JP5344390B2 - Method for screening psychotropic drugs - Google Patents
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Description
本発明は向精神薬のスクリーニング方法に関する。 The present invention relates to a screening method for psychotropic drugs.
精神神経疾患は、脳の機能的・器質的障害によって引き起こされる疾患であり、その症状や治療効果の評価は主観的に成らざるを得ない側面がある。このため、精神神経疾患治療薬の創薬においては、有効性評価の客観性や信頼性を担保するために、試験結果の取得に多大な労力と時間を要していた。 Psychiatric and neurological diseases are diseases caused by functional and organic disorders of the brain, and there is an aspect that the evaluation of symptoms and therapeutic effects must be subjective. For this reason, in the discovery of drugs for treating neuropsychiatric disorders, much labor and time are required to obtain test results in order to ensure the objectivity and reliability of the effectiveness evaluation.
これまで、精神神経疾患治療薬の評価方法としては、ラットを用いた強制水泳試験が抗うつ薬のスクリーニング方法として広く利用されている（非特許文献１参照）。また、神経障害に関連する特定の遺伝子やタンパク質等を用いたスクリーニング方法等も提案されている（例えば特許文献１参照） So far, as a method for evaluating a therapeutic agent for a neuropsychiatric disorder, a forced swimming test using rats has been widely used as a screening method for an antidepressant (see Non-Patent Document 1). In addition, screening methods using specific genes and proteins related to neurological disorders have been proposed (see, for example, Patent Document 1).
しかしながら、上記従来技術によっても、未だ客観性、信頼性の高い精神神経疾患治療薬のスクリーニング方法は確立されていなかった。 However, even with the above prior art, a screening method for a therapeutic agent for a neuropsychiatric disorder with high objectivity and reliability has not yet been established.
本発明は上記従来技術の有する問題点に鑑みなされたものであり、その目的とするところは、客観性、信頼性を担保しつつ投薬の効果を定量的に評価することのできる新規な精神神経疾患のスクリーニング方法を提供することにある。 The present invention has been made in view of the above-mentioned problems of the prior art, and the object of the present invention is to provide a novel neuropsychiatric nerve that can quantitatively evaluate the effects of medication while ensuring objectivity and reliability. It is to provide a screening method for diseases.
本発明の上記目的は、下記の手段によって達成される。 The above object of the present invention is achieved by the following means.
（１）すなわち、本発明は、社会性発達不全モデル動物に対し、高感受性期直前期、高感受性期又は高感受性期直後期の何れかの時期から少なくとも高感受性期直後期後の所定の時期まで継続して投薬を行う投薬ステップと、前記社会性発達不全モデル動物に対し、高感受性期後の前記投薬ステップによる投薬期間またはその直後の何れかの時期から所定期間以上継続して、前記社会性発達不全モデル動物と同種の動物の他の個体との社会性相互作用により前記社会性発達不全モデル動物の社会性発達を誘導する社会性発達誘導ステップと、前記社会性発達不全モデル動物の社会性獲得度を評価することにより前記投薬ステップによる投薬効果を評価する評価ステップと、を有することを特徴とする、向精神薬のスクリーニング方法である。 (1) That is, the present invention relates to a social developmental deficiency model animal at a predetermined time from any time immediately before the high sensitivity period, at any time immediately after the high sensitivity period to at least the predetermined period after the high sensitivity period. a dosing step of dosing and continued until the relative social developmental failure model animals, continuously over a predetermined time period from any of the timing of the dosing period or shortly thereafter by the dosing step after hypersensitive life, the social A social development inducing step for inducing social development of the social developmental deficiency model animal by social interaction between the sexual developmental deficiency model animal and other individuals of the same species, and social of the social developmental deficiency model animal And a psychotropic drug screening method comprising: an evaluation step of evaluating a medication effect of the medication step by evaluating a degree of sex acquisition.
（２）本発明はまた、生後間もなくから高感受性期が開始する前までの間の動物の個体であって社会性発達に関して遺伝的健常性を有するものを少なくとも高感受性期が終了するまでの間前記動物の他の個体から視覚的、聴覚的、嗅覚的又は体性感覚的に隔離して飼育することにより前記社会性発達不全モデル動物を作成する社会性発達不全モデル動物作成ステップを更に有する、（１）に記載の向精神薬のスクリーニング方法である。 (2) The present invention also relates to an animal individual between shortly after birth and before the start of the high sensitivity period, and having at least the high sensitivity period until the end of the high sensitivity period. Further comprising a social developmental deficiency model animal creating step of creating the social developmental deficiency model animal by rearing it visually, auditorily, olfactory or somatosensory from other individuals of the animal, A method for screening a psychotropic drug according to (1).
（３）本発明はまた、前記社会性発達不全モデル動物は、社会性発達に関して遺伝的脆弱性を有する個体が利用される、（１）に記載のスクリーニング方法である。 (3) The present invention is also the screening method according to (1), wherein the social developmental failure model animal is an individual having genetic vulnerability with respect to social development.
（４）本発明はまた、前記社会性発達不全モデル動物と同種の動物の他の個体は、社会性発達不全個体又は社会性発達健常個体である、（１）〜（３）のいずれか１つに記載の向精神薬のスクリーニング方法。 (4) The present invention is also any one of (1) to (3), wherein the other animal of the same species as the social developmental failure model animal is a social developmental failure individual or a socially healthy developmental individual. A screening method for psychotropic drugs as described in 1. above.
（５）本発明はまた、前記評価ステップは、前記社会性発達不全モデル動物の行動から抽出された行動パラメータに基づいて前記社会性発達不全モデル動物の社会性獲得度を評価することを特徴とする、（１）〜（４）のいずれか１つに記載の向精神薬のスクリーニング方法である。 (5) The present invention is also characterized in that the evaluation step evaluates the degree of social gain of the social developmental failure model animal based on behavioral parameters extracted from the behavior of the social developmental failure model animal. to a (1) to (4) a screening method of psychotropic drugs according to any one of.
（６）本発明はまた、前記行動パラメータは、前記社会性発達不全モデル動物の頭の中心位置の時間変化、頭の向きの時間変化、鳴き声の頻度の時間変化、鳴き声の強度又は鳴き声周波数分布の時間変化である、（５）に記載の向精神薬のスクリーニング方法である。 (6) The present invention is also characterized in that the behavior parameter includes a temporal change in the center position of the head of the social developmental deficiency model animal, a temporal change in the head direction, a temporal change in the frequency of calls, the strength of the call or the frequency distribution of the calls. The method for screening a psychotropic drug according to (5) , wherein
（７）本発明はまた、前記社会性発達不全モデル動物は、哺乳類、鳥類、魚類又は軟体動物である、（１）〜（６）のいずれか１つに記載の向精神薬のスクリーニング方法である。 (7) The present invention also relates to the social development failure model animals, mammals, birds, and fish or molluscs (1) - with psychotropic drugs screening method according to any one of (6) is there.
（８）本発明はまた、前記社会性発達不全モデル動物は、コモンマーモセット、タマリンマーモセット、カニクイザル、マカクザル、テナガザル、ゴリラ、オランウータン、チンパンジー、マウス、ラット、モルモット、スンクス、ウサギ、ミニブタ、ブタ、イヌ、ネコ、ウシ、ウマ、ヒツジ、ヤギ、ニワトリ、ウズラ、ハト、キジ、カラス、カケス、インコ、オウム、キュウカンチョウ、カモ、アヒル、エミュー、シチメンチョウ、ハマチ、カンパチ、ブリ、マグロ、アジ、シマアジ、タイ、ヒラメ、アユ、ウナギ、イカ又はタコである、（７）に記載の向精神薬のスクリーニング方法である。 (8) In the present invention, the social developmental deficiency model animal may be a common marmoset, tamarin marmoset, cynomolgus monkey, macaque monkey, gibbon, gorilla, orangutan, chimpanzee, mouse, rat, guinea pig, sunx, rabbit, minipig, pig, dog , Cat, cow, horse, sheep, goat, chicken, quail, pigeon, pheasant, crow, jay, parakeet, parrot, cubanchoe, duck, duck, emu, turkey, yellowtail, amberjack, yellowtail, tuna, horse mackerel, striped horse mackerel, The method for screening a psychotropic drug according to (7), wherein the method is Thai, flounder, sweetfish, eel, squid or octopus.
（９）本発明はまた、前記向精神薬は、精神安定剤、抗うつ薬、抗躁薬、中枢神経刺激薬、睡眠導入剤、鎮静催眠薬又は抗ヒスタミン薬である、（１）〜（８）のいずれか１つに記載の向精神薬のスクリーニング方法である。 (9) In the present invention, the psychotropic agent is a tranquilizer, an antidepressant, an antidepressant, a central nervous stimulant, a sleep inducer, a sedative hypnotic, or an antihistamine. The screening method for psychotropic drugs according to any one of 8).
本発明の向精神薬のスクリーニング方法によれば、社会性発達不全モデル動物に対して、高感受性期を含む前後の時期に投薬を開始するとともに、高感受性期後に投薬と社会性発達誘導処置を併用するので、投薬時期の最適化及び投薬と社会性発達誘導処置との相乗効果によって、向精神薬の作用が増幅される。従って、向精神薬の投薬のみでは治療効果の差異が不明瞭で向精神薬の評価が困難な場合でも、本発明の向精神薬のスクリーニング方法を用いることによって、向精神薬の治療効果の差異が明確になり向精神薬の評価を容易に行うことができる。 According to the method for screening a psychotropic drug of the present invention, a social animal with a social developmental deficiency is started to be administered before and after the high sensitivity period, and after the high sensitivity period, the drug and the social development induction treatment are performed. Because of the combined use, the action of the psychotropic drug is amplified by the optimization of the dosing time and the synergistic effect of the dosing and the social development inducing treatment. Therefore, even when the psychotropic drug alone is not clear and the evaluation of the psychotropic drug is difficult, the difference in the therapeutic effect of the psychotropic drug can be obtained by using the method for screening a psychotropic drug of the present invention. It becomes clear and the evaluation of psychotropic drugs can be easily performed.
以下、本発明の実施の形態について詳細に説明する。 Hereinafter, embodiments of the present invention will be described in detail.
本発明の向精神薬のスクリーニング方法は、モデル動物作成ステップ、投薬ステップ、社会性発達誘導ステップ、及び評価ステップの４つのステップから構成されるものである。 The psychotropic drug screening method of the present invention comprises four steps: a model animal preparation step, a medication step, a social development induction step, and an evaluation step.
まず、モデル動物作成ステップでは、本発明のスクリーニング方法で利用する社会性発達不全モデル動物を作成する。ここで、社会性発達不全モデルとは、遺伝的あるいは環境的要因で発達期に社会性、即ち社会の中での個体間の相互作用に関わる能力が健常に発達しなかった結果、親子間や同士間（兄妹や友達等の他個体）刺激に対して無関心、不安・恐怖などの社会性拒否、コミュニケーション等の社会性相互作用が行えない等の精神的障害を有するに至った生体のモデルをいい、自閉症スペクトラム、広汎性発達障害（ＰＤＤ）や注意欠陥／多動性障害（ＡＤ／ＨＤ）、社会不安、うつ病等の社会性発達障害モデルである。 First, in the model animal creation step, a social developmental failure model animal used in the screening method of the present invention is created. Here, the social developmental deficiency model is a result of genetic or environmental factors that cause sociality, that is, the ability to interact with individuals within a society, during developmental periods. A model of a living body that has a mental disability such as indifference to social stimulation (other individuals such as siblings and friends), social refusal such as anxiety and fear, and social interaction such as communication cannot be performed It is a model for social developmental disorders such as autism spectrum, pervasive developmental disorder (PDD), attention deficit / hyperactivity disorder (AD / HD), social anxiety, and depression.
本発明の向精神薬のスクリーニング方法で利用される社会性発達不全モデル動物は、動物に社会性発達を阻害する処置を施すことにより作成することができる。具体的には、生後間もなくから高感受性期（社会性環境に誘導され社会性機能発達が成立する一定の期間をいう。詳細は後述する。）が開始する前までの間の動物の個体を、少なくとも高感受性期が終了するまでの間、当該動物の他の個体から視覚、聴覚、嗅覚又は体性感覚のいずれか又は全てにおいて隔離した環境で飼育することにより作成される。この際、当該個体は、同種の動物の個体のみならずあらゆる動物の個体や他の動体、音源等、障害目標に応じた社会性機能発達に必要な環境から隔離されていることが好ましく、例えば、視覚的な社会性相互作用を許し聴覚的にだけ社会性相互作用が行えないように、他個体と見合うことができる窓が有りながら防音で外界音が聞こえない飼育環境や、あるいは、社会性相互作用を完全に欠損させるために、不透明な防音壁に囲まれた場所等で個別に飼育される。 The social developmental deficiency model animal used in the method for screening for psychotropic drugs of the present invention can be prepared by applying a treatment that inhibits social development to the animal. Specifically, an individual of an animal from shortly after birth until before the start of the high susceptibility period (a period during which social function development is established by being induced in the social environment; details will be described later) It is created by breeding in an environment isolated in any or all of visual, auditory, olfactory, or somatic sensations from other individuals of the animal at least until the end of the hypersensitive period. In this case, it is preferable that the individual is isolated from the environment necessary for social function development according to the disorder target, such as not only individuals of the same species but also individuals of all animals and other moving bodies, sound sources, etc. In order to allow visual social interaction and not allow auditory social interaction, there is a rearing environment that is soundproof and does not hear external sound while having a window that can match other individuals, or social In order to completely eliminate the interaction, the animals are individually raised in a place surrounded by an opaque soundproof wall.
本発明で利用することができる動物としては、例えば、コモンマーモセット、タマリンマーモセット、カニクイザル、マカクザル、テナガザル、ゴリラ、オランウータン、チンパンジー、マウス、ラット、モルモット、スンクス、ウサギ、ミニブタ、ブタ、イヌ、ネコ、ウシ、ウマ、ヒツジ、ヤギ等の哺乳類、ニワトリ、ウズラ、ハト、キジ、カラス、カケス、インコ、オウム、キュウカンチョウ、カモ、アヒル、エミュー、シチメンチョウ等の鳥類、ハマチ、カンパチ、ブリ、マグロ、アジ、シマアジ、タイ、ヒラメ、アユ、ウナギ等の魚類、イカ、タコ等の軟体動物等が挙げられる。 Examples of animals that can be used in the present invention include common marmoset, tamarin marmoset, cynomolgus monkey, macaque monkey, gibbon, gorilla, orangutan, chimpanzee, mouse, rat, guinea pig, sunks, rabbit, minipig, pig, dog, cat, Mammals such as cows, horses, sheep, goats, chickens, quail, pigeons, pheasants, crows, jays, parrots, parrots, geese, birds such as ducks, ducks, emu, turkeys, yellowtails, amberjack, yellowtails, tuna, horse mackerel , Fish such as striped horse mackerel, Thailand, flounder, sweetfish and eel, and molluscs such as squid and octopus.
なお、本発明では、社会性発達不全モデル動物として何らかの遺伝的脆弱性を持つ個体を取得して利用するものであってもよく、この場合上記モデル動物作成ステップは省略される。 In the present invention, an individual having some genetic vulnerability may be acquired and used as a social developmental failure model animal. In this case, the model animal creation step is omitted.
次に、投薬ステップでは、上記モデル動物作成ステップで得られた社会性発達不全モデル動物に対して、向精神薬の被検薬を投薬する。投薬は、高感受性期直前期、高感受性期又は高感受性期直後期の何れかの時期から開始し、高感受性期後の所定の時期まで継続して行う。ここで、高感受性期とは、生体の社会性獲得に極めて重要な臨界期様の時期をいい、高感受性期においてある必要な刺激を受けることで社会性が著しく発達すると共に高感受性期を過ぎるとその発達がほとんど見られなくなるものである。他個体間の社会性獲得の高感受性期は、コモンマーモセットでは生後１週間〜３カ月以内の一定期間、マウスでは生後３〜９日、ヒヨコでは生後５〜１０日である。また、高感受性期直前期又は高感受性期直後期とは、高感受性期直前又は直後の一定期間（高感受性期の１〜３倍、好ましくは１〜２倍の長さの期間）である。すなわち、投薬ステップにおける投薬は、上記の高感受性期を含む前後の時期に開始することが好ましく、これにより適切な社会性発達誘導処置との併用によって投薬効果を獲得し、あるいは著しく促進させることができる。投薬の開始時期が上記時期を外れると、社会性発達誘導処置との併用によっても投薬効果が無いかまたは低い効果しか得られないので好ましくない。また、その投薬期間は、後述する社会性発達誘導処置を施すのに十分な期間であれば特に限定されるものではなく、投薬の終了時期は高感受性期後の任意の時期が適宜選択される。 Next, in the dosing step, a test drug for a psychotropic drug is administered to the social developmental failure model animal obtained in the model animal creating step. Medication is started from any time immediately before the high sensitivity period, the high sensitivity period, or immediately after the high sensitivity period, and is continued until a predetermined time after the high sensitivity period. Here, the hypersensitive period means a critical period-like period that is extremely important for the acquisition of the social nature of the living body, and when the necessary sensitivity is received in the hypersensitive period, sociality develops significantly and the hypersensitive period passes. And its development is almost unseen. The high susceptibility period of social gain among other individuals is a certain period within 1 week to 3 months after birth for common marmoset, 3-9 days after birth for mice, and 5-10 days for chicks. Moreover, the period immediately before the high sensitivity period or the period immediately after the high sensitivity period is a certain period immediately before or immediately after the high sensitivity period (a period of 1 to 3 times, preferably 1 to 2 times as long as the high sensitivity period). That is, dosing in the dosing step is preferably started at a time before and after the high sensitivity period described above, whereby the dosing effect can be obtained or significantly promoted in combination with appropriate social development induction treatment. it can. If the start time of the medication is out of the above-mentioned time, it is not preferable because there is no medication effect or only a low effect can be obtained even in combination with the social development induction treatment. In addition, the dosing period is not particularly limited as long as it is a period sufficient for performing the social development inducing treatment described later, and an arbitrary period after the hypersensitive period is appropriately selected as the end period of dosing. .
さらに、社会性発達誘導ステップでは、上記社会性発達不全モデル動物に対して、社会性発達の誘導処置を施す。この社会性発達の誘導は、当該個体に対して、当該動物の他の個体との社会性相互作用を誘導することにより行うものであり、具体的には、当該動物の他の個体との視覚的、聴覚的、嗅覚的及び体性感覚的な隔離状態を解いて、個体同士自身、あるいは、ある特定時間だけ他の物質や感覚刺激による支援環境で誘導することで、個体間社会性相互作用を促すことにより行う。例えばヒヨコの例では、他者間で、食欲、閉塞的な環境からの脱出、外界の探索欲求等の同じ目的を動機として持つことができる環境条件、すなわち、餌、水、明るさ、温度、空間面積、外界との遮断等が処置された空間内において、一定時間相互作用を行うか、社会性発達が健常な他個体と共存させた、統合的な環境を供与することで、社会性獲得が成立する。 Further, in the social development induction step, the social development failure model animal is subjected to a social development induction treatment. This induction of social development is performed by inducing social interaction with other individuals of the animal with respect to the individual, and specifically, visual observation with other individuals of the animal. Social, interpersonal interaction by unraveling isolated, auditory, olfactory and somatosensory segregation, and inducing themselves in support environments with other substances or sensory stimuli for a specific period of time This is done by prompting. For example, in the case of the chick, environmental conditions that can have the same purpose as motivation among others, such as appetite, escape from an obstructive environment, the desire to search the outside world, ie, food, water, brightness, temperature, Acquire sociality by providing an integrated environment that interacts for a certain period of time in a space where the space area, blockade from the outside world, etc. are treated, or coexists with other individuals whose social development is healthy. Is established.
社会性発達誘導ステップにおける社会性発達の誘導処置は、高感受性期後の上記投薬ステップによる投薬期間またはその直後の何れかの時期から所定期間実施する。すなわち、社会性発達の誘導処置の開始時期は、高感受性期終了後であることが好ましい。社会性発達の誘導処置を高感受性期に開始したのでは、社会性発達の誘導処置自体で社会性獲得がなされてしまい、被検薬の作用効果が潜在化するので好ましくない。また、社会性発達の誘導は、その処置期間の一部又は全部が投薬期間と重なるか、投薬期間の直後に行われることが好ましい。投薬と社会性発達誘導処置がほぼ同時期に行われないと、社会性発達誘導処置との相乗効果による投薬効果の顕著化が達成されないからである。社会性発達誘導の処置期間の長さは、例えばヒヨコのパロキセチン投与例では３〜５日間以上が好ましい。上記期間より短くては社会性発達誘導処置による相乗効果が得られないからである。 The social development induction treatment in the social development induction step is performed for a predetermined period from the dosing period of the dosing step after the hypersensitive period or any time immediately thereafter. That is, it is preferable that the start time of the social development induction treatment is after the end of the high sensitivity period. It is not preferable that the induction treatment of social development is started in the high sensitivity period, because the social development is performed by the social development induction treatment itself, and the action effect of the test drug becomes latent. In addition, the induction of social development is preferably performed immediately after the dosing period, or a part or all of the treatment period overlaps with the dosing period. This is because if the medication and the social development induction treatment are not performed at the same time, the remarkable effect of the medication due to the synergistic effect with the social development induction treatment cannot be achieved. The length of the treatment period for inducing social development is preferably 3 to 5 days or more in, for example, chick paroxetine administration. This is because if it is shorter than the above period, the synergistic effect by the social development induction treatment cannot be obtained.
そして、評価ステップでは、上記投薬ステップ及び社会性発達誘導ステップの終了後に、上記社会性発達不全モデル動物の社会性獲得度を評価する。ここで、社会性発達不全モデル動物の社会性獲得度は、既知の評価方法、例えば、特開２００８−１８０６６号公報等に記載の方法により評価することができる。即ち、まず、被検個体のゲージを社会性発達健常モデルの個体の飼育ゲージに隣接させて、双方の個体同士が互いに視覚的、聴覚的、嗅覚的及び体性感覚的に認識しうる状態に置く。次に、被検個体の所定時間の行動を俯瞰可能な位置からビデオカメラ等の記録装置により記録し、記録された映像及び音声を分析することにより行動パラメータを抽出する。この行動パラメータとしては、被検個体の頭の中心位置の時間変化、頭の向きの時間変化、鳴き声の頻度の時間変化、鳴き声の強度又は鳴き声周波数分布の時間変化等が挙げられる。そして、得られた多次元の行動パラメータを分析して行動パターンを同定することにより、社会性獲得の有無を判定することができる。 In the evaluation step, the social gain of the social developmental failure model animal is evaluated after the administration step and the social development induction step. Here, the degree of sociality acquisition of the social developmental failure model animal can be evaluated by a known evaluation method, for example, a method described in JP-A-2008-18066. That is, first, the test individual's gauge is adjacent to the social development healthy model individual's breeding gauge so that both individuals can recognize each other visually, auditory, olfactory and somatosensory. Put. Next, the behavior of the test individual for a predetermined time is recorded by a recording device such as a video camera from a position where a bird's eye view is possible, and behavior parameters are extracted by analyzing the recorded video and audio. Examples of the behavior parameters include a time change in the center position of the head of the subject, a time change in the head direction, a time change in the frequency of calls, a time change in the strength of the call or the frequency distribution of calls. Then, by analyzing the obtained multidimensional behavior parameters and identifying the behavior pattern, it is possible to determine the presence or absence of sociality acquisition.
本発明を適用してスクリーニングが可能な向精神薬としては、ベゲタミン等の抗精神病薬（メジャートランキライザー）、ベンゾジアゼピン系等の抗不安薬（マイナートランキライザー）、精神安定剤（トランキライザー）、三環系抗うつ薬、四環系抗うつ薬、選択的セロトニン再取り込み阻害薬(ＳＳＲＩ)、セロトニン・ノルアドレナリン再取り込み阻害薬(ＳＮＲＩ)、ＲＩＭＡ(Ｒｅｖｅｒｓｉｂｌｅ ｉｎｈｉｂｉｔｏｒｓ ｏｆ ｍｏｎｏａｍｉｎｅ ｏｘｉｄａｓｅ ｔｙｐｅ−Ａ)等のモノアミン酸化酵素阻害薬(ＭＡＯＩ)等の抗うつ薬、抗躁薬、メチルフェニデート、アンフェタミン等の中枢神経刺激薬、ベンゾジアゼピン系等の睡眠導入剤、バルビタール等の鎮静催眠薬、抗ヒスタミン薬等が挙げられる。 Examples of psychotropic drugs that can be screened by applying the present invention include antipsychotic drugs such as begetamine (major tranquilizers), anxiolytic drugs such as benzodiazepines (minor tranquilizers), tranquilizers (tranquilizers), and tricyclic anticancer drugs. Monoamine oxidase inhibitors such as antidepressants, tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRI), serotonin / noradrenaline reuptake inhibitors (SNRI), RIMA (Reversible inhibitors of monoamine oxidase type-A) (MAOI) and other antidepressants, antidepressants, methylphenidate, central nervous system stimulants such as amphetamine, benzodiazepine-based sleep inducers, barbital and other sedative hypnotics, antihistamines and the like.
次に、本発明の向精神薬のスクリーニング方法を実施例によりさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 Next, the method for screening a psychotropic drug of the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
［参考例１］
社会性発達健常モデル動物の作成
[Reference Example 1]
Creation of healthy social development model animals
雄性９羽、雌性９羽、計１８羽のヒヨコを１群として、それぞれ雄雌混合して３羽ずつを生後０日目から同一飼育ゲージ中で飼育して社会性発達健常モデルのヒヨコを得た。 Nine males and nine females, a total of 18 chicks, are grouped together, and 3 males and 3 females are bred in the same breeding gauge from day 0 to obtain a healthy social development chick. It was.
［参考例２］
社会性発達不全モデル動物の作成
[Reference Example 2]
Creation of social developmental failure model animals
参考例１で用いたヒヨコと同時期に生まれた雄性３羽、雌性３羽、計６羽のヒヨコを１群として、それぞれ１羽ずつを他の個体と視覚的、聴覚的、嗅覚的及び体性感覚的に完全に隔離した飼育ゲージ中で飼育した以外は参考例１とほぼ同様の条件で飼育して社会性発達不全モデルのヒヨコを得た。 Three chicks born at the same time as the chick used in Reference Example 1, three female chicks, a total of six chicks, each one with each other visually, auditory, olfactory and body A chick of a social developmental deficiency model was obtained by rearing in a condition almost the same as in Reference Example 1 except that it was reared in a rearing gauge completely isolated sexually.
［実施例１］
抗うつ薬投与・社会性発達誘導処置群（１）の作成
[Example 1]
Preparation of antidepressant administration and social development induction treatment group (1)
参考例２の社会性発達不全モデルの個体に、生後５日目から１５日目まで１日体重１ｋｇ当たり３．３ｍｇのパロキセチン塩酸塩水和物を生理食塩水に溶解して経口投与した。 From the fifth day to the fifteenth day after birth, 3.3 mg of paroxetine hydrochloride hydrate per kg of body weight per day was dissolved in physiological saline and orally administered to individuals of the social development failure model of Reference Example 2.
更に、生後１２日目から１４日目までこの個体の飼育ゲージを参考例１の社会性発達健常モデルの個体の飼育ゲージに隣接させて、双方の個体同士が互いに視覚的、聴覚的、嗅覚的及び体性感覚的に認識しうる状態で飼育することにより、この個体に社会性発達健常モデルの個体との社会性相互作用による社会性発達の誘導処置を施して、抗うつ薬投与・社会性発達誘導処置群（１）を得た。 Furthermore, from the 12th day to the 14th day after birth, the breeding gauge of this individual is adjacent to the breeding gauge of the individual of the social development healthy model of Reference Example 1, and both individuals are visually, auditorily, and olfactory. And somatically recognizable so that this individual is treated for induction of social development by social interaction with individuals of a healthy social development model, and antidepressant administration / social A development induction treatment group (1) was obtained.
［実施例２］
抗うつ薬投与・社会性発達誘導処置群（２）の作成
[Example 2]
Preparation of antidepressant administration / social development induction treatment group (2)
パロキセチン塩酸塩水和物の投与量を１日体重１ｋｇ当たり０．４ｍｇとした以外は実施例１とほぼ同様に処理して、抗うつ薬投与・社会性発達誘導処置群（２）を得た。 An antidepressant administration / social development induction treatment group (2) was obtained in substantially the same manner as in Example 1 except that the dose of paroxetine hydrochloride hydrate was 0.4 mg / kg body weight per day.
［実施例３］
抗うつ薬未投与・社会性発達誘導処置群の作成
[Example 3]
Preparation of antidepressant non-administration / social development induction treatment group
パロキセチン塩酸塩水和物の生理食塩水溶液に代えて生理食塩水のみを投与した以外は実施例１とほぼ同様に処理して、抗うつ薬未投与・社会性発達誘導処置群を得た。 An antidepressant non-administration / social development induction treatment group was obtained in the same manner as in Example 1 except that only physiological saline was administered instead of the physiological saline solution of paroxetine hydrochloride hydrate.
［比較例１］
抗うつ薬投与・社会性発達誘導未処置群（１）の作成
[Comparative Example 1]
Preparation of antidepressant drug administration / social development induction untreated group (1)
生後１２日目以降も隔離飼育を続けることにより社会性発達誘導処置を施さなかった以外は実施例１とほぼ同様に処理して、抗うつ薬投与・社会性発達誘導未処置群（１）を得た。 Treated in the same manner as Example 1 except that the social development induction treatment was not performed by continuing the isolation and breeding after the 12th day after birth, and the antidepressant drug administration / social development induction untreated group (1) Obtained.
［比較例２］
抗うつ薬投与・社会性発達誘導未処置群（２）の作成
[Comparative Example 2]
Preparation of antidepressant administration / social development induction untreated group (2)
生後１２日目以降も隔離飼育を続けることにより社会性発達誘導処置を施さなかった以外は実施例２とほぼ同様に処理して、抗うつ薬投与・社会性発達誘導未処置群（２）を得た。 Treated in the same manner as in Example 2 except that the social development induction treatment was not performed by continuing isolation and breeding after the 12th day after birth, and the antidepressant drug administration / social development induction untreated group (2) Obtained.
［比較例３］
抗うつ薬未投与・社会性発達誘導未処置群の作成
[Comparative Example 3]
Preparation of untreated antidepressant medication and social development induction untreated group
生後１２日目以降も隔離飼育を続けることにより社会性発達誘導処置を施さなかった以外は実施例３とほぼ同様に処理して、抗うつ薬未投与・社会性発達誘導未処置群を得た。 The treatment was performed in substantially the same manner as Example 3 except that no isolation treatment was performed by continuing isolation and breeding after the 12th day of birth to obtain an antidepressant non-administration / social development induction untreated group. .
［実施例４］
社会性獲得の評価
[Example 4]
Evaluation of social gain
被検個体のゲージを参考例１の社会性発達健常モデルの個体の飼育ゲージに隣接させて、双方の個体同士が互いに視覚的、聴覚的、嗅覚的及び体性感覚的に認識しうる状態に置いた。被検個体の所定時間の行動を俯瞰可能な位置からビデオカメラにより撮影記録し、記録された映像及び音声を分析することにより、被検個体の頭の中心位置、頭の向き、鳴き声種及び鳴き声頻度を行動パラメータとして抽出した。得られた行動パラメータの経時変化から行動パターンを同定して社会性獲得の有無（強い社会性獲得、弱い社会性獲得又は社会性未獲得）を判定した。社会性獲得度は、群の総個体数に対する社会性獲得個体数の割合で示した。 The test individual's gauge is placed adjacent to the breeding gauge of the social development healthy model in Reference Example 1 so that both individuals can recognize each other visually, auditory, olfactory and somatosensory. placed. The subject's head position, head orientation, cry type, and cry are recorded by video camera recording and recording from a position where the behavior of the subject can be seen over time, and analyzing the recorded video and audio. The frequency was extracted as a behavior parameter. The behavioral pattern was identified from the obtained time-dependent change of the behavioral parameter, and the presence / absence of sociality acquisition (strong sociality acquisition, weak sociality acquisition, or no sociality acquisition) was determined. The degree of sociality acquisition was expressed as the ratio of the number of individuals gaining sociality to the total number of individuals in the group.
実施例１〜３及び比較例１〜３で得られた各群の個体の社会性発達誘導処置前（生後１１日目）及び社会性誘導処置後（生後１５日目）の社会性獲得度の評価結果を表１に示す。
比較例１〜３の結果から明らかなとおり、社会性発達不全モデルに対して、抗うつ薬の投薬のみでは治療効果に差異がなく、抗うつ薬の評価は困難であったのに対し、実施例１〜３の結果から明らかなとおり、抗うつ薬の投薬と社会性発達誘導処置とを併用することによって治療効果の差異が明確になり、抗うつ薬の評価が容易に行えることがわかった。 As is clear from the results of Comparative Examples 1 to 3, the social developmental dysfunction model was not treated with an antidepressant alone, and it was difficult to evaluate the antidepressant. As is clear from the results of Examples 1 to 3, it was found that the combined use of antidepressant medication and social development induction treatment clarified the difference in therapeutic effect and facilitated evaluation of antidepressants. .
上述したように、本発明によれば、投薬時期の最適化及び投薬と社会性発達誘導処置との相乗効果により向精神薬の作用が増幅されるので、向精神薬のスクリーニング方法に利用した場合、向精神薬の治療効果の差異が明確になり向精神薬の評価を容易に行うことができる。 As described above, according to the present invention, the action of the psychotropic drug is amplified by the synergistic effect between the optimization of the dosing time and the dosing and the social development inducing treatment. The difference in the therapeutic effect of the psychotropic drug becomes clear, and the psychotropic drug can be easily evaluated .
Claims (9)
前記社会性発達不全モデル動物に対し、高感受性期後の前記投薬ステップによる投薬期間またはその直後の何れかの時期から所定期間以上継続して、前記社会性発達不全モデル動物と同種の動物の他の個体との社会性相互作用により前記社会性発達不全モデル動物の社会性発達を誘導する社会性発達誘導ステップと、
前記社会性発達不全モデル動物の社会性獲得度を評価することにより前記投薬ステップによる投薬効果を評価する評価ステップと、
を有することを特徴とする、向精神薬のスクリーニング方法。 Dosing step to continuously administer a model animal with social developmental deficiency immediately before the hypersensitive period, at any time during the hypersensitive period or immediately after the hypersensitive period to at least a predetermined period after the highly sensitive period When,
For the social developmental deficiency model animal, other than the same kind of animal as the social developmental deficiency model animal, continue for a predetermined period or more from the dosing period of the dosing step after the hypersensitive period or any time immediately thereafter. Social development step of inducing social development of the social developmental deficiency model animal by social interaction with an individual of
An evaluation step of evaluating the medication effect of the medication step by evaluating the degree of social gain of the social developmental failure model animal;
A screening method for psychotropic drugs, comprising:
請求項１に記載の向精神薬のスクリーニング方法。 Individuals of animals between shortly after birth and before the start of the hypersensitive phase, which have genetic health regarding social development, are visible from other individuals of the animal at least until the end of the hypersensitive phase Further comprising a social developmental deficiency model animal creating step of creating the social developmental deficiency model animal by rearing the animal in an isolated, audible, olfactory or somatosensory manner .
The method for screening a psychotropic drug according to claim 1.
請求項１〜３のいずれか１項に記載の向精神薬のスクリーニング方法。The screening method of the psychotropic drug of any one of Claims 1-3.
請求項１〜４のいずれか１項に記載の向精神薬のスクリーニング方法。 The evaluation step is characterized by evaluating the social gain of the social developmental failure model animal based on behavioral parameters extracted from the behavior of the social developmental failure model animal.
The screening method of the psychotropic drug of any one of Claims 1-4.
請求項５に記載の向精神薬のスクリーニング方法。 The behavior parameter is a temporal change in the central position of the head of the social developmental disorder model animal, a temporal change in the head direction, a temporal change in the frequency of crying, a temporal change in the strength of the cry or the frequency distribution of the crying.
A method for screening a psychotropic drug according to claim 5 .
請求項１〜６のいずれか１項に記載の向精神薬のスクリーニング方法。 The social developmental failure model animal is a mammal, a bird, a fish or a mollusk.
The screening method of the psychotropic drug of any one of Claims 1-6.
請求項７に記載の向精神薬のスクリーニング方法。 The social developmental failure model animals include common marmoset, tamarin marmoset, cynomolgus monkey, macaque monkey, gibbon, gorilla, orangutan, chimpanzee, mouse, rat, guinea pig, sunks, rabbit, minipig, pig, dog, cat, cow, horse, sheep , Goat, chicken, quail, pigeon, pheasant, crow, jay, parakeet, parrot, swanfish, duck, emu, turkey, yellowtail, amberjack, yellowtail, tuna, horse mackerel, striped sea bream, thailand, flounder, sweetfish, eel, Squid or octopus,
The method for screening a psychotropic drug according to claim 7.
請求項１〜８のいずれか１項に記載の向精神薬のスクリーニング方法。 The psychotropic drug is a tranquilizer, antidepressant, antidepressant, central nervous stimulant, sleep inducer, sedative hypnotic or antihistamine,
A method for screening a psychotropic drug according to any one of claims 1 to 8.
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