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screening of anti psychotic drugs
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Screening of anti-psychotic agents
Dr. Salim Sheikh 1st year PG,Dept. of Pharmacology,VMMC & Safdarjung Hospital, delhidrsalimsheikh@yahoo.com
Understanding psychosis
Newer targets or hypothesis
Validity of an model
Ideal animal model
Screening models & methods
Concept of latent inhibition
Overview
symptom of mental illnesses c/b a distorted or non-existent sense of
reality.
Common psychotic disorders include
*schizophrenia
*mood disorders with psychotic features
*substance-induced psychosis
Psychosis
* brief psychotic disorder
*delusional disorder
*schizoaffective disorder
*dementia with psychotic features
*delirium with psychotic features
.
Features of PsychosisPositive symptoms(common to all)
Negative symptoms(specific to szp)
Cognitive symptoms(specific to szp)
Hallucinations apathy working memory
delusions avolition processing speed
disorganized speech alogia social cognition
disorganized or agitated behavior
anhodenia problem solving test
Drugs, that are able to reduce psychotic symptoms in a wide
variety of conditions, (including schizophrenia)
Typical
Atypical
produces minimal or absent EPS
Antipsychotic Agents
1 . Phenothiazines
Aliphatic side :Chlorpromazine,Triflupromazine
Piperidine :Thioridazine
Piperazine :TrifluoperaziL, Fluphenazine
2. Butyrophenones --Haloperidol Trifluperidol ,Penfluridol
3. Thioxanthenes—Flupenthixol
4.Other heterocyclics--Pimozide, Loxapine
5. Atypical--Trifluperazine ,Clozapine,, Risperidone,
Olanzapine, Quetiapine, Aripiprazole,
Ziprasidone
.
By Carlsson, that postsynaptic DA D2 receptor antagonism was the common mechanism
reserpine exerted its effects through depletion of monoamines from presynaptic nerve terminals
high risk for drug-induced psychosis among substances that directly increased synaptic dopamine availability,
Dopamine hypothesis
Fig.
does not account for the cognitive deficits associated with schizophrenia (pre-frontal cortex)
does not explain the psychotomimetic effects
-agonists of other pathways 5-HT2
-antagonists of NMDA glutamate receptor.
Limitations of DA hypothesis
.
NMDA receptors
Antagonism of the 5-HT2 receptor
glutamate and 5-HT7 receptor subtypes
receptors for gamma-aminobutyric acid (GABA)
acetylcholine (M2 polymorphism)
peptide hormone receptors (e.g., oxytocin )
Newer targets/ concepts
excessive DA in mesolimbic dopamine pathways.
decreased DA D1 activity in prefrontal cortex (PFC)
In substance-induced psychotic disorders
*directly increase postsynaptic DA activity
*inhibition of presynaptic DA reuptake
*increased DA availability
Relevant pathophysiology
deficiency in cholinergic neurotransmission
*due to anticholinergic properties of medications
*age- or disease-related neuronal loss (or both)
Certain environmental exposures
*fetal second-trimester viral and nutritional insults
*birth complications
*substance abuse in the late teen or early adult years
.
NMDA antagonists
decrease the glutamate-mediated tonic inhibition of
DA release in the mesolimbic DA pathway
Glutamate NMDA receptor stimulation facilitates mesocortical DA release
.
mutations or polymorphisms of many genes
*neuregulin 1
*(Val{108/158}Met polymorphism of COMT
*dystrobrevin binding protein 1 or dysbindin,
*nicotinic neurotransmission
*disrupted-in-schizophrenia-1
*copy number variants
*epigenetic changes disruptions in DNA methylation
.
Construct validity refers to the disease relevance of the methods by which a model is constructed.
1. genetic mutation
2. by altering the expression or function of particular proteins, biochemical pathways or neural
circuits
3. exposure of an animal to a environmental risk factor or known disease causing agent.
Validation of an animal model of neuropsychiatric disorders
Face validity indicates that a model recapitulates anatomicalBiochemicalneuropathological or
behavioral features of a human disease.
Predictive validity signifies that a model responds to treatments in a way that predicts the effects of those treatments in humans.
.
1. Should have relevance to the clinical condition.
2. The behavioral paradigm used to index the action of APDs can be used in rats and humans
3. The model should be selective and specific to APDs differing in their in vitro and in vivo pharmacology.
Valid behavioral model
4. The model can dissociate between typical and atypical APDs.
5. The model does not require previous pharmacological manipulations to manifest the behavioral index of antipsychotic activity.
6. The model can shed light on the mechanisms of action of APDs.
.
Behavioral tests
Tests based on the mechanism of action
In vitro methods // ex-vivo tests
Types of tests
Golden hamster test
Influence on behavior of the cotton rat
Artificial hibernation in rats
Catalepsy in rodents
Pole climb avoidance in rats
Foot-shock induced aggression in mice
Brain self stimulation
Behavioral tests
PURPOSE AND RATIONALE
Innate behavior of species (Mesocricetus auratus)
The aggressive behavior of male golden hamsters is suppressed
by neuroleptics in doses which do not impair motor function
Golden hamster test
PROCEDURE
Caging of 10-20 golden hamsters , avg. 60gms @2 weeks Fighting behaviour seen
*the hamster throws himself onto his back,
*tries to bite and to push the forceps away with his legs
*utters angry shrieks.
TC are applied either s.c. , i.p. or orally.
Six animals (n=6) are used for each dose.
.
EVALUATION
Stimuli are applied every 20 min for 3 h
Tamed animal selected and checked for coordination
For each dose no. of tamed hamsters and no. of animals
with impaired motor function recorded.
ED50 values for the taming effect and impairment of
motor function are calculated
neuroleptic width indicates the ratio between the ED
50 for taming and the ED50 for motor disturbances
.
CRITICAL ASSESSMENT OF THE METHOD
neuroleptics can easily be differentiated from sedative and
hypnotic drugs
no training of the animals
no expensive apparatus is needed.
.
PURPOSE AND RATIONALE
The cotton rat (Sigmodon hispidus) is a very shy animal which conceals himself at any time
Innate flight reflex is suppressed by centrally active drugs. allows the differentiation between neuroleptic and sedative
drugs.
Influence on behavior of the cotton rat
PROCEDURE
young animals with a body weight of 40 g are used.
Selective shaving of the fur for identification
At least 6 animals (n=6) divided in two cages are used for
each dose of test compound or Standard
.
Fifteen min after application of the drug the test period of 3 h is started.
The tunnel (cylinder) is lifted and placed to another site
non responders ( to air stream) with the flight reflex it is considered to be positively influenced
Motor coordination checked
.
EVALUATION
The test procedure is repeated every 15 min over a period of 3 h.
The animals which show at least one suppression of the flight reflex during the test
period are counted as well as those who slide down on the inclined board.
Using different doses ,ED 50 values are calculated for both parameters.
.
CRITICAL ASSESSMENT OF THE METHOD
The method allows the differentiation of drugs with neuroleptic activity against other centrally active drugs.
No training of the animals
no expensive equipment are necessary.
.
PURPOSE AND RATIONALE
Tests effects of reduced oxygen tension and cold environment on rats.
The animals are submerged in ice-water the animal, they are completely anesthetized and immobilized
This kind of artificial hibernation was augmented by chlorpromazine
Artificial hibernation in rats
PROCEDURE
Male Wistar rats weighing 100–150 g
deprived of food with free access to tap water overnight
TC are injected s.c.15 min prior to the start of the experiment.
.
At 1 hour, the vessels are opened every 10 min for exactly 10 s
observed for signs of artificial hibernation
An animal is considered positive, when it remains on the back, even if the extremities are stretched out
.
EVALUATION
Various doses are applied to groups of 10 animals.
Percentage of positive animals is calculated for each group
ED 50 values with confidence limits
.
PURPOSE AND RATIONALE
failure to correct an externally imposed, unusual posture over a prolonged period of time
APDs which have an inhibitory action on the nigro-striatal dopamine system induce catalepsy
cataleptic symptoms in rodents have been compared to the Parkinson-like extra pyramidal side effects
Catalepsy in rodents
PROCEDURE
Groups of 6 male Sprague-Dawley or Wistar rats with a body weight between 120 and 250 g are used.
They are dosed i.p. with TC or the standard.
Placed individually into translucent plastic boxes
Adaptation time of 2 min
.
Amount of time spent with at least 1 forepaw on the bar is determined
When the animal removes its paws, the time is recorded and the rat is repositioned on the bar
Three trials are conducted for each animal at 30, 60, 120 and 360 min.
.
catalepsy
EVALUATION
Cataleptic if it remains on the bar for 60 s
% of cataleptic animals is calculated
For DRC, the test is repeated with various doses
ED 50 values can be calculated.
.
CRITICAL ASSESSMENT OF THE METHOD
The phenomenon of catalepsy can be used for measuring the efficacy
The potential side effects of neuroleptics are evaluted
.
PURPOSE AND RATIONALE
Avoidance escape procedure used to
separate neuroleptics from sedatives and anxiolytics
Sedative compounds suppress both avoidance and escape
Neuroleptic drugs reduce avoidance without affecting
escape
Pole climb avoidance in rats
PROCEDURE
Male Evans rats 250 g used
Scrambled shock is delivered to the grid floor of the
chamber with 2.8-kHz speaker and a 28-V light on top
Pole suspended from by upper center of the chamber
Response recorded when rat jumps on the pole and activates
the micro switch
Activation of the light and the speaker together are used as
the conditioning stimulus
-Presented alone for 4 s
-Coincided with the unconditioned stimulus, a
scrambled shock for 26 s
Pole climb response during the conditioned stimulus is
considered an avoidance response
A response during the time when both the conditioned and
unconditioned stimuli are present is considered an escape
response
Test sessions consist 60 min
EVALUATION
Data are expressed in terms
-the number of avoidance and
-escape failures relative to standard
ED 50 values can be calculated using different doses.
.
PURPOSE AND RATIONALE
useful to detect neuroleptics but also shows positive effects with anxiolytics and other centrally effective drugs.
fighting behavior seen after lesions in the septal area of the brain
Foot-shock induced aggression
PROCEDURE
Male mice (NMRI), weight between20 and 30 g
A 60-Hz current is delivered for 5s followed by 5 s. intermission for 3 min.
Each pair of mice is dosed and tested without previous exposure.
The total number of fights are recorded for each pair during the 3-min period.
.
The TC or the standard are applied 30 min before the test i.p. or 60 min before the test orally
For a time response, the drug is given 30, 60 and 120 min prior to testing.
.
Six pairs(n=2*6) of drug-treated
two pairs(n=2*2) of vehicle-treated
A dose range is tested at the peak of drug activity
Min. 3 doses (10 pairs of mice/dose) is administered for a range of doses
Control animals receive the vehicle
.
EVALUATION
The percent inhibition of aggression is calculated from the vehicle control
ED 50 -values are calculated.
.
CRITICAL ASSESSMENT OF THE METHOD
Not only neuroleptics but also anxiolytics classes of drugs can be evaluated
Animals required are more(double)
.
PURPOSE AND RATIONALE
Electrical stimulation of selected brain loci produces effects which are positively reinforcing and pleasurable
Implantion in the median forebrain bundle at the level of hypothalamus.
Neuroleptics have been shown to be potent blockers of self stimulation
Brain self stimulation
PROCEDURE
Male Wistar rats (350–400 g) are anesthetized
Heads placed on a level plane in a stereotactic instrument
electrodes placed at the medium forebrain bundle,
The assembly is then permanently affixed
.
10 days for recovery
Animals are trained to bar press in a standard operant box outfitted with a single lever.
The reward stimulus generated .
The parameters are set at a pulse duration of 0.5 ms with 2.5 ms between each pulse pair.
.
The train of pulses are delivered range from 0.1 to 0.5 mA using the lowest setting that will sustain maximal responding.
Compounds are administered 60 min prior to testing.
All data are collected on both cumulative recorders and counters
.
.
EVALUATION
The number of drug responses are compared to the number of responses made during each animal’s 30 min control session on the preceding day
ED 50 values with 95% confidence limits can be calculated.
.
CRITICAL ASSESSMENT OF THE METHOD
Active neuroleptic drugs inhibit the self-stimulation behavior in very small doses.
The relative potency observed in this test of clinically efficacious drugs parallels their potency in the treatment of schizophrenia.
.
Amphetamine group toxicity
Inhibition of amphetamine stereotypy in rats
Inhibition of apomorphine climbing in mice
Inhibition of apomorphine stereotypy in rats
Yawning/penile erection syndrome in rats
Inhibition of mouse jumping
Tests based on the mechanism of action
Antagonism against MK-801 induced locomotion and falling
in mice
Inhibition of apomorphine-induced emesis in the dog
Purposeless chewing in rats
Single unit recording of A9 and A10 midbrain
dopaminergic neurons
In vivo voltammetry
Tests based on the mechanism of action
PURPOSE AND RATIONALE
Mice exhibit an elevated motor activity
after high dose amphetamine ,
increased by aggregation, even
death within 24 h in 80–100% of control animals.
Neuroleptics reduce this death rate
Non-neuroleptic sympatholytics and anxiolytics do not produce
protection
Amphetamine group toxicity
PROCEDURE
Ten male mice of the NMRI-strain
Dosed with TC or the standard either orally or IP
Animals placed in glass jars
30 min after i.p. or 1 h after oral administration
Mice receive 20 mg/kg d-amphetamine s.c.
Mortality is assessed 1, 4 and 24 h after dosing
.
EVALUATION
Mortality of amphetamine only treated animals is at
least 80%
The estimation of ED50 values for protection is
calculated
.
PURPOSE AND RATIONALE
In rats amphetamine induces a characteristic stereotypic
behavior
continuous sniffing, licking or chewing
This behavior prevented by neuroleptic agents
Inhibition of amphetamine stereotypy in rats
Animals are observed 60 min after drug administration
An animal is considered to be protected, if the stereotypic
behavior is reduced or abolished
.
PROCEDURE
Group of 6 Wistar rats ,120 -200 g
Simultaneously injected
s.c.amphetamine (10 mg/kg) and
test compound i.p.
Placed individually in stainless-steel cages
.
.
EVALUATION
Percent effectiveness of a drug determined by the number of
animals protected in each group
ED50 values are calculated
Chlorpromazine 1.75 mg/kg i.p
Haloperidol 0.2 mg/kg i.p.
.
.
.
CRITICAL ASSESSMENT OF THE METHOD
a simple method to detect neuroleptic activity
may reflect the effects in the corpus striatum (Parkinsonism-like side effect)
.
PURPOSE AND RATIONALE
Administration of apomorphine to mice results in a peculiar
climbing behavior
Initially rearing and then full-climbing activity,
predominantly mediated by the mesolimbic DA system
APDs Antagonize this behavior with potential
Inhibition of apomorphine climbing in mice
PROCEDURE
10 male mice (20–22 g) are treated
i.p. or orally with TC or the vehicle
injected s.c. with 3 mg/kg apomorphine 30 min. later
observed for climbing behavior @ 10, 20 and 30 min
.
.
for climbing behavior , they are scored as
0 = four paws on the floor,
1 = forefeet holding the vertical bars,
2 = four feet holding the bars.
.
EVALUATION
Average values of the drug-treated animals are compared with
those of the controls
(the decrease is expressed as %)
The ED50-values and confidence limits are calculated
.
.
PURPOSE AND RATIONALE Apomorphine induces a characteristic stereotyped behavior in
rats, licking, sniffing and gnawing in a repetitive, compulsive manner
Compounds which prevent antagonize DA receptors in the nigrostriatum
predictive for EPS and tardive dyskinesias
Inhibition of apomorphine stereotypy in rats
.
PROCEDURE
Groups of 6 male Wistar rats 120 and 200 g are used
The TC or the standard are administered i.p. 60 min prior apomorphine dosage.
Apomorphine HCl is injected s.c. at a dose of 1.5 mg/kg.
.
The animals are placed in individual plastic cages
A 10 s observation period 10 min after apomorphineadministration.
An animal is considered protected if this behavior is reduced or abolished
.
.
EVALUATION
The % effectiveness of a drug is determined by the number of animals protected in each group.
With a group size of 10 animals dose response curves are obtained and ED 50 values calculated.
0.2 mg/kg s.c. for haloperidol and5.0 mg/kg for chlorpromazineclozapine was ineffective even at high doses.
.
.
PURPOSE AND RATIONALE
Yawning occurs alone or associated with stretching and/orpenile erection in humans and in animals
The yawning-penile erection syndrome can be induced in rats by apomorphine and other DA autoreceptor stimulants
Antagonism against this syndrome can be regarded as indication of antipsychotic activity
Yawning/penile erection syndrome in rats
PROCEDURE
Naive male Wistar rats, weighing 220–280 g
Rats are pretreated with apomorphine (0.02 to 0.25 mg/kg s.c.) Rats are placed in individual transparent cages.
Yawning is a fixed innate motor pattern characterized by a slow, wide opening of the mouth
.
Penile erection behaviours are present if*repeated pelvic thrusts immediately f/b*an upright position and emerging engorged
penis which the rats proceeds to lick while eating the ejaculate.
The number of penile erections and yawns is counted for 30 min following the last injection.
.
.
EVALUATION
The results are expressed as the mean number of yawns and of penile erections per group
The statistical significance is determined by comparing the results of each group with the results of the relevant control group
.
CRITICAL ASSESSMENT OF THE METHOD
yawning and penile erection in rats underlie different neurochemical mechanisms (Ach)
an useful behavioral tool to study putative antipsychotic activity of new compounds.
.
PURPOSE AND RATIONALE
The mouse jumping is due to dopaminergic overstimulation
similar to stereotypy
Induced by higher doses of amphetamine
The phenomenon can be blocked by neuroleptics
Inhibition of mouse jumping
PROCEDURE
Male CD-1 mice 22–25 g
TC injected IP/ Orally
45 mins later 4 mg/kg d-amphetamine sulfate SC
.
15 min. later IP injection of 400 mg/kg L-dopa
Mice spontaneously begin to jump at a high rate
Responses after drug administration measured through
pressure-sensitive switch closure or properly positioned
photoelectric beam disruptions
.
EVALUATION
Jumps of mice treated with TC or standard are counted and
expressed as % of jumps in amphetamine group
CRITICAL ASSESSMENT OF THE METHOD
Sensitive and specific for neuroleptic drugs
.
PURPOSE AND RATIONALE MK-801, a non-competitive NMDA antagonist
Characteristic stereotypy in mice marked by locomotion and falling behavior
both dopamine dependent and dopamine independent mechanisms
Antipsychotic agents dose-dependent antagonize this MK-801 induced behavior.
Antagonism against MK-801 inducedlocomotion and falling in mice
PROCEDURE Male CD-1 mice (20–30 g)
individually placed in activity boxes lined with wire mesh flooring and allowed to acclimate for 60 min.
dosed with TC 30 min prior to s.c. administration of MK-801
at 0.2 mg/kg
Observed for locomotion and the presence of falling behavior 15 min following MK-801 administration.
.
EVALUATION
ED 50 values and 95% confidence limits are calculated
.
PURPOSE AND RATIONALE
The blockade of centrally acting Da mechanisms
Apomorphine pronounces emetic effect in dogs
Anti-emetic activity and anti-psychotic activity are thought to be due to dopaminergic blockade
the sites of action are in different brain areas and there is a lack of complete correlation of these activities.
Inhibition of apomorphine-induced emesis in the dog
PROCEDURE
Adult beagle dogs of either sex are used in treatmentgroups of three to nine dogs/dose.
The dogs are given the TC in a gelatin capsule
then dosed with 0.15 mg/kg apomorphine s.c. at various intervals after administration of the TC
.
observed for overt behavioral effectspupillary response to light
changes in salivation ,sedation, tremors
Then after apomorphine, the dogs are observed for stereotypic sniffing, gnawing and the emetic response.
Emesis is defined as wretching movements followed by an opening of the mouth and either attempted or successful ejection of stomach content.
.
EVALUATION minimal effective dose or an ED 50 value for ant-emetic effect
The ED 50 values for haloperidol 0.06 mg/kg p.o. chlorpromazine 2.0 mg/kg p.o.
Clozapine was not effective at doses between 2 and 10 mg/kg. p.o.
.
CRITICAL ASSESSMENT OF THE METHOD
Non-classical neuroleptics like clozapine did not show pronounced activity the test has been abandoned.
Moreover, tests in higher animals like dogs are limited due to regional regulations.
.
PURPOSE AND RATIONALE
Chewing can also be induced by chronic administration of neuroleptics in rats
Purposeless chewing is mediated by dopaminergic and nicotinic mechanisms.
Purposeless chewing in rats
PROCEDURE Male albino rats are housed 10 per cage The antagonists e.g. sulpiride or mecamylamine as standards,
are given at different doses 30 min before treatment either with 0.01 mg/kg nicotine or 1 mg/kg pilocarpine i.p.
Number of chewings are counted by direct observation immediately after drug administration.
The results are presented as number of chews in a 30 min period..
.
EVALUATION
Analysis of variance (ANOVA) are used to evaluate the significance of theresults obtained.
P< 0.05 is considered as significant.
.
PURPOSE AND RATIONALE
Acute treatment with APDs, the number of spontaneously firing cells is increased in both areas.
After 21 days, ---decrease in the A10neurons, ----APDs with EPS effects induced a decrease A9 cell
also
Clozapine caused depolarization inactivation ofA10 neurons but not A9 cells.
Single unit recording of A9 and A10 midbrain dopaminergic neurons
.
PROCEDURE
Male Wistar rats weighing 280–360 g are anesthetized
The animal is mounted in a stereotaxic apparatus
twelve separate tracks ( 200 µm apart)in each region
.
In an anesthetized rat, a neuron is consideredto be dopaminergic
-triphasic positive-negative-positive spike
-0.4 to 1.5 mV amplitude and 2.5 ms duration
-firing in an irregular pattern of 3 to 9 Hz
.
Animals pretreated with vehicle prior to neuronal sampling serve as controls.
acute single-unit dopamine neuron sampling assay, TC are administered i.p. 1 hr prior to the beginning of dopamine neuron sampling.
chronic single-unit dopamine sampling assay, TC are administered once a day for 21 days
sampling is begun 2 h after the last dose on the 21 st day
.
EVALUATION
Drug treatment groups are compared to vehicle groups with a one-way ANOVA
.
PURPOSE AND RATIONALE
Electrochemical technique that uses carbon fiber microelectrodes stereotactically implanted in brain areas
To monitor monoamine metabolism and release
a miniaturized optoelectronic system for telemetry of in vivo voltammetric signals in freely moving animals
In vivo voltammetry
.
.
PROCEDURE
Electrically pretreated for simultaneous recording of ascorbic acid DOPAC and 5-HIAA
Male Sprague Dawley rats weighing 270–340 g used
Reference and auxiliary electrodes are positioned on the surface of the dura
Test electroes placed in the left or right nucleus accumbens and contralateral anterior striatum,
.
Drugs are injected subcutaneously.
Voltammograms are recorded
alternatively from each region every 5 min and after a 1 h stabilization period.
.
EVALUATION
Voltammetric data are expressed as % changes from pre-injection control values ( mean of the last 6 peak heights)
Paired Student’s t-test done for significance
.
D 1 Receptor assay: [ 3 H]-SCH 23390 binding to rat striatal homogenates
D 2 Receptor assay: [ 3 H]-spiroperidol binding . Dopamine D 2 receptor autoradiography ( 3 H-Spiperone
binding) Binding to the D 3 receptor . Binding to D 4 receptors Determination of dopamine autoreceptor activity(hplc) Dopamine-sensitive adenylate cyclase in rat striatum . α 1 -adrenergic receptor binding in brain. [ 3 H]Spiroperidol binding to 5HT 2 receptors in rat cerebral
cortex
In vitro methods
Serotonin 5HT 2 receptor autoradiography ( 3 H-Spiperone binding)
Binding to the sigma receptor Simultaneous determination of norepinephrine, dopamine,
DOPAC, HVA, HIAA, and 5-HT from rat brain areas . Measurement of neurotransmitters by intracranial
microdialysis Use of push-pull cannulae to determine the release of
endogenous neurotransmitters( in vivo) Fos protein expression in brain (immunocytochemical) Neurotensin receptor binding (endogenous neuroleptic)
In vitro methods
Conditioning stimulus current relationship with a reinforcer, past experience with that stimulus
(LI) indexes the deleterious effects of non reinforced stimulus pre-exposure on the subsequent conditioning to that stimulus.
LATENT INHIBITION
first stage (pre-exposure) one group >stimulus with no consequences, second group does not receive the stimulus.
↓(conditioning)
pre-exposed stimulus reinforcement
↓previous learning stimulus interferes with the expression of subsequent learning
.
LI in an off-baseline conditioned emotional response (CER) procedure using water licking as the operant response
three stages, different day: preexposureconditioningtest
LI consists of the fact that the PE rats show a significantly lower suppression of drinking than their NPE counterparts
LATENT INHIBITION MODEL OFANTI-PSYCHOTIC DRUG ACTION
Procedure LI procedure rats are trained to lick in the experimental
chambers (baseline)
Pre-exposure and conditioning are conducted 24 h apart and are given off-baseline
In addition, we interpolate a day of drinking (re-baseline) between conditioning and test
Drugs are administered in pre-exposure and/or conditioning only.
.
Reversal of Amphetamine-Induced LatentInhibition Disruption
Latent Inhibition Potentiation
Dissociation Between Typical and AtypicalAntipsychotic Drugs in the Latent Inhibition Model
Other tests
FST and in the LI procedure with 40 preexposures and5 conditioning trials
1. Haloperidol increased immobility in the FST andpotentiated LI
2. Clozapine decreased immobility in the FST andpotentiated LI
3. Imipramine decreased immobility in the FSTwhile having no effect on LI
LATENT INHIBITION FORCED-SWIM TEST MODEL
provide more precise information (compared to systemic drug administration) on the site of the damage
conventional hippocampal lesion, excitotoxic entorhinal cortex lesion electrolytic shell lesion)
LESION-BASED MODELS
Double advantage
Non-pharmacological
consistent with neurodevelopmental hypothesis of schizophrenia
rats reared in isolation show PPI deficits in adulthood that are reversed by both typical and atypical APDs
NEURODEVELOPMENTAL BEHAVIORAL MODELS
LI measures a cognitive process
Reflects the operation of analogous processes b/w human & rats
The model predicts antipsychotic activity for bothtypical and atypical APDs
APDs-induced potentiation of LI is specific andselective for APD
LI model does not rely on pharmacologicalmeans to elicit the behavioral index
Merits of LI models
The model has shed light on the mechanism of effect is mediated via DA blockade in the NAC during conditioning.
LI–FST model indicates that the utility for other disorders too.
LI shows the relationship between the effects of these drugs and the site of brain damage,
.
Thank you
.
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