CN105920034A - Application of lithium chloride to preparation of methamphetamine cognitive disorder medicament - Google Patents
Application of lithium chloride to preparation of methamphetamine cognitive disorder medicament Download PDFInfo
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- CN105920034A CN105920034A CN201610368414.9A CN201610368414A CN105920034A CN 105920034 A CN105920034 A CN 105920034A CN 201610368414 A CN201610368414 A CN 201610368414A CN 105920034 A CN105920034 A CN 105920034A
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- methamphetamine
- lithium chloride
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- cognitive disorder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
Abstract
The invention relates to application of lithium chloride to preparation of a methamphetamine cognitive disorder medicament. The experiments of the invention prove that a treatment effect of the lithium chloride on the methamphetamine cognitive disorder is reflected to show that the lithium chloride can serve as a new medicament for improving methamphetamine cognitive disorder by observing that methamphetamine has an inhibit effect on learning and memory of a rat, while the lithium chloride has an obvious promoting effect on the learning and memory of a mouse which is addicted to amphetamines in a water maze test of the lithium chloride on the mouse which is addicted to methamphetamines.
Description
Technical field
The present invention relates to a kind of new application of lithium chloride, be specifically related to lithium chloride after methamphetamine to cognitive and behavior disorder
In application, belong to pharmaceutical technology field.
Background technology
Methamphetamine (METH), is commonly called as methamphetamine hydrochloride, is a kind of white amphetamine synthesis class drugs.High dose or the most anti-
Multiple user can suffer from mental sickness altogether, and including depression, manic, schizophrenia etc., severe patient causes toxic psychosis, table
It is now delusion of persecution and hallucination, excessively uses and even occur committing suiside and tendency of killing a person.Giving up period at methamphetamine hydrochloride, methamphetamine hydrochloride dependence
Person there will be insomnia, depressed, the manic and spiritual emotion changes of anxiety, and these withdrawal symptoms also become and affect methamphetamine hydrochloride
The major physiological factor (.2012 such as Wang Wei) that dependent relapses.Therefore, the principle methamphetamine hydrochloride to be paid close attention to of methamphetamine treatment
Dependent relapses, methamphetamine hydrochloride to be paid close attention to methamphetamine hydrochloride dependent at cognition, behavior, mental disorder and the shadow to quality of life thereof
Ring.
Cognitive function refers to that people skillfully use the ability of knowledge, including the ability of studying new knowledge knowledge with from abundant knowledge base
Recollect the ability of knowledge, such as the similarity between computing capability, abstract summarization, judgement things and difference and analysis and
Use the ability etc. of knowledge.The incidence rate of methamphetamine Patients ' Cognitive infringement is 30%～40%, affects methamphetamine
The factor of Patients ' Cognitive obstacle includes age of onset, lesions position, frequency of disease development, persistent period and seizure types, medicine
Impact, the impact of operation, the impact etc. of socio-psychological factors, wherein the impact of methamphetamine itself is most important.At present
The precise mechanism that cognitive disorder occurs in methamphetamine patient is the most fully aware of, may be with cerebral cortex abnormal development and prominent
Touching textural anomaly to be correlated with, such as schizophrenia and prefrontal cortex abnormal development have close association, it addition, Alzheimer
There are obvious brain atrophy and glia proliferation.And these diseases all refer to glycogen synthetase (glycogen synthase
Kinase 3 β, is abbreviated as GSK-3 β) activity change, wherein GSK-3 β is generally stored in brain district, such as amygdaloid body, volt
Every core and Hippocampus (Woodgett 1990；Leroy and Brion 1999), and these are dopamine key projection area (Robbins
et al.2008).The GSK-3 β abundant expression in brain district implys that it has consequence central nervous system, and
GSK-3 β has been proved to involve multiple brain district disease, including alzheimer's disease, (Pei et al., 1999,
DaRocha-Souto et al., 2012, Ly et al., 2013), schizophrenia (Kozlovsky et al., 2000, Emamian et al.,
2004, Freyberg et al., 2010), Progressive symmetric erythrokeratodermia neuropsychiatric disease (Willi et al., 2013), major depression (Saus et al.,
2010, Diniz et al., 2011), and manic type is depressed (Nishiguchi et al., 2006, Benedetti et al., 2013).Many
Individual evidence support GSK-3 β would is that treatment Central Nervous System Diseases important target spot (Mathew et al., 2008, Li and Jope, 2010,
Maes et al.,2012)。
Having research display GSK-3 β by monoamines oxide, such as dopamine, glutamic acid and serotonin, enter behavior
Row regulation (Li and Gao, 2011, Beaulieu, 2012, Zhu wang et al.2012).Owing to dopamine is extremely in brain district
Important neurotransmitter, makes GSK-3 β come into one's own in addiction field.Lithium chloride (lithium) is a kind of band metallic element lithium (Li)
Compound.On the one hand: lithium chloride was applied to clinical treatment manic (Cade, 1949) first by Cade in 1949.With
Rear research finds that lithium chloride can reduce suicide risk (the Can et of two-way affective disorder (BD) patient and severe depression patient
al.,2014；Cipriani et al.,2013b；Foster, 2013), it becomes as treatment BD and irreplaceable the facing of its recurrence of prevention
Bed medicine (Kovacsics et al., 2009；Muller-Oerlinghausen et al.,2003).Its molecular mechanism is that lithium chloride can
Increased the expression of ARNTL by suppression GSK-3 β, thus intervene the physiology circulation of body so that big brain-capacity is more
Reorientate in the case of Zi Ran self function (Yin et al., 2006；Ramadhan Oruch et al.,2014).
But at present lithium chloride clinic is mainly used in the treatment the most manic to psychosis, and the research in addiction field with
Applying the fewest, lithium chloride is on report the most not relevant on the impact of cognitive behavior after methamphetamine hydrochloride addiction.
Summary of the invention
One to be solved by this invention technical problem is that the present situation for prior art provides a kind of lithium chloride preparing methyl
Application in amfetamine cognitive disorder medicine.
The present invention solves the technical scheme that above-mentioned technical problem used: methamphetamine cognitive disorder medicine prepared by lithium chloride
Application in thing.
Further, the effective dose of described lithium chloride is 3-127mg/kg/d.
As preferably, the effective dose of described lithium chloride is 100mg/kg/d.
The experiment proves that: in the experiment in lithium chloride p-Methylamphetamine class addiction mice addiction stage, by observing chlorine
Change lithium and Methamphetamine award motivation can be played inhibitory action, and the Learning and Memory to amphetamine addiction mice
Obvious facilitation, reflection lithium chloride is had to have therapeutic effect in the methamphetamine addiction stage, illustrate that lithium chloride can be used for
Give up the addiction of methamphetamine, using exploitation as new anti-additive medicament.
Accompanying drawing explanation
(wherein, active poke is effective to Fig. 1: Methamphetamine group with normal saline group intravenous self administration result figure
Nose touches number, and infusion is entry needle number, and inactive poke is that invalid nose touches number)；
The result figure that five Ge Nao district GSK-3 β are expressed by Fig. 2: Methamphetamine self administration；
Fig. 3: lithium chloride intraperitoneal administration in treated rats in Morris water maze performance orientation navigation experiment escape latency affect result figure；
GSK-3 β in explorative experiment Ge Nao district, space in treated rats in Morris water maze performance is expressed by Fig. 4: lithium chloride intraperitoneal administration
Result figure.
Detailed description of the invention
Below by way of combining drawings and Examples, the invention will be further described
The methamphetamine used in the embodiment of the present invention is standard substance, from Ningbo Micro Circulation and Henbanes Medicine Inst.,
Use intravenous administration mode；Lithium chloride comes from Selleck company of the U.S., is dissolved in dimethyl sulfoxide (DMSO), and uses
Intraperitoneal administration.
The foundation of embodiment 1 methamphetamine intravenous self administration model
Intravenous self administration (Intravenous Drug Self-Administration) is the animal mould that drugs addiction is the most classical
One of type, intravenous self administration model is the classical animal model that reflection medication person actively looks for medicine and drug taking behavior, it is possible to use
Laboratory animal is investigated and is administered motivation and actively compulsive drug use behavior.
Classical Methamphetamine methamphetamine self administration model can well simulate drug addict clinically
Behavior sucked by methamphetamine, and rat can produce the automedication of p-Methylamphetamine through training, simultaneously during training
With dosage, the behavior reaction rate of the p-Methylamphetamine constantly risen can reflect that drug addict contacts methylbenzene from the beginning
Propylamine is to the such a process sucking methamphetamine addiction in a large number.
We adopt the self administration model setting up rat with the following method:
First, SD rat carries out jugular vein and intubates operation, inserts one section of PE pipe at right jugular vein, and passes through back external,
Post operation is antibacterial and recovers more than one week.Subsequently, rat is trained respectively in self administration operation cage, every time before training
The PE pipe of connection rat back and the methamphetamine injecting systems in operation cage；Two the nose tentaculums in left and right are set in operation cage,
One of them is effective nose tentaculum, and rat touches nose effectively nose tentaculum once will obtain a pin methamphetamine injection, operate simultaneously
Cage lamp in cage lights (as a kind of clue accompanying medicine), computer recording；Another one is invalid nose tentaculum, and rat touches nose
The most invalid nose tentaculum does not has the injection of any methamphetamine and light, only computer recording.It is injected by twice methamphetamine
Between have the refractory stage of 20 seconds, period to touch nose effective nose tentaculum will not to have methamphetamine injection and light, only computer note
Record, the methamphetamine entry needle number of every day is limited to 50 pins (preventing excess injection death).32 operation cages use large-scale clothes
The computer of business device controls simultaneously, and self administration training software is the AniLabV652 independently write, and training program is fixing ratio
The FR1 of rate, i.e. rat touch nose once effectively nose tentaculum and obtain a pin methamphetamine injection.Rat through 3 days, every day 4
Hour training after, effectively touch rhinoreaction rate and injection volume the most substantially rise, tend towards stability in few days after, thus define
Stable methamphetamine addiction state.
A, method: rat is carried out jugular vein and intubates operation, recover 3 days afterwards.After recovery, start self administration, be divided into
Two groups, i.e. methamphetamine group and normal saline group, often 6 mouse of group.First three sky is to be administered training period, and this stage allows
Mouse association.Continuous administered for fourteen days after association.
A) methamphetamine group: preparation solubility is the methamphetamine of 0.12mg/ml, according to 0.05mg/kg/infusion agent
Amount is administered.
B) normal saline group: this group is matched group, directly substitutes methamphetamine with normal saline and is administered.
It will be seen from figure 1 that administration number of times methamphetamine group is significantly higher than normal saline group, and maintain on certain level,
Methamphetamine group addiction is described, and self administration model has built up.
It will be seen from figure 1 that effective nose tactile (Active poke) is significantly higher than invalid nose touches (Inactive poke), self is described
Administration model is successfully established, and the number of effective nose tactile (Active poke) and administration number of times (infusion) have different, and it is former
Because being that effective nose touches the effective refractory period of 20s, so effective nose touches number has certain difference with administration number of times, can neglect
Slightly.
Embodiment 2 cognitive function detects
The foundation of 2.1 determined with Morris water models
Using Morris water maze as the detection model of rat Spatial memory.Morris water maze video analytic system is examined
The Spatial memory ECT surveying rat disposes beginning Morris determined with Morris water in end 24h.Morris water maze is by all
It is divided into I, II, III, IV 4 quadrants.Contain tap water in water maze, add prepared Chinese ink muddy, before detection, platform is placed in as
Limit underwater 2cm.All experiments are carried out at 9:00am～3:00pm, and indoor quiet, article are placed and light status one
Cause, water temperature (24 ± 1) DEG C.Morris1.0 software track record analysis related data.
(1) orientation navigation test: the 1st～6 day row orientation navigation experiment: the most respectively from I, II, III, IV
Rat is put in water towards pool wall by 4 quadrants, observes and timing 120s, and platform is placed in before detection the I quadrant center water surface
Lower 2cm.It is escape latency (escape latency, EL) that camera system record rat finds and climb up the time of platform, if
Also not finding platform in 120s, then direct it to platform, stop 30s, escape latency is designated as 120s.Detection terminate after with
The meansigma methods of the 1st～6 day escape latency is as school grade, and the shortest display learning capacity is the best.
(2) space exploration test: the 7th day spatial row explorative experiment: remove platform, by rat from away from farthest III quadrant of original platform
Putting in water towards pool wall, camera system record rat all quadrants swimming time in 60s, with original platform quadrant I quadrant
The swimming time i.e. space exploration time, (space exploration time, SET) was as Memory result, the longest display memory ability
The best.
2.2 statistical analysis
Experimental data all represents with X ± S, and application spss 13.0 statistical software carries out statistical analysis.Enumeration data uses
Mann-Whitney U checks, and compares employing one factor analysis of variance and least significant difference (LSD) inspection between continuous data group
Test.Statistically significant with P < 0.05 for difference.
The impact of 2.3 lithium chloride p-Methylamphetamine learning and memory in rats abilities
2.3.1Morris water maze orientation navigation experiment orientation navigation experiment lasts 6d, along with increasing of frequency of training, respectively
Group rat escape latency all has shortening in various degree, compares with matched group, and methamphetamine group escape latency is substantially prolonged
Long (P < 0.05), lithium chloride process group relatively methamphetamine group escape latency substantially shortens (P < 0.05), and at lithium chloride
In reason group, its escape latency of various dose is the most different, wherein, 100mg/kg/d and matched group closest to, at the Ith quadrant
Swimming distance accounts for the percentage ratio of total distance and spanning platform number of times the most relatively methamphetamine group significantly reduces (P < 0.01) effect
Significantly, high dose group 127mg/kg/d is close with the effect of low dose group 3mg/kg/d, accounts for always in the Ith quadrant swim distance
Percentage ratio and the spanning platform number of times the most relatively methamphetamine group of distance do not significantly reduce, and are specifically shown in Table 1 and Fig. 3.
Table 1 is respectively organized rat orientation navigation experiment escape latency (second) and is compared
2.3.2Morris water maze space exploration is tested
Compare with matched group, methamphetamine group the Ith quadrant explore effective time (distance account for total distance percentage ratio and
The number of times of spanning platform) significantly shorten (P < 0.01)；Low dose group 3mg/kg/d and high dose group 127mg/kg/d are not
Having the reverse methamphetamine impact on learning and memory in rats well, low dose group 3mg/kg/d has in the exploration of the 3rd quadrant
The number of times that effect time, distance account for the percentage ratio of total distance and spanning platform is all close with methamphetamine group, high dose group
127mg/kg/d compares the effective of low dose group 3mg/kg/d, but chlorine for this dosage group of dosage group 100mg/kg/d
Change lithium group and account for the percentage ratio of total distance and spanning platform number of times is all obvious compared with methamphetamine group in the Ith quadrant swim distance
Extend (P<0.01) effect notable, close to matched group (P>0.1), be shown in Table 2.
Treated rats in Morris water maze performance space exploration Comparison of experiment results respectively organized by table 2
2, the shadow that P of Rats FC, CPu, NAc, Hip, VTA brain district GSK-3 β are expressed by methamphetamine chronic administration
Ring
After methamphetamine training terminates, row Morris water maze surveys cognitive competence, the research that this patent is rolled into a ball by following core
For explaining contacting of ability of learning and memory that rat is surveyed in cognitive competence at Morris water maze and molecular level:
A, prefrontal cortex (PFC): refer to the whole frontal cortexs beyond primary motor cortex and collateral motion cortex, play cognitive merit
The main senior brain district of energy.Its scalable working memory, attention, decision-making, execution, Impulsive, encourage, suppress control etc.
Function.Forefathers' research shows that the Impulsive selection of drug dependence may be relevant with vmPFC and dmPFC dysfunction,
Peters, Koya, et al. research prove drug dependence show Impulsive selection or reaction, compelling sex behavior (depart from purpose and
The sustained response of award) may be relevant with vmPFC dysfunction.
B, striatum (CPU): the key component of ganglion basal, including lentiform nucleus and caudatum.Voluntomotory surely
Fixed, the maintenance etc. of muscular tension, striatum to the generation of motion, start and the formation of behavioural habits has important function.Make
For entering the major avenues of approach of ganglion basal, striatum accepts the incoming of nearly all brain district and accepts to tie from thalamus and edge
The centripetal fiber of structure.Striatum multiple brain districts relevant with addiction learning and memory have and contact widely, take part in multiple with
The learning and memory process that drug dependence is relevant.
C, nucleus accumbens septi (NAc): accept prefrontal cortex, Hippocampus, corpus amygdaloideum Glutamatergic nerve incoming, research show NAc
Take part in relevant with addiction " stimulating award " study, the nerve fiber of NAc mainly terminates at its shell region, and with projection
GABA serotonergic neuron to VTA forms synaptic contact, directly participates in the motivation with drug reward and emotional activity.
D, Hippocampus (Hip): be to participate in memory and crucial brain district that emotional information processes, Hippocampus and emotion, emotion are closely related,
Rich in various neurotransmitteies and receptor, it is one of most important brain district participating in stress, is also the master easily causing stress damage
Want target organ.There are some researches show, there is a lot of phase in the relevant brain loop of drug dependence with known memory storage associated loop
Like part, enrich district by the glutamic acid of electricity irritation addiction rat model Hippocampus, strong thirsty to dependence producing drug of animal can be caused
Hope, stimulate other brain district the most invalid, further illustrate Hippocampus memory center and neural circuit thereof during addiction
Pivotal role.
E, Ventral Midbrain back-cover district (VTA): as project consciousness and emotion be correlated with cortex and limbic system dopaminergic god
Through the main source of unit, it is one of the key position of reward system, closely related with drug dependence.For VTA dopamine
Serotonergic neuron Effect study during drug dependence, is concentrated mainly on the change of synaptic plasticity during drug dependence.
F, method: 1. rat reaches stable methamphetamine addiction state through training in 14 days, and SD rat is divided into two groups,
Often group 6, respectively 3mg/kg/d, 100mg/kg/d, 127mg/kg/d of matched group, methamphetamine and lithium chloride
Group, broken end takes brain, carries out Western Blotting experiment, respectively by PFC, CPu, NAc, Hip, VTA brain district's stripping
From, be divided in clean grinding pipe is placed in the most stand-by.Each grind pipe adds grinding bead, lysate (RIPA) with
And protease inhibitor, after various reagent accurately add well, take out rapidly after being placed in grinding machine for grinding 30s and be placed on ice.5min
Latter 4 DEG C 13, it is centrifuged 15 minutes under 000g, takes its supernatant after being centrifuged, utilize the taken albumen of BCA kit measurement
Concentration, and be adjusted correspondingly making protein concentration keep consistent as far as possible.The albumen of 5x is added subsequently in often pipe supernatant
Buffer 35 μ l is also placed in boiling water bath cooling after 10min and is placed in the most stand-by.
2. electrophoresis, by the sample after above-mentioned water-bath, carries out PAGE gel electrophoresis, and 3 multiple holes are done in each brain district.
3. transferring film, transferring film liquid wants pre-cooling NC film pretreatment to be balanced 10 to 15 minutes because transferring film liquid is containing formaldehyde, and
The first albumen that handbag has can cause the pollution of film, so clean glove must be brought.Notice that sponge to be sufficiently humidified so as to, bubble
Drive away clean, clip is opened and makes black one side holding level, pad a foam-rubber cushion above, roll back and forth with glass rod several times
To roll away the bubble of the inside.Sponge cushion pads the most fixing filter paper proficiency glass rod of three metafiltration paper and rolls gas therein
Bubble, wants transferring film otherwise albumen at once to spread and causes band to change and then affect experimental result after stopping running glue.Dividing
From glue with concentrate and draw a line between glue, pushing concentration glue aside and it removed gently, NC membrane cover on separation gel also
And alignment adds a little transferring film liquid, film is made to be maintained in moistening state, can not be with bubble under film.
4. immunoreation, puts in box by the above-mentioned film made, will be such as confining liquid (generally defatted milk powder), and it is little that room temperature closes 2
Time or 4 DEG C overnight.After closing completes, removing confining liquid, add one and resist overnight (or room temperature 5h), anti-hatching is over
After, reclaim one and resist and use the TBST of 1X to clean 3 each 5min, add two and resist, lucifuge 2h.After lucifuge terminates, return
Receive two to resist, and clean after 3 times with 1X TBS cleaning 1 time with 1X TBST.
5. develop the color, after above-mentioned steps completes, film is placed on instrument and develops the color, and carry out observation and the gray scale of protein band
The mensuration of value.
6. result: from figure 2 it can be seen that methamphetamine group is compared with normal saline group, p-GSK-3 β/GSK-3 β
In VTA, CPu, PFC, NAc, differential expression is notable, and declines the most notable in Hip；Can also analyze and draw,
Under the effect of methamphetamine, the p-GSK-3 β in above brain district/GSK-3 β expression declines, methamphetamine pair
P-GSK-3 β/GSK-3 β has the effect of downward；Figure 4, it is seen that in the basic, normal, high dosage group of lithium chloride group
In, low dose group 3mg/kg/d dosage is equivalent to methamphetamine group, and the p-GSK-3 β/GSK-3 β rolled into a ball for each core expresses
Amount does not has much affect, and can significantly improve the p-GSK-3 β/GSK-3 β table of each core group in middle dosage group 100mg/kg/d
The amount of reaching, the raising for Hip is the most notable, illustrate that lithium chloride can induce/phosphorylation level the increasing rolled into a ball at Hippocampus core of GSK-3 β
Add, to account for the percentage ratio of total distance in the Ith quadrant swim distance with shape for lithium chloride group 100mg/kg/d in learning and to pass through flat
Platform number of times the most relatively methamphetamine group is obviously prolonged and matches, and the action effect of high dose group 127mg/kg/d relative to
The weak effect of 100mg/kg/d, may lower with p-GSK-3 β/GSK-3 β expression in prefrontal cortex (PFC)
Relation.
Claims (3)
1. lithium chloride application in preparing methamphetamine cognitive disorder medicine.
The lithium chloride the most according to claim 1 application in preparing methamphetamine cognitive disorder medicine, it is special
Levy and be that the effective dose of described lithium chloride is 3-127mg/kg/d.
The lithium chloride the most according to claim 2 application in preparing methamphetamine cognitive disorder medicine, it is special
Levy and be that the effective dose of described lithium chloride is 100mg/kg/d.
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