependently attenuated the biochemical changes of both dopamine and serotonin in the prefrontal cortex of rats treated with phencyclidine without affecting their basal levels in normal rats. The initial findings that TRK-820 potentially modulates such monoamine changes and ameliorates abnormal behaviors related to their changes may suggest its therapeutic potential against the symptoms of schizophrenia.
Yoshikawa
Satoru
S
Pharmaceutical Research Laboratories, Toray Industries, Inc, Kamakura, Japan. Satoru_Yoshikawa@nts.toray.co.jp
Hareyama
Nana
N
Ikeda
Ken
K
Kurokawa
Takahiro
T
Nakajima
Mayumi
M
Nakao
Kaoru
K
Mochizuki
Hidenori
H
Ichinose
Hiroshi
H
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D009019:Morphinans / Q000494:pharmacology* / Q000627:therapeutic use*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010622:Phencyclidine / Q000633:toxicity; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use*
D009019:Morphinans; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820; D012701:Serotonin; C051844:norbinaltorphimine; D009271:Naltrexone; D010622:Phencyclidine; D004298:Dopamine