CN108619517A - It simulates the foundation of the model of mankind's Social behaviors obstacle and treats the drug of Social behaviors obstacle - Google Patents
It simulates the foundation of the model of mankind's Social behaviors obstacle and treats the drug of Social behaviors obstacle Download PDFInfo
- Publication number
- CN108619517A CN108619517A CN201710182297.1A CN201710182297A CN108619517A CN 108619517 A CN108619517 A CN 108619517A CN 201710182297 A CN201710182297 A CN 201710182297A CN 108619517 A CN108619517 A CN 108619517A
- Authority
- CN
- China
- Prior art keywords
- animal
- obstacle
- social
- arm
- channel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
Abstract
The present invention relates to the foundation of the model of simulation mankind's Social behaviors obstacle and the drugs for the treatment of Social behaviors obstacle.The present invention establishes the animal model and device (Ymaze simulates Social behaviors) of the core symptom of simulation mankind's Social behaviors obstacle, can be applied to the drug that screening prevents, alleviates or treat Social behaviors obstacle.The present invention also provides screening acquisitions for prevention, alleviation or to treat the useful drug of Social behaviors obstacle.
Description
Technical field
The invention belongs to field of biology, more particularly it relates to simulate the model of mankind's Social behaviors obstacle
Establish and treat the drug of Social behaviors obstacle.
Background technology
Social behaviors obstacle is in the animal group that community occupies, between a cognition and individual of the same clan in group member
Exchange behavior occurs, this class behavior is defined as Social behaviors, and Social behaviors occur have generality, i.e., wide in community animal
General generation.There is Social behaviors the conservative on science of heredity, i.e., the offspring of social group still to have Social behaviors.Social behaviors
Obstacle is it is usually because individual can not occur normal Social behaviors with same group's individual and be defined.It is main in human society
Show as unsociable and eccentric shy with strangers, social phobia is lived in the world of oneself.Social behaviors obstacle is often associated with other mental diseases
Disease is the potential enemy of mankind's soul health.
Social behaviors obstacle is the core symptom of many mental disorders, so far still without good drug therapy.Mesh
The mainly calm class drug of the preceding drug for improving this kind of disease.Easily cause the anaesthetic of habituation.But effect difference strong man
Meaning, can not effectively achieve expected purpose.The characteristics of this kind of disease is to belong to mental disorder, it is more difficult to find typical cell
Model, animal model also more difficult foundation, these features seriously hinder further investigation and the drug development of such disease.
μ opioid receptors are considered adjusting pain in previous research, and agonist morphine similar drug is widely used in
Analgestic, and μ opioid receptors non-specific antagonist naloxones (naloxone) are currently used for treating opioid excess.
Whether this kind of drug has effect for Social behaviors obstacle, does not report in the prior art.
To sum up, this field also needs to establish the animal model of applicable Social behaviors obstacle, is effectively controlled to choose
Treat drug.
Invention content
The purpose of the present invention is to provide a kind of models and its method for building up of simulation mankind's Social behaviors obstacle.
Another object of the present invention is to provide the drugs for the treatment of Social behaviors obstacle.
In the first aspect of the present invention, the μ purposes of opioid receptors specific antagonists is provided, prevention is used to prepare, delays
The drug of solution or treatment Social behaviors obstacle.
In a preference, the μ opioid receptors specific antagonists include：β-FNA (rich naltrexone amine hydrochloric acid
Salt, beta-funaltrexamine).
In another preferred example, the Social behaviors obstacle is：It is social insensitive after ejaculation.
In another aspect of this invention, a kind of side for the drug screening prevention, alleviation or treatment Social behaviors obstacle is provided
Method, the method includes：
(1) device of a three arm Y shapes is provided, the device of the three arms Y shape there are three interconnected channel (1),
(2), (3) it is movable wherein can to accommodate experimental animal；In channel (1), (2), it is respectively set door (11), (21), door and channel
End constitutes closed area, and the door is visual；
(2) subject male animal is allowed to carry out mating ejaculation, be placed in the device of three arm Y shapes of (1)；The device leads to
Stimulation animal is placed in the closed area in road (1)；Subject male animal after observation administration is present in where stimulation animal
The time in channel is calculated as the time 1；
(3) drug candidate is applied to subject male animal, and subject male animal is allowed to carry out mating ejaculation, be placed on
(1) in the device of three arm Y shapes；Stimulation animal is placed in the closed area in the channel (1) of the device；Observation administration after by
Examination buck is present in the time in the channel where stimulation animal, is calculated as the time 2；
(4) compare time 1 and time 2, if the time 2 is significantly higher than the time 1, which is to prevent, alleviate or control
Treat the potential drug of Social behaviors obstacle.
In a preference, the stimulation animal is jenny or buck.
In another preferred example, further include carrying out the experiment of animal background preference before step (2)；Preferably, the experiment
Including：Subject male animal is positioned in the device of three arm Y shapes of (1), makes it movable at an arbitrary position, observes whether it has
Zone of action preference determines that animal subject does not have zone of action preference.
It is in another preferred example, described that be significantly higher than be high by 5%；It is more preferably high by 10%；It is further more preferably high by 20%.
In another preferred example, the animal subject is mouse.
In another preferred example, the subject male animal is the buck that hypergamasis occurs；Preferably, mating
10~50 minutes afterwards, subject male animal is placed in the device of three arm Y shapes and is tested.
In another aspect of this invention, a kind of device of three arms Y shape is provided, there are three mutually for the device of the three arms Y shape
Channel (1), (2), (3) of connection, it is movable wherein can to accommodate experimental animal；Wherein, in channel (1), (2), door is respectively set
(11), (21), the closed area of door cage similar with the end in channel composition, the door is visual.
In another aspect of this invention, the purposes that the device of the three arm Y shapes is provided, for screen prevent, alleviate or
Treat the drug of Social behaviors obstacle；Preferably, the Social behaviors obstacle is：It is social insensitive after ejaculation.
The other aspects of the present invention are apparent to those skilled in the art due to this disclosure
's.
Description of the drawings
Fig. 1, measure mouse social activity preference three arm Y shapes device.
A, the structural schematic diagram of the device of three arm Y shapes.Wherein, 1,2,3 be three interconnected channels；11,21 is can
The door unlatched and closed.
B, using mouse as experimental animal, the social preference of the device to test mouse of three arm Y shapes is utilized.
Male mouse is decreased obviously the social preference of female mice after Fig. 2, ejaculation.Wherein, the upper figures of Fig. 2 are the signal of experiment process
Figure；Fig. 2 figure below is the column diagram of test result.F1 groups are to carry out the preference ratio female/blank of preference experiment for the first time,
F2 groups are second of preference ratio female/blank for carrying out preference experiment；DB is blank control group.
Male mouse is decreased obviously the social preference of male mouse after Fig. 3, ejaculation.Wherein, the upper figures of Fig. 3 are the signal of experiment process
Figure；Fig. 3 figure below is the column diagram of test result.M1 groups are to carry out the preference ratio female/blank of preference experiment for the first time,
M2 groups are second of preference ratio female/blank for carrying out preference experiment；DB is blank control group.
Male mouse is constant to cheese's piece preference after Fig. 4, ejaculation.Wherein, Fig. 4 left figures are the artwork of cheese's piece embedded experiment；It is right
Figure is the column diagram of the test result of control group collection mating ejaculation group.
Fig. 5, intraperitoneal injection various concentration naloxone can not save social activity caused by ejaculation and not answer.Wherein, F1 groups are the
Primary preference ratio female/blank, the F2 group for carrying out preference experiment is second of preference ratio for carrying out preference experiment
female/blank；DB is blank control group.
Social activity is not answered after Fig. 6, intracerebral injection β-FNA can effectively save ejaculation.Wherein, with the animal of injecting normal saline
As a contrast.F1 groups are to carry out preference ratio female/blank, the F2 group of preference experiment for the first time to carry out preference for second
The preference ratio female/blank of experiment；DB is blank control group.
Specific implementation mode
The present inventor is by mouse the study found that male mice enters Social behaviors refractory period, table in post-coitum
It is now insensitive to the social sexual stimulus of previous preference.Therefore, can be changed with the Social behaviors of this post-coitum of Application mouse,
To simulate the core symptom of mankind's Social behaviors obstacle.
Establish model
Social behaviors obstacle belongs to mental disorder, such disease is more difficult to find typical cell model, animal model
More difficult foundation.Therefore, the present inventor is dedicated to finding the animal model for being suitable for studying such disease.By in-depth study point
Analysis, the inventors discovered that, male mice enters Social behaviors refractory period in post-coitum, shows as the sociability thorn to previous preference
Swash insensitive.Therefore, can be changed with the Social behaviors of this post-coitum of Application mouse, to simulate mankind's Social behaviors obstacle
Core symptom.
As used in the present invention, the Social behaviors obstacle includes：It is social insensitive after ejaculation.
The model of the drug for screening prevention, alleviating or treat Social behaviors obstacle of the present invention, includes one three
The device of arm Y shape, and the experimental animal of test can be completed in a device.Preferably, the experimental animal is mouse, it is such as small
Mouse.
Device of the present invention is the device of a three arm Y shapes, and there are three be interconnected for the device of the three arms Y shape
Three channels, it is movable wherein can to accommodate experimental animal；In two channels therein, door, the end of door and channel is respectively set
The closed area of similar cage is constituted, the door is visual, and animal outdoors can see that the animal being held in door.More
Goodly, the door is grille door or screen door (such as wire netting).When carrying out zoopery, there are the channel of door (arms)
As stimulation arm.
In a preferred embodiment of the invention, a kind of device suitable for this experimental animal of mouse is provided.This three
The length in each channel of the device of arm Y shape is about 30 centimetres, and width is about 10 centimetres, about 20 centimetres of height.Door and channel
To constitute the closed area of similar cage be about 100 square centimeters (10cm square) for end.The inventors discovered that this size
Device relatively be suitble to mouse, can allow for its in a certain range activity, do not constitute movable limitation.
Drug screening method
On the basis of the screening model of foundation, the present invention also provides a kind of screenings to prevent, alleviates or treat social row
For the method for the drug of obstacle, the method includes：
(1) device of a three arm Y shapes is provided, the device of the three arms Y shape there are three interconnected channel (1),
(2), (3) it is movable wherein can to accommodate experimental animal；In channel (1), (2), it is respectively set door (11), (21), door and channel
End constitutes closed area, and the door is visual；
(2) subject male animal is allowed to carry out mating ejaculation, be placed in the device of three arm Y shapes of (1)；The device leads to
Stimulation animal is placed in the closed area in road (1)；Subject male animal after observation administration is present in where stimulation animal
The time in channel is calculated as the time 1；
(3) drug candidate is applied to subject male animal, and subject male animal is allowed to carry out mating ejaculation, be placed on
(1) in the device of three arm Y shapes；Stimulation animal is placed in the closed area in the channel (1) of the device；Observation administration after by
Examination buck is present in the time in the channel where stimulation animal, is calculated as the time 2；
(4) compare time 1 and time 2, if the time 2 is significantly higher than the time 1, which is to prevent, alleviate or control
Treat the potential drug of Social behaviors obstacle.
Further include carrying out the experiment of animal background preference before step (2) as the preferred embodiment of the present invention；Preferably,
The experiment includes：Subject male animal is positioned in the device of three arm Y shapes of (1), makes it movable at an arbitrary position, observes it
Whether there is zone of action preference, determines that animal subject does not have zone of action preference.This method can be excluded since animal background is inclined
Experimental error caused by good.
As the preferred embodiment of the present invention, in the screening technique, the subject male animal is that hypergamasis occurs
Buck；Preferably, in post-coitum 10~50 minutes, subject male animal is placed in the device of three arm Y shapes and is surveyed
Examination.
The drug candidate can be originated from some existing protein pools or compound library.Such as selected from：Peptide, polymerization
Peptide, peptidomimetic, non-peptide compound, carbohydrate, fat, antibody or antibody fragment, ligand, organic molecule, inorganic molecules and
Nucleic acid sequence.Already exist in the art that many commercializations or non-profit-making disclosed various candidate substances libraries, usual this field
Personnel are clear how to obtain the library of this substance for screening.Also, according to the existing background knowledge in this field, mesh is carried out
Ground selection may improve the efficiency of screening.
As a preferred mode, the method further includes：Further cell is carried out to the potential substance of acquisition
Experiment and/or animal experiment are selected and are determined for prevention, alleviation or treat the useful substance of Social behaviors obstacle.
The substance that these preliminary screenings go out may make up one screening library, in order to people may finally therefrom filter out can
Useful substance is determined for preventing or treating Social behaviors obstacle.
Medicinal usage and composition
New discovery based on the present inventor, the present invention also provides the purposes of μ opioid receptors specific antagonists, are used for
The drug for preparing prevention, alleviating or treat Social behaviors obstacle.
The inventors discovered that intracerebral injection μ opioid receptors specific antagonists β-FNA can effectively reverse male small
Social behaviors obstacle after mouse mating behavior, it is the active drug for treating Social behaviors obstacle to prompt μ opioid receptors antagonists.
Exploitation can across blood-brain barrier μ opioid receptors antagonist futures can be used as treat Social behaviors obstacle nerve medicine
Object.
The μ opioid receptors specific antagonists of the present invention can be used for preparing pharmaceutical composition, and pharmaceutical carrier can be
Solid or liquid, solid pharmaceutical preparation include lyophilized preparation, powder, tablet, pill, capsule, cachet, suppository and dispersible particle
Agent, solid carrier can be one or more substances, they can be used as diluent, corrigent, binder, preservative, tablet
Disintegrant or coating material.In powder, carrier is fine point of solid, the compound of the present invention and fine point of active constituent
It is present in mixture.In tablets, this compound mixes in appropriate proportions with required bonding carrier, and is pressed into required
Shapes and sizes.In powder and tablet preferentially contain 1 to 70% reactive compound, suitable carrier be magnesium carbonate, magnesium stearate,
Talcum, sugar, lactose, pectin, dextrin, starch, gelatin, carboxymethyl cellulose, sodium carboxymethylcellulose, low melting point be cured and cocoa butter
Deng.Equally, cachet or pastille, tablet, powder, capsule, pill, cachet and pastille can be suitable for consolidating for oral medication
Body dosage form.
The μ opioid receptors specific antagonists of the present invention can be prepared into unit dose formulations.In unit dose formulations
The amount of active constituent can change according to the effect of specific application and active constituent, be adjusted from 0.001mg to about 1g.Example
Such as, in medical usage, which can be with 0.01 to about 50mg capsule daily administration three times, and the composition can be with when necessary
Containing other compatible therapeutic agents.
In therapeutical uses, for the compound of the present invention with the daily 0.00001mg of initial dose to 10mg/kg weight.
But these dosage can change according to the needs of patient, the seriousness of condition being treated and the compound that uses, generally
For, start, to treat less than the smaller dose of the compound optimal dose, hereafter, to increase this dosage in a small amount and reach best effective
Total daily dose can be sub-divided into divided doses in one day by fruit if necessary for the sake of convenient.
The pharmaceutical composition of the present invention can also be used in combination with other therapeutic agents or adjuvant simultaneously.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part such as J. Pehanorm Brookers etc. is write, Molecular Cloning:A Laboratory guide, the third edition, Science Press, the condition described in 2002, or
According to the normal condition proposed by manufacturer.
Embodiment 1, the device for measuring mouse social activity hobby
1, device
The present inventor prepares the device of a three arm Y shapes, as shown in Figure 1A using mouse as experimental animal.
It is movable wherein can to accommodate mouse there are three interconnected channel 1,2,3 for the device of the three arms Y shape.
In channel 1,2, the door 11,21 that can be unlatched and closed is respectively set, the form design of door is closed for upper semisection, lower half
Section (i.e. mouse can be with range section) is stainless steel fence, and column spacing is 8mm.Mouse can be positioned over to the blind end in channel 1,2, when
When door 11 or 21 is closed, the closed area of door cage similar with the end in channel composition so that including mouse is kept in detention；Described
Door is visual, and the animal in region can see that the animal of an inner region outdoors.When carrying out zoopery, there are doors 11 or 21
The channel (arm) 1,2 at place is as stimulation arm.
The length in each channel of the device of the three arms Y shape is about 30 centimetres, and width is about 10 centimetres, about 20 lis of height
Rice.The closed area of door cage similar with the end in channel composition is about 100 square centimeters (10cm square).
2, the applicability of device is investigated
The present inventor with mouse (Mouse, 6-7 weeks big, is purchased from Ling Chang companies) it is experimental animal, allow the hero of wild type
Property mouse (experiment male mouse) free movement 6 minutes in three arm Y type devices；Observe three arms of the male mice during finding this
Each region in the device of Y shape does not have preference.Later, it proceeds as follows：
A, such as Figure 1B are placed on a thorn of three arm Y type devices using the female mice of wild type as social stimulation animal
Swash in the closed area that the door in arm is constituted with channel end.Statistical experiment hero mouse is in stimulation time for being waited for of arm and non-stimulated
The time that arm is waited for.And obtain a preference ratio using stimulation arm activity time divided by non-stimulated arm activity time.As a result
It has been shown that, male mouse preference are significantly more than other in the stimulation arm region activity that there is stimulation animal in the activity time of the stimulation arm
Region.
B is placed on the male mice of wild type as social stimulation animal in a stimulation arm of three arm Y type devices
In the closed area that door is constituted with channel end.The time and non-stimulated arm that statistical experiment hero mouse is waited in stimulation arm are waited for
Time.And obtain a preference ratio using stimulation arm time divided by non-stimulated arm time.The results show that male mouse preference is being deposited
In the stimulation arm region activity of stimulation animal, other regions are significantly more than in the activity time of the stimulation arm.
Wherein, position 1 is the zone of action in the presence of the arm of stimulation animal；Position 2 is that there is no the work of the arm of stimulation animal
Dynamic region.
By result as it can be seen that the device of three arm Y shapes can reflect the social preference of male mice well.
Embodiment 2, human communication disorders animal model foundation and the male mice state after ejaculation analysis
1, using female mice as the test of stimulation animal
The present inventor establishes the animal model of social refractory period by male mouse mating behavior.Described in Application Example 1
The device of three arm Y shapes.Hereinafter, " cage " is the abbreviation of the closed area of door cage similar with the end in channel composition.
First, non-stimulated, the i.e. background of hero mouse when bilateral blank (Double Blank, DB) was measured at first day
Preference.It stimulates arm not place stimulation animal at two and allows male mouse activity 6min in the device of three arm Y shapes, as a result, it has been found that, hero
Mouse stimulates movable preference ratio approach in arm at two, without significant difference.
At second day of experiment, first carries out primary male mouse and the preference of female mice is tested, the social activity as tested male mouse is partially
Good background, is denoted as F1 (Female test 1).Between dark place, mouse preferentially adapts to the environment 1 hour.Arm is stimulated at one
Female mice is randomly placed in cage, the male mouse of experiment is put into, movable 6min；As a result, it has been found that male mouse stimulates the activity of arm where female mice
Time is significantly more than other regions.Illustrate that male mouse is strong for the background preference of female mice.Then, the present inventor will test male mouse and be divided into
Two groups：
1 (control group) of group：It is placed in mouse cage (non-Y types device) and does not handle as a control group,
2 (test groups) of group：Mating behavior is carried out in mouse cage (non-Y types device).
After post-coitum 30 minutes, the present inventor carries out the preference test of female mice by male mouse is tested again, is denoted as F2
(Female test 2)：The test environment is as F1, and animal configurations are as F1, activity time 6min.As a result, it has been found that male
Mouse stimulates the activity time of arm considerably less than F1 where female mice, illustrates that the social preference in post-coitum hero mouse is remarkably decreased.
Count preference ratio the results show that when experiment mice is there is no mating process, or mating does not proceed to ejaculation
State (Non-ejaculation groups), the preference ratio of F2 have no the difference of conspicuousness compared with F1.And it mates and ejaculates in male mice
After (Ejaculation groups), the preference conspicuousness of F2 is less than F1, in addition with the no marked difference of DB groups, such as Fig. 2.
2, using male mouse as the test of stimulation animal
Test method only difference is that the stimulation animal in F1 and F2 tests replacing with male mouse by female mice with aforementioned 1.
F1 (Female test 1) above-mentioned is replaced with M1 (Male test 1), and F2 (Female test 2) above-mentioned is with M2
(Male test 2) replaces.
Count result such as Fig. 3 of preference ratio.The results show that male mouse also shows the social preference of other male mouse after ejaculation
Work property reduces.
The above results illustrate that the male mice after ejaculation is in an insensitive state of social preference.
Embodiment 3, analysis male mice state after ejaculation：Buried cheese's piece experiment
In order to further study male mice state after ejaculation, the present inventor, which introduces, explores buried cheese's piece experiment,
Mouse behavioral study is carried out using cheese's piece of mouse preference.
In the mouse cage of a new not food pollution, cheese's piece is embedded in mouse cage bedding and padding (commercially available corn stalk
Stalk compressed after smashing made of mat material) below, observation male mice changes the preference of cheese's piece.
The male mouse of experiment is divided into two groups：
1 (control group) of group：In mouse cage, do not mate as a control group；After move into new mouse cage, an area of the new mouse cage
Cheese's piece is placed under the bedding and padding in domain；
2 (test groups) of group：Mating behavior is carried out in mouse cage；After move into new mouse cage, a region of the new mouse cage
Cheese's piece is placed under bedding and padding.
Male mouse, which is organized, in 9 minutes after the new mouse cage of statistics immigration, after control group hero mouse and ejaculation buries region institute in cheese's piece
The time of consumption, finding the two, there is no apparent difference, such as Fig. 4.
The above results show preference of the male mouse there is no missing to food after ejaculation, and have only been missing to of the same race small
The preference of mouse social activity.One of the important behavior characterization of many complexity the nervous system disease such as self-closing diseases and anxiety etc. is exactly social row
It is the latent of research human communication disorders that for obstacle or missing, therefore after ejaculating, male mouse, which significantly reduces the social preference of female mice,
In animal model.
Embodiment 4, drug effectiveness research
Judge drug for social insensitive influence situation after male mice ejaculation by male mouse mating behavior.Using reality
Device, the test method progress drug efficacy study with reference to embodiment 2 for applying three arm Y shapes described in example 1.
(1) dopamine study on the efficiency
The present inventor will test male mouse and be divided into two groups：
1 (control group) of group：Physiological saline is given, preference test is carried out in the device of three arm Y shapes.
2 (test groups) of group：The apomorphine intraperitoneal injections of dopamine-receptor stimulant A Pu morphines are given, DOPA is adjusted
Amine level；Preference test is carried out in the device of three arm Y shapes.
The results show that there was no significant difference for the social preference of 2 mouse of group 1 and group, dopamine level has no effect on male mouse
Social preference.
(2) serotonin study on the efficiency
The present inventor will test male mouse and be divided into two groups：
1 (control group) of group：Physiological saline is given, preference test is carried out in the device of three arm Y shapes.
2 (test groups) of group：Giving pcpa, either containing for serotonin can be lowered or be raised to both drugs of 5HTP (
Amount) intraperitoneal injection, preference test is carried out in the device of three arm Y shapes.
The results show that there was no significant difference for the social preference of 2 mouse of group 1 and group, serotonin level has no effect on male mouse
Social preference.
(3) stosterone study on the efficiency
The present inventor will test male mouse and be divided into two groups：
1 (control group) of group：The male mouse for carrying out false castration operation, carries out preference test in the device of three arm Y shapes.
2 (test groups) of group：Carry out castration operation male mouse, to testosterone levels decline, in the device of three arm Y shapes into
Row preference is tested.
The results show that there was no significant difference for the social preference of 2 mouse of group 1 and group, testosterone levels have no effect on male mouse
Social preference.
(4) morphine study on the efficiency
The present inventor will test male mouse and be divided into two groups：
1 (control group) of group：Physiological saline is given, preference test is carried out in the device of three arm Y shapes.
2 (test groups) of group：Morphine intraperitoneal injection is given, preference test is carried out in the device of three arm Y shapes.
The results show that test group is remarkably decreased the social Preference of female mice and male mouse, injection of morphia can cause to influence
The social preference of male mouse declines.
As a result, it has been found that the morphine of 8mg/kg weight is injected intraperitoneally to male mice, male mouse can be made for the preference of female mice
The decline of conspicuousness.Morphinoid drug is a kind of common drugs for nervous, it mainly acts on the crow of central nervous system
Piece receptor system.
(5) Allylnoroxymorphone (naloxone) study on the efficiency
Allylnoroxymorphone (naloxone) is a kind of opioid receptors non-specific antagonist, studies it for ejaculation Hou Xiong mouse society
Hand over the adjustment effect of preference.
The present inventor will test male mouse and be divided into two groups：
1 (control group) of group：Give physiological saline；
2 (test groups) of group：Give Allylnoroxymorphone intraperitoneal injection.
Test method gives physiological saline or Allylnoroxymorphone injection with reference to embodiment 2 before testing on day 2.
The results are shown in Figure 5, it is found that opioid receptors non-specific antagonist Allylnoroxymorphone can't influence to hand over to conspicuousness
With behavior, social insensitive state after ejaculation will not be restored.
Simultaneously, it was also found that the Allylnoroxymorphone of intraperitoneal injection 10mg/kg then largely reduces completion of the male mouse mating to ejaculation
Probability.
(6) μ opioid receptors specific antagonists β-FNA study on the efficiency
Drug is injected directly into the ventricles of the brain of mouse (site by experimental animal using the method for intracerebral heeling-in casing:x
1.000y-0.150z-1.800)。
Reagent β-FNA (CAS number：TOCRIS companies 72786-10-8) are purchased from, molecular weight 518.01,10mg are made into
The storing liquid of 20mM and packing.The use of a concentration of 50nM injection total amounts is 200ul.
Have chosen μ opioid receptors specific antagonists β-FNA.The present inventor uses physiological saline as the control of β-FNA
Group.
The present inventor will test male mouse (Mouse, 6-7 weeks big) it is divided into two groups：
1 (control group) of group：Give physiological saline；
2 (test groups) of group：Give β-Funaltrexamine (β-FNA) intracerebroventricular, injection volume 50nmol/200ul.
For test method with reference to embodiment 2, injection enters test in 24 hours after giving physiological saline or β-FNA.
As a result, it has been found that the means being administered by the ventricles of the brain, β-FNA can effectively reverse the society after male mice mating behavior
Behavior disorder is handed over, it is the active drug for treating Social behaviors obstacle, such as Fig. 6 to prompt μ opioid receptors antagonists.
In different times, present inventor has performed multiple batches of animal experiment, the result of acquisition proves that β-FNA can be with
Effectively reverse the Social behaviors obstacle after male mice mating behavior.
Discussion of results：
According to the above results, the morphine intraperitoneal injection of mice of 8mg/kg weight can be such that its social preference declines.General significance
On think, μ opioid receptors specific antagonists are exactly β-FNA.After β-FNA can effectively reverse male mice mating behavior
Social behaviors obstacle.
Opiate receptors have many partings, however, the present inventor uses wide spectrum receptor antagonist naloxone (naloxone),
Do not have consistent with β-FNA as a result, but consistent with physiological saline group.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To be made various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (11)
1. the purposes of μ opioid receptors specific antagonists is used to prepare prevention, alleviation or the medicine for treating Social behaviors obstacle
Object.
2. purposes as described in claim 1, which is characterized in that the μ opioid receptors specific antagonists include：β-
FNA。
3. purposes as described in claim 1, which is characterized in that the Social behaviors obstacle is：It is social insensitive after ejaculation.
4. a kind of method of screening prevention, the drug alleviated or treat Social behaviors obstacle, which is characterized in that the method packet
It includes：
(1) device of a three arm Y shapes is provided, the device of the three arms Y shape there are three interconnected channel (1), (2),
(3), can to accommodate experimental animal movable wherein；In channel (1), (2), door (11), (21), the end of door and channel is respectively set
Closed area is constituted, the door is visual；
(2) subject male animal is allowed to carry out mating ejaculation, be placed in the device of three arm Y shapes of (1)；The channel of the device
(1) stimulation animal is placed in closed area；Subject male animal after observation administration is present in logical where stimulating animal
The time in road is calculated as the time 1；
(3) drug candidate is applied to subject male animal, and subject male animal is allowed to carry out mating ejaculation, be placed on (1)
In the device of three arm Y shapes；Stimulation animal is placed in the closed area in the channel (1) of the device；Tested hero after observation administration
Property animal be present in stimulation animal where channel time, be calculated as the time 2；
(4) compare time 1 and time 2, if the time 2 is significantly higher than the time 1, which is to prevent, alleviate or treat society
Hand over the potential drug of behavior disorder.
5. method as claimed in claim 4, which is characterized in that further include carrying out animal background preference reality before step (2)
It tests；Preferably, the experiment includes：Subject male animal is positioned in the device of three arm Y shapes of (1), allow its at an arbitrary position
Activity, observes whether it has zone of action preference, determines that animal subject does not have zone of action preference.
6. method as claimed in claim 4, which is characterized in that the stimulation animal is jenny or buck.
7. method as claimed in claim 4, which is characterized in that described being significantly higher than is high by 5%；It is more preferably high by 10%；Into
One step is more preferably high by 20%.
8. method as claimed in claim 4, which is characterized in that the animal subject is mouse.
9. method as claimed in claim 4, which is characterized in that the subject male animal is that the male of generation hypergamasis is dynamic
Object；Preferably, in post-coitum 10~50 minutes, subject male animal is placed in the device of three arm Y shapes and is tested.
10. a kind of device of three arms Y shape, which is characterized in that the device of the three arms Y shape there are three interconnected channel (1),
(2), (3) it is movable wherein can to accommodate experimental animal；
Wherein, in channel (1), (2), door (11), (21), the enclosed area of door cage similar with the end in channel composition is respectively set
Domain, the door are visual.
11. the purposes of the device of three arms Y shape according to any one of claims 10, which is characterized in that prevent, alleviate or treat for screening
The drug of Social behaviors obstacle；Preferably, the Social behaviors obstacle is：It is social insensitive after ejaculation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710182297.1A CN108619517B (en) | 2017-03-24 | 2017-03-24 | Establishment of model simulating human social behavior disorder and medicine for treating social behavior disorder |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710182297.1A CN108619517B (en) | 2017-03-24 | 2017-03-24 | Establishment of model simulating human social behavior disorder and medicine for treating social behavior disorder |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108619517A true CN108619517A (en) | 2018-10-09 |
| CN108619517B CN108619517B (en) | 2021-08-06 |
Family
ID=63707746
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710182297.1A Active CN108619517B (en) | 2017-03-24 | 2017-03-24 | Establishment of model simulating human social behavior disorder and medicine for treating social behavior disorder |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108619517B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN201235002Y (en) * | 2008-08-11 | 2009-05-13 | 严维辉 | Water maze for testing chemical signal selective action of aquatic animal |
| WO2011145062A1 (en) * | 2010-05-21 | 2011-11-24 | Link Research & Grants Corporation | Treatment of tinnitus and related auditory dysfunctions |
-
2017
- 2017-03-24 CN CN201710182297.1A patent/CN108619517B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN201235002Y (en) * | 2008-08-11 | 2009-05-13 | 严维辉 | Water maze for testing chemical signal selective action of aquatic animal |
| WO2011145062A1 (en) * | 2010-05-21 | 2011-11-24 | Link Research & Grants Corporation | Treatment of tinnitus and related auditory dysfunctions |
Non-Patent Citations (3)
| Title |
|---|
| DT HSU,ET AL: "It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder", 《MOLECULAR PSYCHIATRY》 * |
| H.KOMATSU，ET AL: "Decreased response to social defeat stress in μ-opioid-receptor knockout mice", 《PHARMACOLOGY, BIOCHEMISTRY AND BEHAVIOR》 * |
| S.A.LAREDO，ET AL: "Effects of defeat stress on behavioral flexibility in males and females: modulation by the mu-opioid receptor", 《EUROPEAN JOURNAL OF NEUROSCIENCE》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108619517B (en) | 2021-08-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Brock et al. | Opioid-induced bowel dysfunction: pathophysiology and management | |
| Fields et al. | Toward a neurobiology of placebo analgesia | |
| Hutchinson et al. | Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences | |
| Kerstman et al. | Neuropathic pain | |
| Kivell et al. | Kappa opioids and the modulation of pain | |
| Lewanowitsch et al. | Reversal of morphine, methadone and heroin induced effects in mice by naloxone methiodide | |
| Sánchez et al. | Contributions of peripheral and central opioid receptors to antinociception in rat muscle pain models | |
| Behnood-Rod et al. | Evaluation of the rewarding effects of mitragynine and 7‐hydroxymitragynine in an intracranial self-stimulation procedure in male and female rats | |
| US9956232B2 (en) | Dialkyl-phosphinoyl-alkane (Dapa) compounds and compositions for treatment of lower gastrointestinal tract disorders | |
| Yoo et al. | Analgesic mechanism of electroacupuncture in an arthritic pain model of rats: a neurotransmitter study | |
| Yeung et al. | Effect on the nociceptive threshold and EEG activity in the rat of morphine injected into the medial thalamus and the periaqueductal gray | |
| Wang et al. | Effect of morphine and pregabalin compared with diphenhydramine hydrochloride and placebo on hyperalgesia and allodynia induced by intradermal capsaicin in healthy male subjects | |
| Hu et al. | Characterization of opioidergic mechanisms related to the anti-migraine effect of vagus nerve stimulation | |
| Khatri et al. | Xylazine suppresses fentanyl consumption during self-administration and induces a unique sex-specific withdrawal syndrome that is not altered by naloxone in rats. | |
| Hermansen et al. | The analgesic effect of buprenorphine, etorphine and pethidine in the pig: a randomized double blind cross‐over study | |
| CN108619517A (en) | It simulates the foundation of the model of mankind's Social behaviors obstacle and treats the drug of Social behaviors obstacle | |
| Levionnois et al. | Colon constipation in horses after sustained-release buprenorphine administration | |
| Dailey et al. | The Influence of opioids on transcutaneous electrical nerve stimulation effects in women with fibromyalgia | |
| CN112569237B (en) | Application of combination or compound of imatinib and derivatives thereof and nicotine or analogues thereof in preventing and treating nicotine addiction and relapse | |
| Malek et al. | The therapeutic effect of adding dextromethorphan to clonidine for reducing symptoms of opioid withdrawal: a randomized clinical trial | |
| Wilsey et al. | Sustained analgesic effect of clonidine co-polymer depot in a porcine incisional pain model | |
| Larsson et al. | Involvement of κ‐opioid receptors in visceral nociception in mice | |
| Maney et al. | Morphine in donkeys: Antinociceptive effect and preliminary pharmacokinetics | |
| CN107531670B (en) | Diarylmethylidene piperidine derivatives and their use as opioid receptor agonists | |
| Kuroda et al. | Effects of narcotics, including morphine, on visual evoked potential in rats |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20200609 Address after: 200031 No. 320, Yueyang Road, Shanghai, Xuhui District Applicant after: Center for excellence and innovation of brain science and intelligent technology, Chinese Academy of Sciences Address before: 200031, 319 Yueyang Road, Shanghai, Shanghai, Xuhui District Applicant before: SHANGHAI INSTITUTES FOR BIOLOGICAL SCIENCES, CHINESE ACADEMY OF SCIENCES |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |