Psychotropic

Guided by: Dr. Kirti V. Patel Prepared by: Tejas Kathiriya Pharmacology Sem-2

Anand Pharmacy College,anand.

PSYCHOSIS :It is mental disorder caused by some inherent dysfunction of brain, in which there is not only marked impairment of behavior but also a serious inability coherently, to the presence of these abnormalities.

SYMPTOMS:-

Delusion Hallucination Thinking or speech disturbance Lack of sleep and concentration Angry response Withdrawal from social contacts

CLASSIFICATION:-

(A) TYPICAL NEUROLEPTIC OR ANTIPSYCHOTIC (LOW POTENCY)

Chlorpromazine Prochlorperazine Promethazine Thioridazone

(B) TYPICAL NEUROLEPTIC (high potency) Fluphenazine Haloperidol Pimozide Thiothixene (C) ATYPICAL NEUROLEPTIC Aripiprazole Clozapine Olanzapine Quetiapine Risperidone

MECHANISM OF ACTION:Dopamine receptor blocking activity in brain All the neuroleptic drugs block the dopamine receptor in the brain and the periphery. Five types of dopamine receptor have been identified : D1 and D5 receptors activate adenylyl cyclase/ whereas D2,D3,D4 receptors inhibit adenylyl cyclase. The neuroleptic drugs bind to these receptors to varying degrees.

Serotonin receptor blocking activity in the brain. The newer atypical agents show their unique action through inhibition of serotonin receptors(5-HT). Many of these agents block cholinergic, adrenergic, and histaminergic receptors. ADVERSE EFFECTS: Extrapyramidal side effects: Tardive dyskinesia: Neuroleptic malignant syndrome:

Evaluation test
Effect

on behavior Open field test Hole-board test Combined open field test Effect on muscle co-ordination: Inclined plane test Chimney test Grip strength test Rotarod method

Open field test

PURPOSE AND RATIONALE Interruption of light beams as a measure of movements of rats or mice in a cage (open field) has been used. Recently developed devices allow to register not only general motor activity but also locomotion, rearing and the speed of locomotion .

PROCEDURE Animal: Sprague-Dawley rats Gender: male Weight: between 280 and 320 g Experimental condition: temperature:18-29 c humidity:35-55 %RH light & dark:12/12 hr food: chow diet Acclimatization:15 days

Group: normal control: test: standrad:

The rats are observed in a square open field area (68 68 45 cm) equipped with 2 rows of 8 photocells, sensitive to infrared light, placed 40 and 125 mm above the floor, respectively. The photocells are spaced 90 mm apart and the last photocell in a row is spaced 25 mm from the wall. Measurements are made in the dark in a ventilated, sound-attenuating box. Interruptions of photocell beams can be collected by a microcomputer and the following variables can be evaluated

Motor activity: All interruptions of photo beams in the lower rows. Peripheral motor activity: Activation of photo beams in the lower rows, provided that the photo-beams spaced 25 mm from the wall were also activated. Rearing: All interruption of the photo beams in the upper rows. Peripheral rearing: Interruption of photo beams in the upper rows, provided that the photo beams spaced 25 mm from the wall were also activated.

Locomotion: Successive interruptions of photocells in the lower rows when the animal is moving in the same direction. Speed: The time between successive photo beam interruptions during locomotion collected in 0.1 s categories.

Drugs are injected subcutaneously 10 to 40 min. before test. The rats are observed for 15 min whereby counts per min. are averaged for 3 min intervals.

EVALUATION Dose-response curves can be obtained for sedative and stimulant drugs, whereby the various parameters show different results. The effects of various doses are compared statistically with the values of controls and among themselves.

Hole-board test
PURPOSE AND RATIONALE The evaluation of certain components of behavior of mice such as curiosity or exploration has been attempted. They used an open field with holes on the bottom into which the animals could poke their noses. The planche trous or hole-board test has become very well recognized and has been modified and automatized by many authors.

PROCEDURE Animal: Mice NMRI strain Gender: either sex weight : between 18 and 22 g Experimental condition: temperature:18-29 c humidity:35-65 %RH light & dark:12/12 hr. food:chow diet Acclimatization:15 days

Group: normal control: test: standard: Apperatus: The hole-board has a size of 40 40 cm. Sixteen holes with a diameter of 3 cm each are distributed evenly on the floor. The board is elevated so that the mouse poking its nose into the hole does not see the bottom.

Nose-poking is thought to indicate curiosity and is measured by visual observation in the earliest description and counted by electronic devices in more recent modifications. Moreover, in the newer modifications motility is measured in addition by counting interruption of light beams. Usually, 6 animals are used for each dose and for controls. Thirty minutes after administration of the test compound the first animal is placed on the holeboard and tested for 5 min.

Evaluation: The number of counts for nose-poking of treated animals is calculated as percentage of control animals. MODIFICATIONS OF THE METHOD A hole-poke measuring system is commercially available from Technical and Scientific Equipment.

Combined open field test

PURPOSE AND RATIONALE The simultaneous determination of locomotion and curiosity by using a modification of the hole-board test and a photo-beam system has been proposed as a relatively simple test. Several types of such equipment are commercially available.

PROCEDURE Animal: mice (NMRI-strain) Gender: Male weight : 30 g Experimental condition: temperature:18-29 c humidity:35-65 %RH light & dark:12/12 hr. food:chow diet Acclimatization:15 days

Group: normal control: test: standard: (10 mice is used in each groups).

Each animal is tested individually in an automated open-field box which consists of a black Plexiglass cage (35 35 20 cm) with a post (8 8 20 cm) in the center of the cage. Two evenly spaced photo cell beams perpendicular to the wall and 2 cm above the floor divide the box into 4 compartments. Every photo cell beam interruption is registered automatically as an activity count.

Each wall of the cage contains 4 evenly spaced 2 cm diameter holes in a horizontal array 7 cm above the floor. A row of 4 photocell beams is mounted 1 cm outside of the holes and automatically records every exploratory nose-poke. Thirty min. after intraperitoneal and 60 min. after oral administration of the test compound the animal is placed into the cage and the behavior recorded for a period of 5 min. 10 mice are used for each dose as well as for controls.

EVALUATION Counts for motility (interruption of photo cell beams inside the cage) and for curiosity (interruption of photo cell beams outside the cage due to nose-poking) are recorded individually. The mean values of the treated groups are expressed as percentage of the control group. Using different doses, dose-response curves can be obtained.

MODIFICATIONS OF THE TEST behavioral monitor which was designed to assess the spatial and temporal sequences of locomotor movements in rats. There is also video recording of the movements of mice in the evening hours at low illumination and counted the locomotor activity as the number of field crossings and the exploratory activity as the number of rearings.

Effect on muscle co-ordination

Inclined plane
PURPOSE AND RATIONALE The method of Allmark and Bachinski (1949) using an inclined screen was originally developed for testing curare-like agents. Later on, it has been used by many authors (e.g. Randall et al. 1961) for testing compounds for muscle relaxant activity. The principle of an inclined plane for differentiating neuroleptics from other centrally active drugs.

PROCEDURE Animal:mice (Charles River strain) Gender: male weight between 20 and 30 g Experimental condition: temperature:18-29 c humidity:35-55% RH light & dark:12/12 hr. food:chow diet Accimatization:15 days

Group: normal control: test: standard: Apperatus: The plane consists of two rectangular plywood boards connected at one end by a hinge. One board is the base, the other is the movable inclined plane. Two plywood side panels with degrees marked on their surface are fixed on the base.

A rubber mat with ridges 0.2 cm in height is fixed to the inclined plane which is set at 65 degrees. The test compound or the standard are administered to groups of 10 mice either i.p. or s.c. or orally. Thirty, 60 and 90 min thereafter, the mice are placed at the upper part of the inclined plane and are given 30 s to hang on or to fall off.

EVALUATION The peak time is determined as the time at which a compound produces the maximum performance deficit. At this time interval, a range of doses is tested using 10 animals per group. ED50 values are calculated.

MODIFICATIONS OF THE METHOD Instead of an inclined wooden board, an inclined screen has been used.

Chimney test
PURPOSE AND RATIONALE The test de la chemine is a simple test for tranquilizing and muscle relaxant activity.

Procedure: Animal: mice (CD1, Charles River) Gender:Male weighing between 16 and 22 g Experimental condition: temperature:18-29 c humidity:35-65 %RH light & dark:12/12 hr. food:chow diet Acclimatization:15 days

Group:each group contain 10 animal per dose. normal control: test: standard:

Pyrex-glass cylinders 30 cm long are required. The internal diameter varies with the animals weight: for mice weighing 16 to 18 g, the diameter is 22 mm, for mice weighing 18 to 20 g, 25 mm; for mice weighing 20 to 22 g, 28 mm. Each tube has a mark 20 cm from its base. Initially, the tube is held in a horizontal position. At the end of the tube, near the mark, a mouse is introduced with the head forward.

When the mouse reaches the other end of the tube, toward which it is pushed if necessary with a rod, the tube is moved to a vertical position. Immediately, the mouse tries to climb backwards and performs coordinated movements similar to an alpinist to pass a chimney in the mountains. This gave the name for the test. The time required by the mouse to climb backwards out at the top of the cylinder is noted.

EVALUATION The ED50 (with 95% confidence limits), the dose for which 50% of the animals fail to climb backwards out of the tube within 30 s, is calculated by log-probit analysis.

Grip strength
PURPOSE AND RATIONALE The test is being used to assess muscular strength or neuromuscular function in rodents which can be influenced not only by sedative drugs and muscle relaxant compounds but also by toxic agents.

PROCEDURE The method was described as test de lagrippement. Male or female mice with an average weight of 22 g are used. In a preliminary experiment the animals are tested for their normal reactivity. The animals are exposed to a horizontal thin thread or metallic wire suspended about 30 cm into the air which they immediately grasp with the forepaws. The mouse is released to hang on with its

Normal animals are able to catch the thread with the hind limbs and to climb up within 5 s. Only animals who fulfill this criterion are included into the experiment. 10 mice are used in the control group and in the experimental groups. After oral or subcutaneous administration the animals are tested every 15 min. Animals which are not able to touch the thread with the hind limbs within 5 s or fall off from the threat are considered to be impaired.

The test is continued for 2 h. The animals are observed for their behavior in the cages. Only if their behavior and their motility in the cage seem to be normal the disturbance of the grasping reflex can be considered as caused by central relaxation.

EVALUATION The percentage of animals loosing the catching reflex is calculated. By use of different doses, ED50-values are calculated. Likewise, time-response curves can be established.

MODIFICATIONS OF THE METHOD Kondziella (1964) described a method for the measurement of muscular relaxation in mice based on the capacity of hanging from a horizontal griddle. Deacon and Gardner (1984) described the pullup test in rats. A rat is held by its hind legs in an inverted position. The time taken by the rat to pull itself up and grasp the hand of the experimenter is used as the test parameter.

Rotarod method
PURPOSE AND RATIONALE The test is used to evaluate the activity of drugs interfering with motor coordination. The skeletal muscle relaxation induced by a test compound could be evaluated by testing the ability of mice or rats to remain on a revolving rod.

This forced motor activity has subsequently been used by many investigators. The dose which impairs the ability of 50% of the mice to remain on the revolving rod is considered the endpoint.

PROCEDURE Animal: mice CD-1 Charles River strain Gender:male weight between 20 and 30 g Only those animals which have demonstrated their ability to remain on the revolving rod for at least 1 minute are used for the test. Experimental condition; temperature: 18-29 c humidity:35-55% RH light & dark:12/12 hr. food:chow diet

Group; normal control: test: standard: Apparatus: The apparatus consists of a horizontal wooden rod or metal rod coated with rubber with 3 cm diameter attached to a motor with the speed adjusted to 2 rotations per minute. The rod is 75 cm in length and is divided into 6 sections by plastic discs, thereby allowing the simultaneous testing of 6 mice.

The rod is in a height of about 50 cm above the table top in order to discourage the animals from jumping off the roller. Cages below the sections serve to restrict the movements of the animals when they fall from the roller.

The test compounds are administered intraperitoneally or orally. 30 minutes after intraperitoneal or 60 min after oral administration the mice are placed for 1 min on the rotating rod. The number of animals falling from the roller during this time is counted. Using different doses, ED50 values can be calculated. Moreover, testing at various time intervals, time response curves can be obtained.

CALCULATION Percent animals falling from the rotarod within the test period is calculated for every drug concentration tested. ED50 is defined as the dose of drug at which 50% of the test animals fall from the rotarod.

MODIFICATIONS OF THE METHOD A comparison of the rotarod method in rats with other tests, such as blockade of morphineinduced rigidity in rats, decerebrate rigidity in cats, and polysynapticmonosynaptic reflex preparations in cats was published by Novack and Zwolshen (1983). Rozas et al. (1997) described a drug-free rotarod test that was used to evaluate the effects of unilateral 6-hydroxydopamine lesions, nigral grafts, and subrotational doses of apomorphine.

The rotarod unit was automated and interfaced with a personal computer allowing automatic recording of the time that each rat was able to stay on the rod at different rotational speeds.