1. INTRODUCTION:

The main effect of a wide range of pharmacological substances is to stimulate the central nervous system (CNS), which is also a side effect of the administration of an even wider range of medications. Convulsions, a moderate increase in attentiveness, increased anxiousness and anxiety, and other behaviours are all examples of CNS stimulation.

Any hyperexcitability brought on by drug administration typically stems from a change in the delicate equilibrium between excitatory and inhibitory forces that is normally maintained in the CNS.

So, modifying the integration of excitatory and inhibitory impacts at the level of the individual neuron is the basis for CNS stimulation by the class of medications. One or more of the following mechanisms appear to be used by an agent to stimulate the CNS:

· Potentiation or enhancement of excitatory neurotransmissions

· Depression or antagonism of inhibitory neurotransmission

· Altered presynaptic control of neurotransmitter release.

Although the usage of CNS stimulants has decreased, several of the substances in this class have some clinical use. In the past, general CNS stimulants were first utilised as respiratory stimulants to treat acute CNS depressant overdose. The almost complete absence of CNS stimulants in this clinical setting is the result of a number of factors. First off, the stimulants were generally ineffective at reversing severe pharmacologically induced CNS depression because they were not selective antagonists for the depressant drugs. Second, compared to depressants, the CNS stimulants' average duration of action was shorter. Finally, the dosage needed for the majority of CNS stimulants to reverse severe CNS depression was very near to the dosage needed to cause convulsions and cardiac rhythms. In these situations, the CNS stimulants frequently made the clinical picture worse by resulting in serious, potentially fatal consequences. The creation of generally safer patient care practises has been a significant contributor in the fall of CNS stimulant use for drug-induced CNS depression. Supporting interventions, such as maintaining a patent airway and raising low blood pressure, frequently benefit the patient more than doses of analeptic medication. Additional issues with the use of psychomotor stimulants like amphetamine and many of its congeners include tolerance and abuse potential.¹

1.1 Classification of CNS stimulants:

1. Cortical stimulants

2. Brainstem stimulants

3. Spinal cord stimulants

Cortical stimulants:

· Psychomimetics – Amphetamine and related rugs Cocaine

· Hallucinogens

· Methylxanthines

· Nootropic drugs

1.1.1 Mechanism of action of Amphetamines:

They primarily act on the cortex, and their psychic effects have a greater impact than those on the medullary vital centres. They primarily affect the brain by releasing NA and DA. They have a direct impact on receptors, inhibit MAO, and prevent NA reuptake. At levels that have little impact on other central and peripheral functions, they boost brain activity.

1.1.2 Mechanism of action of Hallucinogens:

Methoxylated amphetamines are what they are. Serotonin is a neurotransmitter that has a specific receptor that LSD (Lysergic Acid Diethylamide) binds to and activates. Typically, serotonin binds to, activates, and then returns to the neuron from which it was released. LSD, on the other hand, binds to the serotonin receptor very strongly, activating it more than is typical.

1.1.3 Mechanism of action of Methylxanthines:

· Phosposesodiesterase is inhibited, which raises C-AMP and C-GMP and, in turn, relaxes smooth muscle.

· Releases calcium ions while preventing cell influx.

· Adenosine receptor opposition.²

1.1.4 Mechanism of action of nootropic drugs:

The word "nootropic" is derived from a Greek verb that means "to act on the mind." Although piracetam is derived from the inhibitory neurotransmitter GABA, its mode of action is distinct from that of GABA. Piracetam has different effects on glutamate neurotransmission despite having limited affinity for glutamate receptors.One subtype of the glutamate receptor is the AMPA receptor. Piracetam is taken orally in micromolar doses, which improve the effectiveness of AMPA-induced calcium influx in brain cells. Due to the recruitment of a subgroup of AMPA receptors that do not typically contribute to synaptic transmission, piracetam also enhances the maximal density of AMPA receptors in synaptic membranes from rat cortex.³

1.2 Preclinical Screening of CNS (Central Nervous System) Stimulants:

The following is a description of some CNS stimulant drug testing procedures.

In vivo methods:

1.2.1 Jiggle-cage:

Rats were used to study the effects of medication dose and time. Seven hours following treatment, the animals were evaluated in jiggle-cage actographs. The actometer units were described as having a jiggle cage that records the oscillatory movements of the spring holding the activity cage on a kymograph. The analysis of variance was used to examine the motility score data as response surfaces.⁴

1.2.2 Run away Test or Y Maze Test:

This test is designed to examine how a medication affects motor coordination and spontaneous behaviour. Both sexes of Swiss albino rats were chosen. The mice were each given a 33cm x 38cm x 13cm symmetrical Y-shaped runway for three minutes, and the number of the mazes with all four feet (an "entry") were counted.⁵

1.2.3 Radial Arm Maze Test:

RAM is made up of eight radially arranged horizontal arms measuring 57 by 11cm that are positioned above the floor. At the beginning of each arm are automated doors (20cm high). On a central platform, experimental participants are positioned, and they must retrieve hidden baits that have been put at the ends of the arms.

RAM's usual configuration Animals are introduced to the surroundings, put on the centre platform, and given 15minutes each day to explore the maze. On the arms are a variety of reinforcements (or baits). The reinforcer dosage is halved on the third day of habituation, and the session is over when all eight arms have been visited. The animals are trained once daily for eight straight days after becoming accustomed to it. The animal is free to roam the maze once one reinforcer is inserted at the end of each arm in a well that conceals the food from view. Each session lasts until one of the following conditions is met: (a) all eight arms have been entered (consider an arm entered when the entire body, excluding the tail, is inside the arm); (b) 10 minutes have passed since the test began; or (c) 2 minutes have passed since the animal's last arm entrance. Arm entries are kept for analysis at a later time. The maze needs to be well cleaned in between animals to avoid odour cues. The variables typically used for performance analysis are: (a) the number of errors in each session (entering an arm that has already been visited counts as an error), (b) the number of correct choices in the first eight arm entries of each session, (c) the location of the first error in each session, (d) the number of adjacent arm entries in each session, and (e) the total amount of time (t) spent visiting each arm.⁵

1.2.4 Actophotometer:

Actophotometer is a simple tool for studying locomotor activity. Swiss Albino mice (20–25g, any sex) were divided into three groups of six at random. During 10 minutes, each rat was separately placed in the actophotometer chamber, and the basal activity score was recorded. The animals were given medication, and after 30 minutes, the mice were again placed in the actophotometer for 10 minutes, with activity being recorded. Activity percentage increases were determined.⁶

1.2.5 Open Field Test:

The Open Field Test offers measurements of movement, exploration, and anxiety all at once. The open field apparatus had walls that were 36cm thick, was made of white plywood, and measured 72 by 72cm. Mice could be seen within the equipment since one of the walls was made of transparent Plexiglas. The floor had been marked with blue marker and was visible through the Plexiglas covering. The floor was split into sixteen 18 × 18cm squares by the lines. The open field had a central square (18cm x 18cm) drawn in the centre of it. Because some mouse strains have great locomotor activity and frequently cross the lines of the test chamber during a test session, the centre square is used. Also, the central square has enough room around it to indicate that it is different from the neighbouring areas. A 60-watt red lamp provided ambient lighting for the maze, which was situated in a test room that measured 1.8 by 4.6 metres. With 70% ethyl alcohol, the open field maze was cleaned after each mouse. Each trial was videotaped for further analysis using a video camcorder (Hitachi, VM-7500LA) that was placed above the apparatus. Behavior was graded using Hindsight for MS-dos (ver 1.5). The camera was attached to the ceiling, 2.1m above the equipment, and the measurements of line crosses were taken using an automated camera-based computer tracking system (Limelight, Actimetrics) on an IBM PC computer.

Procedure:

Mice were always handled by the base of their tails and brought to the test room in their home cages. Mice were placed in the open field's middle or one of its corners, and they were free to explore the equipment for five minutes. Mice were put back in their cages after the five-minute test, and the open field was cleaned with 70% ethyl alcohol and left to dry in between experiments. Mice were exposed to the apparatus for 5 minutes on two consecutive days to measure the process of acclimatisation to the novelty of the arena.⁷

1.2.6 Hole Board Test:

To reduce the transfer effect, rats were moved from the housing room to the testing room inside of their home cages. The animals were given 30minutes to acclimatise away from the observational equipment in order to avoid any potential visual and/or olfactory impacts. The ambient temperature was kept constant with the housing room's temperature. At the start of the test, each subject was placed in the centre of the arena and given 10 minutes to wander around at their leisure. To remove fragrance cues left by the previous subject, the hole-board device was wiped with ethylic alcohol (70%) after each observation. A digital video camera was used to capture the experiments, and the video files were stored on a computer for further analysis.⁸

1.2.7 Elevated Plus Maze:

The validity of this test for assessing anxiety in rodents is well established. Two open arms (30cm 5cm) and two closed arms (30cm 5cm) with 25cm walls made up this Plexiglas device. From a 5-cm-square centre platform, the arms expanded. The maze was raised 38.5cm off the ground. Three sets of six albino rats of either sex (weighing between 150 and 200g) were randomly selected. Each animal was positioned in the middle of the labyrinth, facing one of the walls. For the five-minute test, the number of entrances and the amount of time spent in closed and open arms were noted. The animal has to place all four paws on the arm in order to enter it. A video camera was used to record each exam. After each test, a moist tissue paper (10% ethanol solution) was used to properly wipe the maze.⁹

1.2.8 Hole cross test:

The procedure followed the guidelines laid out by Islam et al.¹⁰. While Group II got diazepam (1mg/kg, i. p.), Group I received 1% Tween-80 in saline administered orally. The remaining experimental groups, however, were given oral amounts of test drug extracts at mg/kg body weight. At 0, 30, 60, 90, and 120 minutes, the mice's 3 minute crossing of the openings was counted¹¹.

1.2.9 Forced Swim Test:

Rats weighing between 150 and 200g and being albino were chosen. Each rat was put into a transparent glass cylinder of 12cm in diameter and 25cm in height that was 15cm tall and filled with water. Two swimming sessions were held. A 6-minute test was administered 24 hours after the initial 15-minute pre-test. The mice that had not yet received treatment were made to swim for 15 minutes in a glass cylinder during the pre-test session. The second session involved placing each mouse in the cylinders for a second time for six minutes after receiving their appropriate dose of sample an hour before the test. The following actions took place over the past four minutes.

1. Immobility: floating in water without swimming.

2. Swimming: circling in the container and vigorous movements of the extremities.

3. Climbing: making forceful forelimb motions against the container wall.¹²

1.2.10 Light Dark Test:

The device consists of a box made of plexiglas with two compartments (20cm 20cm each), one of which is lighted and faces a dark section. For five minutes, the amount of time spent in brightly lit and darkly lit areas, as well as the number of entries in each area, were recorded.¹³

1.2.11 Barbiturate induced sleeping time:

Before administering phenobarbitone (40mg/kg) intraperitoneally, all treatments were completed 30 minutes earlier. Each animal's start of sleep and amount of sleep were recorded, and the average for each group was calculated.¹⁴

1.2.12 Motor coordination:

The Ugo Basile Rota rod bar was used to measure muscle coordination. Swiss albino mice were put on rota rods both before and after treatment at 0, 0.5, 1, 2, 3, 4, and 5hours. Any mouse that left the trial before the 2-minute cutoff time was over was not included.¹⁵

1.2.13 Tail Suspension test:

Adhesive tape was used to secure the mice in the test, which was performed with them hanging 58 cm from the floor on the edge of a shelf. Five minutes following the medication treatment, the length of immobility was timed.¹⁶

1.2.14 Jumping Box:

This experiment measured the nootropic potential. It consists of a 50 X 25 X 25cm acrylic shuttle avoidance box with a 1m high acrylic hurdle dividing the parallel 1 mm calibre bronze bars at the midline. The conditioned stimulus was a 1kilohertz, 70 decibel buzzer that lasted for 5 seconds. An unconditioned stimulus of two seconds' worth of 0.5 miliampere foot shocks was given after each sound. Procedure-wise, the training and test periods were similar. Rats are given three to five minutes to explore the box at their leisure before receiving foot shock trials with a ten to fifty second inter-trial break. Each animal had a ten-cycle experimental session. Each cycle lasted a total of 60 seconds and began with a training warning stimulus that was followed by a proper avoidance reaction, in this case an electric shock. Jumping into the other container was the appropriate escape behaviour, which ended the unpleasant stimuli. Rats learned to cross the threshold when the buzzer sounded to avoid shocks.¹⁷

3. CONCLUSION:

Caffeine, ephedrine, amphetamine, methylphenidate, pemoline, pentylenetetrazole, picrotoxin, doxapram, and strychnine are CNS stimulant drugs that are used to increase motivation, alertness, mood energy, and wakefulness. A detailed study of the literature on the screening procedures for these drugs reveals the various stimulants' activities. Usually, a drug that stimulates the central nervous system, causing alertness, elevated mood, increased speech and physical activity, and decreased appetite. Medication that excites anyone's function. Several screening techniques mentioned in this paper are used to assess CNS stimulant activity.

4. REFERENCES:

1. Taylor DA. http://el.trc.gov.om:4000/htmlroot/MEDICAL/ tcolon/neurology/General/E-Books/Central%20Nervous%20System.pdf

2. Tripathi KD. Essentials of Medical Pharmacology, VI edition, Jaypee brothers medical publishers, New Delhi. (2010) 126-127, 218-222, 437-438.

3. Winnicka K. Piracetam an old drug with novel properties. Acta Poloniae Pharmaceutica Drug Research. 62 (5) (2005) 405-409.

4. Bajsbini M, Gaiardi M and Bartoletti M. Motility effects of methamphetamine in rats chronically treated with morphine. Neuropharmacology. 17: 979-983

5. Sambath R, Sundram S, Kumar S, Netaji, Tarragon SV, Lopez, Ros-Bernal, Yuste, Ortiz, Martin, Schenker, Aujard, Bordet, Richardson, Herrero. The radial arm maze for the evaluation of working and reference memory deficits in the diurnal rodent Octodon degus. The Netherlands. 2012: 28-31.

6. Vikram, Swati. Evaluation of antidepressant like effects of Citrus maxima leaves in animal models of depression. Iranian Journal of Basic Medical Sciences. 14(5) (2011) 478-483.

7. Woode, Amidu, William, Boakye, Laing, Ansah, Duwiejua. Anxio genic like effects of a root extract of Sphenocentrum jollyanum Pierre in murine behavioral models. Journal of Pharmacology and Toxicology. 2009; 4(3): 91-106.

8. Casarrubea M, Santangelo A, Sorbera F, Crescimanno G. Microstructural assesment of rodent behavior in the hole board experiment assay. The Netherlands. 2010: 24-27.

9. Khan ZA, Ghosh AR. L-Arginine abolishes the anxiolytic like effects of withaferin A in the elevated plus maze test in rats. African Journal of Pharmacy and Pharmacology. 2011; 5(2): 234-237.

10. Islam MR, Naima J, Proma NM, Hussain MS, Uddin SN, Hossain MK, In-vivo and in-vitro evaluation of pharmacological activities of Ardisia solanacea leaf extract, Phytomedicine. 2019; 5: 1–11.

11. Nagandla K, De S, Restless legs syndrome: pathophysiology and modern management, Postgrad. Med. 2013; 89: 402–410.

12. Paulo LJ, Silvania, Gislei, Emmanuelle, Patricia, Glauce. Behavioral and neurochemical effects on rat ofspring sfter prenatal exposure to ethanol. Neurotoxicology and Teratology. 2005; 27: 585-592.

13. Doke, Tare, Sherikar, Shende, Deore, Dama. Central nervous system stimulant of the oils obtained from seeds of Cucurbita maxima. International Journal of Pharmaceutical Biology. 2011; 1(1): 30-36.

14. Dnyandeo R, Jayam M. Analgesic and CNS depressant activities of extracts of Annona reticulata Linn. bark. Phytopharmacology. 2011: 1(5): 160-165.

15. Owolabi, Amaechina, Eledan. Central nervous system stimulant effect of the ethanolic extract of Kigelia africana. Journal of Medicinal Plants Research. 2(2) (2008) 20-23.

16. Kumar S, Kishore K, Singh V. Central nervous system activity of acute administration of ethanol extract of Punica granatum L. seeds. Indian Journal of Experimental Biology. 2008; 46: 811-816.

17. Kothiyal P. Comparative nootropic effects of Evolvulus alsinoides and Convolvulus pluricaulis. International Journal of Pharma and Biosciences. 2011; 2(1): 616-621.

Received on 28.04.2023 Modified on 25.11.2023

Asian J. Pharm. Res. 2024; 14(2):148-152.

DOI: 10.52711/2231-5691.2024.00025