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.