1. Atypical antipsychotic properties of AD-6048, a primary metabolite of blonanserin.
- Author
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Tatara A, Shimizu S, Masui A, Tamura M, Minamimoto S, Mizuguchi Y, Ochiai M, Mizobe Y, and Ohno Y
- Subjects
- Animals, Apomorphine antagonists & inhibitors, Apomorphine pharmacology, Basal Ganglia Diseases psychology, Behavior, Animal drug effects, Catalepsy chemically induced, Catalepsy psychology, Corpus Striatum drug effects, Corpus Striatum metabolism, Dose-Response Relationship, Drug, Gene Expression drug effects, Haloperidol pharmacology, Injections, Subcutaneous, Male, Mice, Nucleus Accumbens drug effects, Nucleus Accumbens metabolism, Oncogene Proteins v-fos biosynthesis, Oncogene Proteins v-fos drug effects, Antipsychotic Agents pharmacology, Piperazines pharmacokinetics, Piperazines pharmacology, Piperidines pharmacokinetics, Pyridines pharmacology
- Abstract
Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3-1mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED50 value of 0.200mg/kg, the potency being 1/3-1/5 times that of haloperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10mg/kg, s.c.), whereas HAL at doses of 0.1-3mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of haloperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of Fos protein expression revealed that both AD-6048 and HAL significantly increased Fos expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal Fos expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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