Download preclinical evaluation of central nervous system stimulant agents

International Standard Serial Number (ISSN): 2249-6793
International Journal of Universal Pharmacy and Life Sciences 2(2): March-April 2012
INTERNATIONAL JOURNAL OF UNIVERSAL
PHARMACY AND LIFE SCIENCES
Pharmaceutical Sciences
Review Article……!!!
Received: 10-03-2012; Accepted: 14-03-2012
PRECLINICAL EVALUATION OF CENTRAL NERVOUS SYSTEM STIMULANT
AGENTS: AN OVERVIEW
J.M. Sonpetkar*, U.S. Patil, P.A.Shenoy, A.H. Tiwari, S.S.Nipate, D.D.Bandawane, P.D.Chaudhari
Progressive Education Society’s Modern College of Pharmacy, Sector no 21, Yamunanagar, Nigdi,
Pune-44, Maharashtra, India.
Keywords:
CNS Stimulant drugs,
Attention-deficit
hyperactivity disorder, In
vivo methods,
Herbal/Synthetic drugs
For Correspondence:
J.M. Sonpetkar
Progressive Education
Society’s Modern College
of Pharmacy, Sector no 21,
Yamunanagar, Nigdi, Pune44, Maharashtra, India.
E-mail:
[email protected]
48
ABSTRACT
Central nervous system (CNS) stimulants speed up mental
and physical processes in the body. This can be useful in the
treatment of certain medical conditions. Stimulants are
psychoactive drugs which induce temporary improvements in
either mental or physical function or both. These kinds of
effects may include enhanced alertness, wakefulness, and
locomotion, among others. Stimulants (analeptics) produce a
variety of different kinds of effects by enhancing the activity
of the central and peripheral nervous systems. Common
effects may include enhanced alertness, awareness,
wakefulness, endurance, productivity, and motivation,
increased arousal, locomotion, heart rate, and blood pressure,
and the perception of a diminished requirement for food and
sleep. Many stimulants are also capable of improving mood
and relieving anxiety, and some can even induce feelings of
euphoria. Stimulants exert their effects through a number of
different pharmacological mechanisms, the most prominent
of which include facilitation of norepinephrine
(noradrenaline) and/or dopamine activity. The review on
central nervous system stimulants gives detail study of CNS
stimulant drugs, their mechanism of action and in vivo
models of CNS stimulants.
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
1. INTRODUCTION
Central nervous system (CNS) stimulants are agents that speed up physical and mental
processes. The middle of the 20th centuries identifies a pivotal period in the treatment of
mentally ill. Since the 1950's the development of psychopharmacology has expanded to
include wide spread use of antipsychotic, antidepressants and antianxiety medications.
Psychotropic medications are not intended to cure the mental illness, but are used to relieve
physical and behavioral symptoms. The psycho stimulants, also called sympathomimetics and
analeptics, can improve the mood, apathy and anhedonia of depressed older persons and are
effective in the treatment of various other mental illness. Central nervous system stimulants,
such as amphetamines and methylphenidate (Ritalin), are used to treat attention-deficit
hyperactivity disorder (ADHD), a condition in which people have unusually high activity
levels and short attention spans. People with this condition are easily distracted and may have
trouble sitting still, planning ahead, or finishing what they start. Central nervous system
stimulants increase attention, decrease restlessness, and improve physical coordination in
people who have ADHD. The drugs may also curb impulsive behavior. When used to treat
ADHD, central nervous system stimulants are just one part of the total treatment program,
which also includes social, educational, and psychological help. Although central nervous
system stimulants are effective in treating ADHD, their use is controversial, especially in
children. Because they may cause unwanted side effects, parents and doctors of children who
need the drugs must carefully weigh the risks and benefits. There is also concern that these
drugs are being prescribed for some children who do not need them. Other physical and
mental conditions can have some of the same symptoms as ADHD, so it is important to rule
out other causes before starting treatment with central nervous system stimulants. This type
of medicine is also used to treat narcolepsy, in which people have an uncontrollable desire to
sleep or may suddenly fall into a deep sleep. The medication is prescribed in an effort to
reduce the frequency and severity of attacks of narcolepsy. Central nervous system stimulants
should not be used to increase alertness or to substitute for sleep. Commonly used central
nervous system stimulants are amphetamine, dextroamphetamine (Dexedrine, DextroStat),
methamphetamine (Desoxyn), pemoline (Cylert), and methylphenidate (Ritalin).
2. CLASSIFICATION OF CENTRAL NERVOUS SYSTEM AGENTS
a. Cerebral or Psychomotor Stimulants: Xanthine (caffeine), Ephedrine, Amphetamine
Methyl phenidate, Atropine, Pemoline.
49
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
b. Brainstem Stimulants or Analeptics: Pentylenetetrazol (Metrazol), Picrotoxin,
Doxapram. c. Spinal or Convulsant: Strychnine.
3. MECHANISM OF ACTION OF CENTRAL NERVOUS SYSTEM AGENTS
Fig.1. Mechanism of Action of Amphetamine
Amphetamine and dextroamphetamine stimulate the release of norepinephrine from central
adrenergic receptors. At higher dosages, they cause release of dopamine from the
mesocorticolimbic system and the nigrostriatal dopamine systems. Amphetamine may also
act as a direct agonist on central 5-HT receptors and may inhibit monoamine oxidase (MAO).
In the periphery, amphetamines are believed to cause the release of noradrenaline by acting
on the adrenergic nerve terminals and alpha- and beta-receptors. Modulation of serotonergic
pathways may contribute to the calming effect.
4. PRECLINICAL SCREENING OF CENTRAL NERVOUS SYSTEM STIMULANTS
Some screening methods for CNS stimulant drugs are described as follows:
4.1 IN VIVO METHODS
4.1.1 SANDAUSWURF’’ (DISPLACEMENT OF SAND) 4 METHOD:
Purpose & Rationale:
This method is useful for detecting stimulant of all types. Amount displace sand in graduated
cylinder is measuring parameter of this method.
Procedure
A cylinder diameter 10 cm height 12cm. The cylinder cages have a rubber torus around its
lowest part to prevent motion of cages. Then the cage is placed in glass funnel so that only
50
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
rubber torus touches the funnel. The cage is loaded with 50 ml dry sand contains 10 ml blue
gel for absorption for moisture. Beneath the glass funnel, graduated glass cylinder having
volume (10 ml), capable of being read to 0.1 ml. Quantity of sand is recorded every
15minute.
Evaluation
Amount of sand displaced by control group is compare to the test group.
4.1.2 RUNWAY TEST:
Purpose & Rationale
To study the effect of a drug on spontaneous activity and motor coordination.
Fig.2 Y-Maze Apparatus
Procedure
Age of 115-140 days wistar rats are used for the the experiment. 8-19 rats are used for each
dose the apparatus is symmetrical Y shaped runway made of wood and 13 inches high. Each
arm is 15 inches long and 5 inches wide. A trial consists of placing a rat in the center of the Y
and leaving it in the apparatus for 5 minutes. The number of times it enter the arms of the
apparatus, so that all of its feet are arm, is recorded as a measure of activity. In order to
estimates the degree of ataxia, the rat is then placed on a runway covered with paper, so that
footprint record of control rat shows that the regularity of spacing, is a measure of ataxia.
The group of control rats had 14.7 as the mean of spontaneous activity. Amphetamine at a
dose of 0.19mg/kg caused this number to increase to 20. Amylobarbitone sodium at a dose of
15 mg/kg caused it to increase to 22.But at high doses; decreases in the number of entries
were found.
51
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
Evaluation
There are increase the mean value of various CNS stimulants at specific dose than the control
animal group.
4.1.3 PTOSIS TEST
Purpose & Rationale
Reserpine causes the complete ptosis (depletion of neurotransmitter leads to depression like
state) owing to central depression & this state is useful in evaluating CNS stimulant.
Fig No.3 Ptosis Test
Procedure
Reserpines in 5% ascorbic acid, and test compounds in aqueous solution, are administered
i.p. to male albino mice. With about 4mg/kg reserpine, complete ptosis is reached at about
3hr. 2-3quarters hours after the reserpine injection, the test compound is administered. The
ptotic rating is made 15 min. later: 4 for complete ptosis; 3 for ¾ complete; 2 for ½ complete;
and 1 for ¼ complete. Two reading on each mouse are taken, are averaged. Compound which
antagonized the ptosis cause by reserpine, and which served as guides, were :
deoxyephedrine, 5mg/kg; cocaine ,40mg/kg and lysergic acid diethylamide,2mg/kg.some
compounds were effective only when given 2hr before reserpine administration.
Evaluation
There are two unique neuropharmacological effects of reserpine in mice: ptosis and
facilitation of extensor seizures.reserpine induce Ptosis is generally considered to be owing to
central depression. Thus central stimulants overcome the effect.
4.1.4 REGISTRATION OF MOTOR ACTIVITY
Purpose & Rationale
This method may be used to detect increase motor activity.
52
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
Fig No.4 Actophotometer
Procedure
The rectangular cage is constructed with floor and ends of wood, and with plastic sides. A
beam of light is passed through a plastic side to a photo electric cell, so adjusted that, when a
mouse breaks the beam of light, the cell activates a digital counter. The drug are dissolved in
a 0.9% sodium chloride and injected intraperitonially.the number of counts or interruption of
the light beam from the time of injection until 15minutes later is noted.
Evaluation
The ratio of this count to the count for control mice is measure of activity. For screening, a
drug is tested initially at dose level of 50% and 10% of its LD 50 for comparison,
amphetamine, 5mg/kg or more is used.
4.1.5 OPEN FIELD TEST 3
Principle
Interruption of light beams as a measure of movements of rats or mice in a cage. General
motor activity also locomotion, rearing and the speed of locomotion can be determined.
Purpose and Rationale
Interruption of light beams as a measure of movements of rats or mice in a cage (“open
field”) has been used by many authors such as Dews (1953), Saelens et al. (1968) Nakatsu
and Owen, (1980). Recently developed devices allow to register not only general motor
activity but also locomotion, rearing, the speed of locomotion (Barros; Ericson et al. 1991).
Procedure
The rats are observed in a square open field arena(68 × 68 × 45 cm) equipped with 2 rows of
8 photocells, sensitive to infrared light, placed 40 and 125 mm above the floor, respectively.
53
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
The photocells are spaced90 mm apart and the last photocell in a row is spaced25 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 micro computer 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 beams in the upper rows, provided that the photo beams
Spaced 25 mm from the wall were also activated.
Locomotion: Successive interruptions of photo cells 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 categories.Adult male Sprague-Dawley rats with a weight between280 and 320 g are
used. Drugs are injected subcutaneously10 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.
4.1.6 HOLE-BOARD TEST 3
Principle: Evaluation of certain components of behavior of mice such as curiosity
Fig. No.5 Hole-board Apparatus
54
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
Purpose and Rationale
The evaluation of certain components of behavior of mice such as curiosity or exploration has
been attempted by Boissier et al. (1964) and Boissier and Simon (1964). They used an open
field with holes on the bottom into which the animals could poke their noses. The “planche à
trous” or “hole-board” test has become very well recognized and has been modified and
automatized by many authors.
Procedure
Mice of either sex (NMRI strain) with a weight between18 and 22 g are used. The holeboard 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 hole-board and tested for 5 min.
Evaluation
The number of counts for nose-poking of treated
animals is calculated as percentage of
control animals.
4.1.7 COMBINED OPEN FIELD TEST3
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
(Weischer et al. 1976). Several types of such equipment are commercially available.
Procedure
Male mice (NMRI-strain) with an average weight of 30 g are used. Each animal is tested
individually in an automated open-field box which consists of a black Plexiglas 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 mounted1 cm outside of the holes
and automatically records. Every exploratory nose-poke. Thirty min. after intraperitoneal and
55
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
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. ten 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 photocell 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.
5. RESEARCH WORK DID TILL NOW
Various research works done on plants and synthetic drugs having central nervous system
stimulant activity have been tabulated as follows.
Table 1: Research works done on plants and synthetic drugs having CNS stimulant activity.
Sr.
No.
Name of plant/
synthetic drug
1
Amphetamine,
caffeine,nikethamide,
Laptazole
Strychnine,picrotoxin
Ricinine
2
Chemical
Model used for
constituents CNS Stimulant
activity
Hole-board
_
Author name
Referenc
e no.
A.K. Agrawal
12
Albumin,
Ricin,
Octacosanol
Amphetamine ,Caffeine, _
Dopamine,
_
Anete c. Ferraz
13
_
14
4
Davillo Rugosa
Open field
15
5
_
L.Avois,et al
16
6
Ephedrine,amphetamine
,
cocaine
Kigelia africana
Alkaloids,
flavonoids,
saponins,
polyphenols
/tannins
_
Anders Agmo,
Adrana
Villalpando
L.Guaraldo
Rota-rod
Owolabi O.J
17
7
Punica granatum
Pinnatal,iso
pinnatal
ethyl
brevifolinca
rboxylate
Elevated plus
maze test
Sokindra
Kumar,Vijendra
Singh
18
3
56
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
8
Strychnus nux vomica
9
10
Amphetamine ,
Caffeine
Amphetamine
11
12
Strychnine
Open field
and Brucine, (technomodel)
_
Open field test
S.Ganpaty,et al
19
S.K.Kulakarni
20
_
Open field test
21
Picrotoxin
_
_
Diphenhydramine,
cocaine
Ephedrine,
amphetamine
Cocaine
Caffeine ,ephedrine
_
_
S.K.pathi &
P.C.Dandia
A.S.Buchanan,et
al
Graham Chen and
Barbora Boehner
L.Avois, Et Al
_
_
27
_
_
_
_
Seger D.,et al
29
17
Caffeine,ginseng,
ephedrine
Cocaine,metamphetami
ne
Metamphetamine
Magkos F,
Kavouras S.A
Liberman H.R
_
_
Schep L.J,et al
30
18
Cocaine, amphetamine
_
Hole-board
19
chlorpheniramine
_
Open field
20
Effects Of CNS
stimulant
NidhiGupta,P.Pan 31
dhi
Petros
32
N.Karamanakos
F.B. Bilodil
23
_
_
21
Caffeine
_
_
22
Alseodaphne andersonii
Actophotometer
23
Pemoline
dihydroisoo
btusilactone
_
24
Caffeine
_
Open field
25
3,4_
methylenedioxyampheta
mine and 3,4methylenedioxymetham
phetamine
Picrotoxin
_
13
14
15
16
26
57
_
24
25
26
_
_
_
Open field
Doherty M.
Smith P.M, et al
Indu Dhillon,
Atul Kaushik
Gutierrez, J.,
Eisenberg et al
Saida
Haider,Anila
Tasmeen, et al
P. M. Callahan
and J. B. Appel
Mithlesh Garg
28
33
36
37
38
39
40
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
6. CONCLUSION
The detail study of literature survey of screening procedures of CNS stimulant drugs like
Caffeine, Ephedrine,
Amphetamine, Methylphenidate, Pemoline,
Pentylenetetrazole,
Picrotoxin, Doxapram, strychnine, shows the various stimulants activities and used to
increase motivation alertness ,mood energy, and wakefulness. Drug that excites any body
function; usually one that stimulates the central nervous system, inducing alertness, elevated
mood, increased speech and motor activity, and decreased appetite. CNS stimulant activity is
evaluated by these screening method mentions in this study.
7. REFERENCES
1. Barar F.S.K., ‘Essential of Pharmacotherapeutics’, 4th ed., S. chand publication New
Delhi (2008), 153.
2. Rang H.P., Dale M.M., Ritter J.M., Pharmacology, 4th ed., New Delhi (2000), 604.
3. Vogel HG. “Drug Discovery and Evaluation Pharmacological Assay” 3rd ed.; Springer
publication, New York, (2008). 391-393.
4. Turner R.A. “screening procedure in pharmacology” vol-I, academic press Publication,
New York.178-187.
5. Tripathi K.D, Essential of medical pharmacology, Jaypee brothers Medical
publishers,
fifth edition, (2003), 469-471.
6. P Knapp., ‘Amphetamine and addiction. Journal of Nervous and Mental Disorders,’
115(1952), 406-409.
7. Kaplan and Sadock. Synopsis of psychiatry-behavioral science, clinical approach.
(6thedition) Williams and Wilkins publishers. Baltimore: (1998).
8. Townsend M C. Psychiatric mental health nursing-concepts of care. (3 rd edition) F.H
Davis publishers; Philadelphia :( 2005).
9. Anderson I, Reid I .Fundamentals of clinical psychopharmacology. Martin Dunitz
publishers. London: (2002).
10. Charach A et.al. Stimulant treatment over 5 years: effects on growth. J AM ACAD. Child
adollesc psychiatry. (2006). April 45(4).
11. Gorman, E B. et.al. Effects of methylphenidate on subtypes of attention deficit
hyperactivity disorder. J AM ACAD. Child adollesc psychiatry. 2006. April 45(7).
12. Agrawal A.K., ‘suppression of exploration and locomotion by central nervous system
stimulants’, Indian journal of pharmacology.27 (1995), 178-182.
58
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
13. Anete C. Ferraz, ‘pharmacological evaluation of ricinine,a central nervous system
stimulants isolated from Ricinus Communis’, pharmacology biochemistry and behaviour,
vol.63,(1999) ,367-375.
14. Anders Agmo, ‘Central nervous stimulants facilitate sexual behaviour in male rats with
medical profontal cortex lesions, brain research, 696(1995), 187-193.
15. Guaraldo,D.A.Chagas,A.C.Conno,G.P.Korn,T.Pfiffer.A.G.Nasello,‘Hydroalcoholic Extract
And Fractions Of Davillo Rugosa poiret : effects on spontaneous motor activity and
elevated plus maze bahaviour,’ journal of ethnopharmacology,72(2000), 61-67.
16. L.Avois, et al ‘central nervous system stimulants and sport practice, Br. Journal sports
med, 40(2006), 116-120.
17. Owolabi O.J, Amachina F.C And Eledon A.B, ‘ Central Nervous System stimulant effect
of the ethanolic extract of kigelia africana,’ Journal Of Medicinal Plant Research ,
vol.2(2), (2008), 20-23.
18. Sokindra Kumar, Kamal Kishore Maheshwari And Vijendra Shah, ‘ Central Nervous
System Activity Of Acute Administration Of Ethanol Extract Of Punica Granatum
L.Seeds In Mice,’ Indian journal of experimental biology, vol.46(2008),811-816.
19. S.Ganapaty, S.Nyamathulla, ‘Central Nervous System Activity Of 4-Hydroxy, 3Methoxy Strychnine, An Alkaloid From The Roots Of Strychnous Nux-Vomica Linn.,’
International Journal Of Pharmacy And Technology, vol.2 (2010),issue no.3.588-594.
20. Kulkarni S.K, Open Field Test: In Status In Psychopharmacology, Indian journal of
pharmacology,9(1977), 241-246.
21. Pathi S.K and. Dandiya P.C, ‘Effect Of Amphetamine At Various Time Intervals In Open
Field Situation In Rats’, Indian Journal Of Pharmacology ,7(3).(1975) 38-43
22. Achliya G.S.,A.K.Dorle,‘Evaluation Of CNS Activity Of Brahmi Ghrita’ 37(2005)33-36.
23. Bilodil F.B, ‘Effects Of Stimulants Of The Central Nervous System On The Pyrodoxal
Phosphate Content Of rat brain,’ 12(1965), 671-678.
24. Buchanan A.S., Glenda M. Laycock, ‘Action of central nervous stimulant and depressant
drugs in intact animal: part 4 surface activity of drugs with central stimulant, depressant
or dual stimulant-depressant action ,’ journal pf pharmacology,7(1969),60-65
25. Graham Chen and Barbora Boehner, ‘A Study of Central Nervous System Stimulants,’
research laboratories 1958.
26. L.Avois, Et Al , ‘Central Nervous System Stimulants and sports practice’ , British Journal
Of Sports Medicine , 40(2006), i16-i20
59
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
27. Magkos F, Kavouras S.A, ‘Caffine And Ephedrine physiological, metabolic and
performance enhancing effects , Pubmed, 34(2004),871-889
28. Liberman H.R, ‘The Effects Of Ginseng, Ephedrine And Caffeine on Cognitive
Performance , Mood , And Energy, pubmed’,59(2001) , 91-102
29. Seger D., ‘Cocaine , Matamphetamine And MDMA Abuse , The role and clinical
importance of neuoadaption,’ clinical toxicology,48(20100695-708
30. Schep
L.J,
slaughter
R.J,
Beasley
D.M,,
‘The
clinical
toxicology
of
metamfetamine’,48(2010),975-694
31. Nidhi Gupta,P.Pandhi, ‘Role Of Nitric Oxide In Cocaine And Amphetamine Induced
Dopaminergic Increased Locomotor Activity And Reverse Tolerance’, ‘indian journal of
pharmacology 32(2000), 353-356
32. Doherty M. Smith P.M, ‘Effect of caffeine ingestion on rating of perceived excretion
during and after exercise ameta-analysis’ , journal of medicinal science sports,
2005,15(2005) 69-78
33. Almat G. Winterstein, ‘Cardiac Safety Of Central Nervous System Stimulants In Children
And Aldolescents With Attention- Deficil/Hyper Activity Disorder’, published
online,120(2007),e1494-e1501.
34. Sanford Bolten, And Gary Null, ‘Caffeine: Psychological Effects, Use And
Abuse’,10(1981), 202-211.
35. Indu Dhillon, Atul Kaushik* & Jeevan Jyoti Kaushik , ‘Anti-Inflammatory and Effect on
Central Nervous System of Alseodaphne Andersonii In Experimental Animal Models’,
The Pharma Research (T. Pharm. Res.),2(2009),8-15.
36. Gutierrez, J., Eisenberg, R. L., Koval, N. J., Armstrong, E. R., Tharappel, J.,Hughes, C.
G., Tobin, T. ‘Pemoline and tetramisole ‘positives’ in English racehorses following
levamisole administration’, Irish Veterinary Journal,63(2010),498-500.
37. Saida Haider, Tahira Praveen And Darakhshan , J.Haleem, ‘ Neurochemical Of Long
Term Intake Of Tea’Pakistan journal of pharmaceutical sciences ,11(1998),55-60.
38. P. M. Callahan and J. B. Appel, ‘Differences in stimulus properties of
3,4-
methylenedioxyamphetamine and 3, 4-methylenedioxymethamphetamine in animals
trained to discriminate hallucinogens from saline,’ the journal of pharmacology and
experimental pharmacotherapeutics,246(1988),866-870.
39. Mithlesh Garg, ‘The effect of some central nervous system stimulants and depressant
drugs on rearing activity in rats, psychopharmacologia, 14(1969), 150-156.
60
Full Text Available On www.ijupls.com
International Standard Serial Number (ISSN): 2249-6793
40. Sanford Bolton, Ph.D. and Gary Null, M.S., ‘caffeine psychological effect, use and
abuse,’ Orthomolecular Psychiatry, volume 10, number 3, (1981), 202-211.
41. Dandiya P.C., Kulkarni S.K, ‘Introduction to pharmacology,’ 6th edi. (2002), Vallabh
publication, New Delhi, 232-235.
42. A.V.Yadav,‘Pharmacology and toxicology’,6th edi.(2007), Nirali Prakashan, Pune,75-79.
61
Full Text Available On www.ijupls.com