INTRODUCTION:

Nicotine:

Nicotine, the primary component of tobacco produces powerful addiction in humans. Tobacco users or smokers experience considerable withdrawal symptoms, which make them highly susceptible to relapse during cessation attempts¹. Withdrawal symptoms include irritability, anxiety, and difficulty in concentration, insomnia, fatigue, depressed mood, restlessness, impatience, hostility, weight gain and craving². In animals after prolonged administration, cessation of nicotine, exhibits most prominently somatic withdrawal signs as well as anxiety likes symptoms³. More than one billion people absorb nicotine into their bodies chronically through cigarette smoking and billions more are exposed daily to Environmental Tobacco Smoke (ETS), so that elucidation of the complex fate of nicotine has worldwide implications⁴.Smoking is also reinforced by conditioning, such that speciﬁc stimuli that are psychologically associated with smoking become cues for an urge to smoke. These include the taste and smell of tobacco, as well as particular moods, situations, and environmental cues. Pharmacotherapies to aid smoking cessation should ideally reduce nicotine withdrawal symptoms and block the reinforcing effects of nicotine obtained from smoking without causing excessive adverse effects⁵. Nicotine, the primary component of tobacco produces powerful addiction in humans. Nicotine sustains tobacco addiction, a major cause of disability and premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating neurotransmitter release. Dopamine, Glutamate, and Gamma Aminobutyric acid release are particularly important in the development of nicotine dependence, and Corticotropin-Releasing Factor appears to contribute to nicotine withdrawal⁶. Thus NMDA receptor antagonist (Kynurenic acid) decreases all the function of NMDA receptor. Whereas NMDA receptor agonist (D-cycloserine) increases all function of NMDA receptor. The present study, first time provide evidence that, chronic treatment with Kynurenic acid is effective in attenuating nicotine withdrawal syndrome. Nicotine dependence was produced by chronic exposure of mice to nicotine and modified liquid diet for 10 days with gradual increase in concentration of nicotine up to 10% (v/v). Rest of animals continued on nutritionally balanced isocalaoric control liquid diet containing BOURNVITA as caloric substituted to nicotine. (Pair fed liquid groups). Chronic nicotine treatment was discontinued after 10 days and withdrawal signs were evaluated such as, hyper excitability signs, Anxiety. Chronic treatment of Kynurenic acid attenuated nicotine withdrawal hyper excitability signs. Chronic administration of Kynurenic acid also counteracts anxiety by increasing social interaction time in social interaction test apparatus but chronic administration of D-cycloserine by decreasing social interaction time in social interaction test apparatus. However, administration of acute (single dose) after termination of nicotine treatment failed to attenuate nicotine withdrawal. Hence, Kynurenic acid is a novel target for drugs that reduced nicotine intake and may be used to treatment of nicotine withdrawal induced behavioural changes. The pharmacologically active form of nicotine closely resembles the acetylcholine (ACh) molecule, although nicotine is less flexible and only binds to one of the two types of cholinergic receptors, known as the Nicotinic Cholinergic Receptors⁷.

In laboratory animals, repeated Nicotine administration produces several behavioural responses that can be related to its addictive properties, such as Reinforcing effects and physical dependence⁸.

Nicotine dependence:

Nicotine is very addictive when delivered to the lungs by inhaling tobacco smoke. It increases the release of brain chemicals called neurotransmitters, which help regulate mood and behaviour. One of these neurotransmitters is dopamine, which may improve your mood and activate feelings of pleasure. Nicotine act on Nicotinine Acetylcholine Receptor. It is increased levels of Dopamine in the reward circuits of the brain⁹.

Fig. 1. Relationship between Different Levels of Analysis in the Study of Addiction

The Role of Neuroadaptive Processes Neuroadaptive mechanisms have been hypothesized to contribute to Compulsive Behavior and addiction by acting at different levels of the spiralling cycle of the development of dependence. Thus, certain genetic sources of smoking relapse risk (e.g., dopaminergic genes associated with poor impulse control; may be expressed to a greater extent when coupled with a strong drive to smoke characteristic of severe nicotine dependence¹⁰.

Kynurenic acid:

Kynurenic acid is a recognized broad-spectrum antagonist of excitatory amino acid receptors with a particularly high affinity for the glycine co-agonist site of the N-methyl-D-aspartate (NMDA) receptor complex. Kynurenic acid is also a putative endogenous neuroprotectant. Kynurenic acid strongly blocks α7 subtype of nicotinic acetylcholine receptors (nAChRs)¹¹. Kynurenic acid (KYNA) is the only known endogenous broad-spectrum antagonist of ionotropic glutamate receptors¹². Three kynurenine aminotransferases (KAT I, KAT II and KAT III) are responsible for irreversible conversion of L-Kynurenine to Kynurenic acid in the brain^13-14.

The neuroactive effects of Kynurenic acid have been long attributed to its action as a competitive antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptors and this compound strongly inhibits α7 nicotinic receptors (nAChRs)¹⁵.

Kynurenic acid is an Excitatory Amino Acid (EAA) receptor antagonist that can partially act at both the a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-d-aspartate (NMDA) subunits of the glutamate receptors. Its action at the AMPA receptors requires relatively high concentrations (ED50 > 100 lM) as compared with the concentrations, which are known to affect the NMDA receptors¹⁶.

D-Cycloserine:

D-Cycloserine is an antibiotic effective against Mycobacterium Tuberculosis. It is used for the treatment of tuberculosis. It is also being trialed as an adjuvant to exposure therapy for anxiety disorders, depression, Obsessive-Compulsive Disorder and Schizophrenia. It has been experimentally used for treatment of Gaucher's disease. D - Cycloserine's act as a agonist of the neuronal NMDA receptor for glutamate and have been examined in implications with sensory-related fear extinction in the amygdala, and extinction of cocaine seeking in the nucleus accumbens has been shown to have cognition-enhancing properties for models of Parkinson’s disease. D - Cycloserine, an agonist at the glycine site of the NMDA receptor, enhances the development of rapid tolerance. D-cycloserine, a partial agonist at the glycine modulatory site associated with the glutaminergic NMDA receptor complex and exerts anticonvulsants activities and improves cognition function and noncompetitively enhancing NMDA neurotransmission^17,18. D-cycloserine may have cognition-enhancing properties and diminished negative symptoms¹⁹.

MATERIALS AND METHODS:

Subject:

Adult male (Swiss) mice of the weighing 21-25gm., breed in the animal house of Institute of Pharmaceutical Education and Research Wardha, were procured. All animals were housed in polypropylene cages under controlled conditions of temperature (22±2⁰C), humidity controlled (50+5%) environment and illumination (12 h light–dark cycle), with free access to food (Isocalaric diet) and water. The animals were treated in accordance with the CPCSEA guidelines for the care and use of laboratory animals and in agreement with the Institutional Animal Ethical Committee (Reg. No.535/02/a/CPCSEA/Jan2002) of IPER, Wardha. The number of animals used and their sufferings were minimized in all experiments designed.

Drugs and Solution:

Kynurenic acid wasobtained from (Sigma- Aldrich Co, St Louis, MO USA), Administered by Intraperitonial route (I.P.) D- Cycloserine (Sigma- Aldrich Co, St Louis, MO USA) Administered by Intraperitonial route (I.P.). Nicotine (Sigma- Aldrich Co, St Louis, MO USA),

Induction of Nicotine dependence in mice.

Nicotine dependence was induced in mice using an earlier reported method. To develop nicotine dependence, the mice were housed individually in small cages (28 ×14 × 14cm) and provided with a nutritionally balanced control liquid diet (on day 0 as their sole nutrient source (600 kcal/L). From days 1 to 4, nicotine (25ug) was incorporated into the liquid diet, followed by 50ug of nicotine (days 5–7) and 100ug of nicotine (days 8–10). On day 11, at 0800 h, the nicotine liquid diet was replaced with a nutritionally balanced control liquid diet. Mice from the control group were provided with liquid diet without nicotine from days 0 to 10, which was isocaloric to the nicotine liquid diet on respective days. Liquid diets was daily prepared and replaced at 0800 h. At the end of this feeding pattern, no significant difference was observed in the weights of mice from the nicotine liquid diet and control liquid diet groups.

Measurement of Nicotine Withdrawal Syndrome in Mice:

Following parameters were measured during nicotine withdrawal

1) Hyper excitability sign

2) Social interaction test

Hyperexcitabilty sign:

The Nicotine dependence was assessed by scoring the withdrawal-induced physical signs of Hyperexcitability, graded as shown in Table 1. In brief, each mouse was lifted by the tail, spun gently through a 180° arc and held 30 cm away under an angle poise lamp (60watt) for 3s; nicotine withdrawal-induced physical signs were observed and graded at hourly intervals for 10 h to determine the time of peak withdrawal signs. The observations and grading were made by an experimenter who was unaware of treatment groupidentity²⁰.

Table 1: Rating Score for Ethanol Withdrawal Sign

Sr. No.	Withdrawal sign	Score
1	Vocalization on handing	1
2	Urination on handing	1
3	Defecation on handing	1
4	Caudal posture (3-0) Limp or normal tail Stuff, curls around fingers Stiff, curls around finger, stays elevated after release Spontaneous abnormal posture of tail such as lift above back, stiff, curls around fingers and stays elevated after released	0 1 2 3
5	Tremor (0-3) No tremors Mild tremor in one portion of body (i. e. face) Occasional generalized tremor Constant generalized tremor	0 1 2 3
6	Startle (3-0) None Twitch Jump of freeze Exaggerated jump of freeze	0 1 2 3
7	Convulsions on handling (0-3) None Short duration clonic Multiple clonic Tonic-clonic	0 1 2 3
8	Death	10

Social interaction test:

The social interaction test was performed in a clear plastic box (neutral cage: 60×60×35cm) as described earlier experimentations were carried out in a sound attenuated chamber illuminated with white light LED (50 lux). On the 1st and 2nd day, each mouse was subjected to the neutral cage for 5 min to acclimatize. On day 3rd (test day), after i.p. (30 min) injections, each treated mouse was paired with unfamiliar non-treated mouse and placed in the neutral cage for 5 min. The experimenter remained outside the sound attenuated chamber during the test period. Behaviour of mice was video recorded by a camera placed 2m above the cage and then cumulative time spent in social interaction behaviour such as sniffing, adjacent lying, following, crawling under/over partner and mutual grooming was measured for 5 min. After each test, the fecal matter from the cage was removed and the cage was cleaned with damp cotton soaked with nicotine. Trained experimenter blind to the treatments carried out the analysis of the recordings. Increase social interaction was considered as an anxiolytic effect²¹.

Influence of KYNA and D-cycloserine on Nicotine Withdrawal Syndrome:

Chronic Treatment (Administered from day 1-10):

To assess the influence of chronic treatment of kynurenic acid and D-cycloserine on hyperexcitability signs of nicotine withdrawal, separate groups of mice administered with kynurenic acid (50mg/kg, 100mg/kg, i.p.), D-cycloserine (10mg/kg, 20mg/kg, i.p.) or saline once daily along with nicotine exposure. Twenty four hour after nicotine withdrawal individual mice was subjected for assessment of hyper excitability signs like vocalization on handling, urination on handling, defecation on handling, caudal posture, tremor, startle, convulsion on handling, death etc. (Table 1). The experiment was also designed to evaluate the effect of chronic treatment of kynurenic acid and D-cycloserineon nicotine withdrawal induced anxiety. 24 h post withdrawal condition during which maximum anxiety observed; the animals were challenged with kynurenic acid (50 and 100mg/kg, i.p.) or D-cycloserine (10mg/kg, 20mg/kg, i.p) or saline. Thirty minutes after, all the animals were subjected to the social interaction test.

Acute treatment (Administered 30 min before withdrawal):

This experiment examined the influence of acute effect of kynurenic acid or D-cycloserine (10mg/kg, 20mg/kg, and i.p) on hyper excitability signs of nicotine withdrawal. Separate groups of mice were administered with kynurenic acid (50 and 100mg/kg i.p.) or D-cycloserine (10mg/kg, 20mg/kg, i.p) or saline 30 min prior to nicotine withdrawal. Thirty minutes thereafter, individual mice were subjected for assessment of hyper excitability sign as described earlier. The experiment was also designed to evaluate the effect of acute treatment of kynurenic acid and D-cycloserineon nicotine withdrawal induced anxiety. 24 h post withdrawal condition during which maximum anxiety observed; the animals were challenged with kynurenic acid (50 and 100mg/kg, i.p.) or D-cycloserine (10mg/kg, 20mg/kg, i.p) or saline. Thirty minutes after, all the animals were subjected to the social interaction test.

Statistical analysis:

Data were analysed using Prism 5 for Windows (version 5.02). The data are presented as mean ± SEM. Statistical significance was determined by Student’s t-test. The data obtained from nicotine-withdrawn and pair fed mice were compared by two way ANOVA followed by Bonferroni post-test. Treatment of drugs in nicotine-withdrawn mice was analysed by one-way repeated-measures ANOVA, and individual means were compared by Tukey’s t-test. A value of P < 0.05 was considered significant.

RESULTS:

Nicotine withdrawal-induced behavioral changes:

Behavioral signs of nicotine withdrawal syndrome, such as vocalization on handling, urination on handling, defecation on handling, caudal posture, tremor, startle, convulsion on handling, etc. appeared during the whole observation period (Table 1) and peak effect were observed at 24 h of nicotine withdrawal as compared to control group on modified liquid diet. Moreover, anxiety increases social interaction time in the nicotine-dependent groups at the 24 h of the withdrawal-testing period as compared to the nicotine non-dependent saline groups (Student's t test; P<0.05). No nicotine withdrawal signs were observed in the nicotine non-dependent mice. Significant interaction was observed between 24 h time interval and withdrawal signs.

Acute effect of Kynurenic acid and D-cycloserine on Nicotine Withdrawal Induced Hyperexcitability signs in mice.

The effect of different treatments of kynurenic acid (50 and 100mg/kg) and D-cycloserine (10mg/kg and 20mg/kg) on nicotine withdrawal scores in nicotine withdrawal induces Hyper excitability signs. The effect of different treatments of kynurenic acid (50 and 100mg/kg) and D-cycloserine (10mg/kg and 20mg/kg) on nicotine withdrawal scores in nicotine withdrawal induces Hyper excitability signs.

DISCUSSION:

In the present study, nicotine dependence was induced in mice by chronic administration of nicotine liquid diet for 10 days as described earlier²⁰. On day 11, withdrawal produced an increase in the scores of physical activity at 5–9 h with a peak at 7 h indicating withdrawal-induced hyperexcitability in mice. Glutamate is the most abundant excitatory neurotransmitter in the central nervous system (CNS). It was reported that local administration of nicotine could elevate extracellular levels of glutamate in the rat NTS, while the release of glutamate in the NTS in response to baroreceptor stimulation could be suppressed by nicotinic antagonist. Microinjections of glutamate and the ionotropic glutamate receptor agonists, NMDA and AMPA, into the NTS can produce pronounce hypotension and bradycardia. Thus, gating ionotropic glutamate receptors might be involved in the mechanism of nAChRs modulated cardiovascular effects in the NTS²². The observations further indicated that acute treatment with kynurenic acid dose-dependently attenuated nicotine withdrawal-induced hyperexcitability signs, whereas mice treated with kunurenic acid during the development of nicotine dependence failed to show nicotine withdrawal-induced hyperexcitability signs. The mechanism by which kynurenic acid produced these effects is not known. Moreover, reduction of KYNA levels increases vulnerability to excitotoxic insults, whereas elevation of KYNA content has an opposite effect²³. Chronic exposure to nicotine modulates dopamine transmission by directly activating dopamine neurons in the VTA or by indirectly modulating excitatory glutamate or inhibitory GABA transmission. This hypothesis is based on ﬁndings that chronic nicotine self- administration up regulated NMDA and AMPA receptor subunit expression in the VTA and amygdala. The role of mGluRs in nicotine dependence and withdrawal has been investigated the down regulation of mGluRfunction in the NAc shell, hypothalamus, and hippocampus was observed during early withdrawal from nicotine self-administration²⁴. These data indicate that activation of excitatory nAChRs on glutamatergic terminals also may contribute to the acute reinforcing properties of nicotine²⁵. Kynurenic acids (KYNA), an endogenous antagonist of the a7 nicotinic acetylcholine (ACh) receptor, modulate extracellular ACh levels in the medial prefrontal cortex in rats. A non-competitive a7nAChR antagonist, KYNA acts as an allosteric inhibitory factor at a site that is very similar to that activated by the cognition enhancer galantamine²⁶. Dysfunctions of the excitatory amino acid system may also play a role in the pathophysiology of dystonia, i.e., a relatively common neurological syndrome of involuntary muscle contractions causing twisting movements or abnormal postures²⁷. Glutamatergic neurotransmission plays a pivotal role in the pathogenesis of epilepsy and antagonists of glutamate receptors are powerful anticonvulsants. The drug used in present study i.e. Kynurenic acid is a NMDA receptor antagonist and D-cycloserine is a NMDA receptor agonist. Kynurenic acid is also agonist of dopamine receptor.

CONCLUSION:

The present study demonstrated that chronic treatment of kynurenic acid produced inhibitory effect of withdrawal syndrome in mice. However, administration of kynurenic acid 30 min before nicotine withdrawal did not alter the enhance hyper excitability signs in nicotine dependent in mice. Whereas D-cycloserine 30 min before alter the enhance hyper excitability signs in nicotine dependent in mice. The present investigation revealed that chronic nicotine exposure significantly (***p<0.001) prevent the induction of nicotine dependence as characterized by reduction in several hyper excitability signs of nicotine withdrawal and not associated with acute effect of kynurenic acid and D-cycloserine. In agreement with earlier finding, with our experiment schedule, mice that received nicotine with liquid diet showed increase in several hyper excitability sign such as vocalization on handling, defecation on handling, urination on handling, caudal posture, tremor, startle response, and also increase in anxiety as characteristic features of nicotine withdrawal syndrome in nicotine dependent mice. Thus NMDA receptor antagonist (Kynurenic acid) decreases all the function of NMDA receptor. Whereas NMDA receptor agonist (D-cycloserine) increases all function of NMDA receptor. The present study, first time provide evidence that chronic treatment with kynurenic acid is effective in attenuating nicotine withdrawal syndrome. Nicotine dependence was produced by chronic exposure of mice to nicotine and modified liquid diet for 10 days with gradual increase in concentration of nicotine up to 10 % (v/v). Rest of animals continued on nutritionally balanced isocalaoric control liquid diet containing BOURNVITA as caloric substituted to nicotine. (Pair fed liquid groups). Chronic nicotine treatment was discontinued after 10 days and withdrawal signs were evaluated such as, hyper excitability signs, Anxiety. Chronic treatment of kynurenic acid attenuated nicotine withdrawal hyper excitability signs. Chronic administration of kynurenic acid also counteracts anxiety by increasing social interaction time in social interaction test apparatus but chronic administration of D-cycloserine by decreasing social interaction time in social interaction test apparatus. However, administration of acute (single dose) after termination of nicotine treatment failed to attenuate nicotine withdrawal. Hence, kynurenic acid is a novel target for drugs that reduced nicotine intake and may be used to treatment of nicotine withdrawal induced behavioural changes. In conclusion, the results and evidence suggest that kynurenic acid exhibited an inhibitory influence against nicotine withdrawal-induced hyperexcitability signs which could be mediated through its neuromodulatory action.

ACKNOWLEDGEMENT:

The authors would like to thank Dr. P.G. Yeole, (Principal) Institute of Pharmaceutical Education and Research, Borgaon Meghe Wardha, for funding the research under the head of Excellence in Research and Academics.

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Received on 12.02.2021 Modified on 27.04.2021

Asian J. Res. Pharm. Sci. 2021; 11(3):205-212.

DOI: 10.52711/2231-5659.2021.00033