INTRODUCTION:

Central nervous system (CNS) stimulation is the primary action of a diverse group of pharmacological agents and an adverse effect associated with the administration of an even larger group of drugs. CNS stimulation consists of a range of behaviors including mild elevation in alertness, increased nervousness and anxiety and convulsions.

In general, any hyper excitability associated with drug administration results from an alteration in the fine balance normally maintained in the CNS between excitatory and inhibitory influences. Thus, the bases for CNS stimulation by the class of drugs reside in adjusting the integration of excitatory and inhibitory influences at the level of the individual neuron. An agent that induces CNS stimulation appears to act by one or more of the following mechanisms:

Ø Potentiation or enhancement of excitatory neurotransmissions

Ø Depression or antagonism of inhibitory neurotransmission

Ø Altered presynaptic control of neurotransmitter release.

Although the use of CNS stimulants has declined, certain compounds within this category do possess some clinical utility. Historically, general CNS stimulants were used preliminary as respiratory stimulants in the treatment of acute over dosage with CNS depressants. Several factors have contributed to the almost complete lack of use of CNS stimulants in this clinical situation. First, since the stimulants were not specific antagonists for the depressant agents, they frequently were not effective in reversing severe pharmacologically induced CNS depression. Second the duration of action of the CNS stimulants was generally shorter than that of the depressant. Third, the dose of most CNS stimulants require to reverse severe CNS depression was quite close to the dose that produced convulsions and cardiac arrhythmias. In such cases, the CNS stimulants often exacerbated the clinical picture by producing severe life threatening complications. Another important factor contributing to the decline in CNS stimulants use for drug-induced CNS depression has been the development of generally safer procedures for patient management. Supportive measures (e.g., maintenance of a patent airway, elevation of low blood pressure) often provide greater benefit to the patient than doses the use of analeptic drugs. Tolerance and abuse potential are additional problems associated with the use of such psychomotor stimulants as amphetamine and many of its congeners (David).

1.1 CLASSIFICATION OF CNS STIMULANTS:

1. Cortical stimulants

2. Brainstem stimulants

3. Spinal cord stimulants

Cortical stimulants:

Ø Psychomimetics – Amphetamine and related rugs Cocaine

Ø Hallucinogens

Ø Methylxanthines

Ø Nootropic drugs

1.1.1 Mechanism of action of Amphetamines:

They have predominant cortical action; their psychic effects are more important than those on medullary vital centres. They act primarily by releasing NA and DA in the brain. They block NA reuptake, inhibits MAO and has direct effect on receptors. They produce increase in mental activity at doses which have little action on other central and peripheral functions.

1.1.2 Mechanism of action of Hallucinogens:

They are methoxylated amphetamines. LSD (Lysergic Acid Diethylamide) binds to and activates a specific receptor for the neurotransmitter, serotonin. Normally serotonin binds to and activates its receptors andthen is taken back up into the neuron that released it. In contrast, LSD binds very tightly to the serotonin receptor, causing a greater than normal activation of the receptor.

1.1.3 Mechanism of action of Methylxanthines:

Ø Inhibition of phosphsesodiesterase which increases C-AMP and C-GMP which in turn causes smooth muscle relaxation.

Ø Causes calcium ions release and prevents influx into cells.

Ø Antagonism of adenosine receptors (K. D. Tripathi 2010).

1.1.4 Mechanism of action of nootropic drugs:

The term nootropic comes from a Greek word meaning “acting on the mind.” Piracetam is a derivative of the inhibitory neurotransmitter GABA, the mechanism of its action is not related to that of GABA. Piracetam has little affinity for glutamate receptors, yet it does have various effects on glutamate neurotransmission. One subtype of glutamate receptor is the AMPA receptor. Micromolar amounts (levels which are achieved through oral piracetam intake) of piracetam enhance the efficacy of AMPAinduced calcium influx in brain cells. Piracetam also increases the maximal density of AMPA receptors in synaptic membranes from rat cortex due to the recruitment of a subset of AMPA receptors which do not normally contribute to synaptic transmission (Katarzyna Winnicka 2005).

1.2 PRECLINICAL SCREENING OF CENTRAL NERVOUS SYSTEM (CNS) STIMULANTS:

Some screening methods for CNS stimulant drugs are described as follows

Invivo methods:

1.2.1 Run away Test or Y Maze Test:

This test is used to study the effect of a drug on spontaneous activity and motor coordination. Swiss albino rats of either sex were selected. The mice were placed individually in a symmetrical Y–shaped runway (33 cm x 38 cm x 13 cm) for 3 min and the number of the maze with all 4 ft (an‘entry’) were counted (Ramanathan 2008).

1.2.2 Radial Arm Maze Test:

RAM consists of eight horizontal arms (57x11 cm) placed radially around a central platform above the floor. Automated doors (20 cm high) are located at the entrance of each arm. Experimental subjects are placed on a central platform from which they have to collect hidden baits placed at the end of the arms.

The standard version of the RAM animals are habituated to the environment, placed on the central platform and allowed to explore the maze for 15 min per day. Reinforcers (or baits) are scattered on the arms. On the last day of habituation (day 3), the amount of reinforcer is reduced to half, and the session ends when all eight arms have been visited. Following habituation, the animals are trained one session per day for eight consecutive days. One piece of reinforcer is placed at the end of each arm in a well that hides the food from sight, and the animal is allowed to freely explore the maze. Each session lasts until (a) all eight arms have been entered (consider enter an arm when the whole body, except the tail, is inside the arm), (b) 10 min passed since the start of the test, or (c) 2 min passed since the animal’s last arm entrance. Arm entries are recorded for later analysis. To prevent odour cues, the maze must be wiped clean between animals. The variables commonly used for the analysis of the performance are (a) the number of errors in each session (entering an arm that has been visited previously counted as an error) and the total number of errors across eight sessions, (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, (e) the time taken to visit each arm (total time to complete the session divided by the total number of arm entries), and (f) the number of sessions to reach the criterion of one error or less, averaged over four consecutive days of training (Tarragon 2012).

1.2.3 Actophotometer:

The locomotor activity can be easily studied by using Actophotometer. Swiss Albino mice of either sex (20 - 25 g) were randomly divided into three groups of six animals. The rats were placed individually inside the chamber of actophotometer for 10 min and basal activity score was noted. The animals were treated with drug and after 30 min of mice are placed again in actophotometer for 10 min and the activity was monitored. Percentage increases in activities were calculated (Vikram 2011).

1.2.4 Open Field Test:

The Open Field Test provides simultaneous measures of locomotion, exploration and anxiety. The open field apparatus was constructed of white plywood and measured 72 x 72 cm with 36 cm walls. One of the walls was clear Plexiglas, so mice could be visible in the apparatus. Blue lines were drawn on the floor with a marker and were visible through the clear Plexiglas floor. The lines divided the floor into sixteen 18 x 18 cm squares. A central square (18 cm x 18 cm) was drawn in the middle of the open field. The central square is used because some mouse strains have high locomotor activity and cross the lines of the test chamber many times during a test session. Also, the central square has sufficient space surrounding it to give meaning to the central location as being distinct from the outer locations. The maze was located in a 1.8 x 4.6 m test room and lit by a 60-watt red lamp for background lighting. The open field maze was cleaned between each mouse using 70 % ethyl alcohol. Behavior was scored with Hindsight for MS-dos (ver 1.5), and each trial was recorded for latter analysis, using a video camcorder (Hitachi, VM-7500LA) positioned above the apparatus. Measures of line crosses were obtained with an Automated camera-based computer tracking system (Limelight, Actimetrics) on an IBM PC computer with the camera fixed to the ceiling, 2.1 m above the apparatus.

Procedure:

Mice were carried to the test room in their home cages and were handled by the base of their tails at all times. Mice were placed into the center or one of the four corners of the open field and allowed to explore the apparatus for 5 minutes. After the 5 minute test, mice were returned in their home cages and the open field was cleaned with 70 % ethyl alcohol and permitted to dry between tests. To assess the process of habituation to the novelty of the arena, mice were exposed to the apparatus for 5 minutes on 2 consecutive days (Woode 2009).

1.2.5 Hole Board Test:

Rats were transported from housing room to testing room inside their home-cages to minimize transfer effect. To avoid possible visual and/or olfactive influences, animals were allowed to acclimate for 30 minutes far from observational apparatus. Environmental temperature was maintained equal to temperature in the housing room. Each subject, experimentally naïve at test beginning, was placed in the arena centre and allowed to freely explore for 10 min. After each observation, hole-board apparatus was cleaned with ethylic alcohol (70%) to remove scent cues left from the preceding subject. Experiments were recorded through a digital video camera and video files stored in a personal computer for following analyses (Maurizio Casarrubea 2010).

1.2.6 Elevated Plus Maze:

This test has been widely validated to measure anxiety in rodents. This apparatus was made of Plexiglas and consisted of two open arms (30cm × 5cm) and two closed arms (30cm × 5cm) with 25cm walls. The arms extended from a central platform (5cm ×5cm). The maze was elevated 38.5cm from the room floor. Albino rats of either sex (150 - 200 g) were randomly divided into three groups of six animals.. Each animal was placed at the center of the maze, facing one of the enclosed arms. Number of entries and the time spent in enclosed and open arms was recorded for 5 min test. Entry into an arm was defined as the animal placing all four paws onto the arm. All tests were taped by a video camera. After each test, the maze was carefully cleaned up with a wet tissue paper (10% ethanol solution) (Zaved Ahmed Khan 2011).

1.2.7 Forced Swim Test:

Albino rats of either sex (150 - 200 g) were selected. Rats were placed individually in a transparent glass cylinder (12 cm in diameter, height 25 cm), which was filled with water to a height of 15 cm. Two swim sessions were conducted. An initial 15-min pre-test followed 24 hr later by a 6 min test. In the pre test session, the mice which have not yet treated were forced to swim in a glass cylinder for 15 min. In the second session, each mouse received a respective dose of sample 1 hour prior to test, and placed in the cylinders again for 6 min. The following behaviors were recorded during the last 4 min.

1. Immobility: floating in water without swimming.

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

3. Climbing: active movements of forelimbs on the container wall (Lyvia 2005).

1.2.8 Light Dark Test:

The apparatus consists of a plexiglas box with two compartments (20cm × 20cm each), one of which illuminated compartment, facing one of the dark areas. The time spent in illuminated and dark places, as well as the number of entries in each space, was recorded for 5 min (Doke 2011).

1.2.9 Barbiturate induced sleeping time:

All treatments were done 30 min prior to intraperitoneal injection of phenobarbitone (40mg/kg). The onset of sleep and duration of sleeping time for each animal was determined and mean for each group is calculated (Rasika 2011).

1.2.10 Motor coordination:

Muscle coordination was determined via the use of Ugo Basile Rota rod bar. Swiss albino mice were placed on rota rod prior to treatment and at 0.5, 1, 2, 3, 4 and 5 hrs after treatment. Any mouse that fell off before the cut off time 2 min were excluded from the experiment (Owolabi 2008).

1.2.11 Tail Suspension test:

For the test, mice were suspended on the edge of a shelf, 58 cm above the ground with adhesive tape placed approximately 1 cm from the tip of the tail. The duration of immobility was recorded for a period of 5 min after the drug treatment (Sokindra 2008).

1.2.12 Jumping Box:

This test was used to evaluate the nootropicpotential. It comprises of a acrylic shuttle avoidance box (50 X 25 X 25cms) whose floor is made of a series of 1mm caliber parallel bronze bars divided at the mid line by a 1m high acrylic hurdle. The conditioned stimulus was a 5 second, 70 decibel, 1 kilohertz buzzer. Each sound was immediately followed by an unconditioned stimulus of 2 seconds, 0.5 miliampere foot shocks. Training and test sessions were procedurally identical. Rats are allowed to explore the box freely for 3 to 5 minutes after which they received foot shock trials with an inter trial interval of 10 to 50 seconds. Each animal was subjected to an experimental session of ten cycles .Each cycle had a total duration of sixty second and started with a conditioning warning stimulus which was terminated by a correct avoidance response i,e ,electric shock. The aversive stimulus was terminated by a correct escape response i.e, jumping into the other compartment. Rats avoided shocks by crossing the hurdle during the buzzer sound (conditioned response) (Preeti Kothiyal 2011).

3. 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 anybody 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.

4. REFERENCES:

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

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

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

4. Lyvia, Joao Paulo, Silvania, Gislei, Emmanuelle, Patricia, Glauce. Behavioral and neurochemical effects on rat ofspring sfter prenatal exposure to ethanol. Neurotoxicology and Teratology. 27 (2005) 585-592.

5. Maurizio Casarrubea, Andrea Santangelo, Filippina Sorbera, Giuseppe Crescimanno. Microstructural assesment of rodent behavior in the hole board experiment assay. The Netherlands. (2010) 24-27.

6. Murthy, Kanagasabi. CNS activity of the methanol extracts of Careya arborea in experimental animal model. A Journal of the Bangladesh Pharmacological Society. 3 (2008) 36-43.

7. 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.

8. Preeti Kothiyal. Comparative nootropic effects of Evolvulus alsinoides and Convolvulus pluricaulis. International Journal of Pharma and Biosciences. 2(1) (2011) 616-621.

9. Rasika Dnyandeo, Machindra Jayam. Analgesic and CNS depressant activities of extracts of Annona reticulata Linn. bark. Phytopharmacology. 1(5) (2011)160-165.

10. Ramanathan Sambath, Shanmuga Sundram, Siva Kumar, Netaji, Senthil Venkateswara Tarragon, 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.

11. Sokindra kumar, Kamal Kishore, Vijender Singh. Central nervous system activity of acute administration of ethanol extract of Punica granatum L. seeds. Indian Journal of Experimental Biology. 46 (2008) 811-816.

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

13. 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.

14. 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. 4(3) ( 2009) 91-106.

15. Zaved Ahmed Khan, Asit Ranjan Ghosh. L-Arginine abolishes the anxiolytic like effects of withaferin A in the elevated plus maze test in rats. African Journal of Pharmacy and Pharmacology. 5(2) (2011) 234-237.

Received on 30.07.2013 Modified on 12.08.2013

Asian J. Pharm. Res. 3(3): July-Sept. 2013; Page 151-155