Screening of anti psychotic drugs salim

Screening of anti-psychotic agents

Dr. Salim Sheikh 1st year PG,Dept. of Pharmacology,VMMC & Safdarjung Hospital, [email protected]

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

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.

.


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.

.


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.

.


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

.


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.

.


The phenomenon of catalepsy can be used for measuring the efficacy

The potential side effects of neuroleptics are evaluted

.


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.

.


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.

.


Not only neuroleptics but also anxiolytics classes of drugs can be evaluated

Animals required are more(double)

.


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.

.


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


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



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

.


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.

.


a simple method to detect neuroleptic activity

may reflect the effects in the corpus striatum (Parkinsonism-like side effect)

.


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.

.


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

.


yawning and penile erection in rats underlie different neurochemical mechanisms (Ach)

an useful behavioral tool to study putative antipsychotic activity of new compounds.

.


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


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

.


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.

.


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.

.


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.

.


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

.


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

.

Screening of anti psychotic drugs salim

Education

Transcript of Screening of anti psychotic drugs salim