著者

今井 英明 Nina Dedic Heather Dworak Seth Hopkins Courtney Zeni Kenneth Koblan

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第96回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-B-S21-2, 2022 (Released:2022-12-26)

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Since the discovery of chlorpromazine, antagonism of dopamine D2 receptors has been central to the mechanism of antipsychotic drug efficacy. Currently approved antipsychotics effectively manage the positive symptoms of schizophrenia, however, their effects on negative and cognitive symptoms are negligible. Moreover, these drugs are associated with many serious side effects (e.g., motor and endocrine abnormalities, sedation, and weight gain) which negatively impact medication adherence. Researchers have vigorously pursued new therapeutic targets to treat schizophrenia beyond D2 receptor blockade. Recently, trace amine-associated receptor1 (TAAR1) has emerged as a promising new drug target. This review will discuss the current state of research of TAAR1 and will summarize the status of TAAR1 agonists in clinical development and their potential treatments for psychiatric disorders. Ulotaront is a TAAR1 agonist with 5-HT1A agonist activity under investigation for the treatment of schizophrenia. Ulotaront is the first TAAR1 agonist to progress to randomized controlled clinical trials and has demonstrated broad efficacy in animal models of schizophrenia. Unlike all approved antipsychotic drugs, ulotaront does not exert its effects via blockade of dopamine D2 or serotonin 5-HT2A receptors. In a randomized, double-blind, placebo-controlled clinical trial in patients with an acute exacerbation of schizophrenia, ulotaront demonstrated efficacy for both positive and negative symptoms, with continued symptom improvement observed over the course of the optional 6-month open-label extension study. In these studies, ulotaront was generally safe and well-tolerated with a tolerability profile similar to placebo and distinguished from the antipsychotic class, supporting its novel mechanism of action and absence of D2-receptor blockade. Taken together, these results are supportive of the therapeutic potential of TAAR1 agonists as a possible new drug class for the treatment of schizophrenia.

著者

衣斐 大祐

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第96回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.4-B-S43-2, 2022 (Released:2022-12-26)

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Serotonergic psychedelics such as psilocybin, the psychoactive substance found in the magic mushroom, have hallucinatory effect through stimulation of the cortical serotonin 5-HT2A receptor (5-HT2A). Recently, FDA has called psilocybin a 'breakthrough therapy' for severe depression. We have already demonstrated that 5-HT2A in the lateral septum (LS) plays a responsible role in antidepressant-like effect of psilocin, an active metabolite of psilocybin, whereas hallucinatory effect of psilocin was attributed to 5-HT2A stimulation in the visual cortex (V1) in mice. Here, we investigated the neural network responsible for antidepressant effect of psilocin. The histological study with anterograde and retrograde transports of adeno-associated viruses showed that 5-HT2A in LS abundantly expressed in GABAergic neurons, which projects to the dorsomedial hypothalamic nucleus (DM) in mice. Therefore, we investigated the functional role of 5-HT2A-positive LS-DM pathway in antidepressant effect by optogenetic and chemogenetic approaches. Selective inhibition of 5-HT2A-positive LS-DM pathway eliminated the antidepressant-like effect of psilocin in mice in forced-swim test as well as social defeat stress test. On the other hand, activation of the LS-DM pathway induced antidepressant-like effect in mice. Lastly, microinjection of bicuculline, an antagonist of GABAA receptor, into the DM diminished such effect of psilocin in mice. These suggest that 5-HT2A-positive LS-DM GABAergic network contributes to antidepressant effect of serotonergic psychedelics.

著者

島田 眞路

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第96回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-B-SL09, 2022 (Released:2022-12-26)

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わが国の科学技術力の衰退、低迷が止まらない。先日、世界各国のTop10%論文数が公表されたが、日本は長期低迷傾向にあり、今年は2カ国に抜かれ、10位から12位となってしまった。何とヨーロッパ諸国の中で後塵を拝してきたスペインとアジアの隣国韓国に抜かれたのである。その原因は、国の科学技術研究費を抑制してきた財務省/文科省にある。国立大学法人化をきっかけに、国立大学運営費交付金を2004年から毎年1%減らし続け、現在では10%以上減額となっている。厚労省も基礎医学研究に対してバッシングを行い続け、卒後臨床研修制度=大学否定、日本専門医機構=学会否定を行ってきた。このアカデミズム否定は、かつての文化大革命を想起させる暴挙である。これらの政策のおかげで日本の研究力は顕著に低下した。そのよい例が今般の新型コロナウイルス感染症対応で露わになった。ワクチン、治療薬ともその開発は、欧米に大きく遅れをとってしまった。これらの科学技術研究を中心とするアカデミズム抑制政策を即刻転換しなければ、日本の科学技術力は本当に地に堕ちる可能性があり、深く憂慮している。

著者

関口 拓己 櫻井 隆 山下 直也

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第96回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.4-B-P-301, 2022 (Released:2022-12-26)

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Amyloid-beta (Aβ) aggregation has been believed to be the fundamental trigger of the development of Alzheimer's disease (AD). Therefore, elucidating the mechanisms that induce Aβ overproduction from its type I transmembrane precursor protein (APP) is one of the important issues in providing potential therapeutic targets for AD. Semaphorin3A (Sema3A), a secreted type of repulsive axon guidance molecule, is implicated in the development of various neurodegenerative diseases. It was previously reported that Sema3A and its signaling molecules accumulate and aggregate in AD patients' brain. However, the molecular link between Sema3A signaling and AD pathogenesis remains unknown. Here we show evidence that APP interacts with PlexinA, a Sema3A receptor component. APP and PlexinA interacted through the extracellular regions and we were able to narrow down these regions to less than 100 amino acids. Based on these findings, we are now investigating whether the APP-PlexinA interaction affects APP function and metabolism, which might provide new perspective that aberrant Sema3A signaling induces Aβ overproduction.