Printer Friendly

Chronic administration of sertraline, clozapine, amitriptyline and imipramine affects brain serotonin, liver enzymes and blood chemistry of rabbit.

Introduction

Major depression is one of the most common psychiatric disorders afflicting mankind. It is believed to arise from disturbances in brain neurotransmitters' systems [36]. For the past 30 years, monoamine hypothesis of depression has been the theory of explaining biological basis of depression [36], which states that depression is essentially due to a deficiency in one of the three catecholamines, serotonin, norepinephrine and dopamine[19-21]. Antidepressants help restore the chemistry of the brain so that normal mood and behaviour can be returned. Antidepressants are classes of psychotherapeutic drugs that are used to treat major depression [36,23]. They are classified into 4 groups, namely monoamine oxidase (MAO) inhibitors, tricyclic anti-depressants, selective serotonin reuptake inhibitors, (SSRI) and atypical antidepressants [25,4].

Sertraline and clozapine belong to antidepressant and antipsychotic drugs respectively, while imipramine is a tricyclic antidepressant. Biochemical studies on imipramine demonstrated that this drug increased the activity of monoamine neurotransmitters, norepinephrine and serotonin by inhibiting their reuptake into neurons. SSRIs are widely prescribed to treat depression [5,25]. Sertraline is an oral antidepressant drug of the selective serotonin reuptake type. It increases serotonin level in the CNS by inhibiting reuptake of serotonin [4,33].

Antipsychotic drugs can ameliorate the types of delusions and hallucinations characteristic of bipolar disorder (such as depression and schizophrenia). They act in part by blocking dopamine receptors at the synapse, reducing brain activity. Sertraline has been reported to cause weight loss [6]. Sertraline potentiates serotonin by inhibiting its neuronal reuptake [3.8]. Clozapine is a dibenzodiazepine derivative and a truly atypical antipsychotic drug. Its therapeutic effects are probably mediated by dopaminergic and serotoninergic activities. It appears to be the most effective antipsychotic drug for treatment-resistant schizophrenia [23].

Depression is as common as and often more debilitating than chronic medical ailments, such as arthritis and diabetes [4,33]. Serotonin is a neurotransmitter synthesized from tryptophan and is responsible for emotional stability, mood, anxiety, arousal, aggression, nutrient selection, sleep and sex [18]. Amitriptyline inhibits the reuptake of noradrenaline and serotonin with similar potency, while the metabolic nortriptyline inhibits the reuptake of noradrenaline to a great degree than serotonin. It is a potent antagonist of both peripheral and central muscarinic drolinergic receptors. It is used to elevate the mood of patients with depression [23,28,24,26] with insomnia, restlessness and nervousness.

Imipramine is an antidepressant of the dibenzazepine group, mainly used in the treatment of clinical depression and enuresis [38]. Clozapine causes nausea, vomiting, constipation, elevation of liver enzymes (up to 10%), hypersalivation, confusion, impotence (6%), benign hyperthermia (5-15%) and development or exacerbation of obsessive compulsive symptoms.

From the wealth of literature, there is scanty or no report on the effect of administration of antidepressants on the brain serotonin, liver enzymes and blood chemistry. In view of the use of antidepressants, such as, sertraline, clozapine, amitriptyline and imipramine in the management of psychiatric disorders, it is therefore imperative to decipher whether these drugs affect brain serotonin levels, activities of liver enzymes and blood chemistry of patients. The aim of the present study therefore, is to determine whether chronic administration of sertraline, clozapine, amitriptyline and imipramine affect brain serotonin level, activities of liver enzymes and blood chemistry of rabbits. The information obtained from this study could be extrapolated to humans, and be useful in biological psychiatry.

Drugs

Sertraline, Clozapine, amitriptyline and imipramine were purchased from reputable pharmacy. Tablets of setraline (50mg) were manufactured by Pfizer Italian S. P. A., Latina, Italy under authority of Pfizer Inc., New York, USA, while tablets of amitriptyline (25mg) from a reputable government owned psychiatric hospital, Yaba, Lagos State, Nigeria. Tablets of clozapine (100mg) were manufactured by Novartis Pharmaceuticals and marketed as clozaril, lepones and fazaclo.

Five tablets of 100mg of clozapine were homogenized and dissolved in 1 litre of saline concentration; 2ml of the 0.5mg/ml clozapine solution were intraperitoneally administered per kg body weight of rabbits. 10 tablets of 50mg sertraline were homogenized and dissolved in 1 litre of saline to produce 0.5mg/ml drug solution. 20 tablets of 25mg amitriptyline or imipramine were homogenized and dissolved in 1 litre of saline to produce 0.5mg/ml drug solution; while 0.89g of NaCl was dissolved in 100ml deionized water, to produce 0.89% saline solution.

Drug administration

Sixty rabbits (1.06 [+ or -] 0.031kg) were equally divided into 5 groups, and kept in a room with a temperature of 28 [+ or -] 2 [degrees]C, illuminated for 12h per day o (0700-1900h). The rabbits were housed 3 in a metallic cage and fed commercial rabbit pellet containing 21% protein and water ad libitum to acclimatized for 14 days. Cares of all animals were as in accordance with the national law on animal care and use.

After 14 days of acclimatization, the rabbits were intraperitoneally administered 2ml of 0.5mg per kg body weight of sertraline, clozapine, amitryptyline, imipramine and 0.89% saline daily for 28 days between 0800 and 1000h. Each group labeled A, B, C, D and E comprising 12 rabbits were separately administrated the respective drugs or saline. Group A, B, C and D represented rabbits administered sertraline, clozapine, amitryptyline and imipramine respectively, while Group E administered saline served as control. The body weight, feed and water intake of the rabbits were computed every other day. From these values, the organo- somatic index (OSI), was calculated by the following formula: Organo-somatic index: Weight (g) of the organ / Day 28 total body weight (g) x 100/1

Three rabbits from each group were sacrificed by decapitation after an overnight fast weekly. Blood was quickly taken by cardiac puncture into heparinized tube, brain and liver were excised. The organs were dried and weighed, placed on ice before storage at -20 C until further analysis. Blood was o centrifuged at 3000g for 10min in an automated refrigerated centrifuge and the plasma was extracted. One gram of brain or liver was homogenized with 10ml of ice cold 0.05M phosphate buffer pH 7.0, using a Teflon glass homogenizer. The homogenate was centrifuged at 7000 rpm for 15min and the supernatant obtained was stored for further analysis. The serotonin concentrations in the brain and liver supernatants were determined using high performance liquid chromatography (HPLC), Agilent 100 series with VWD detector degasser, Quat Pump, Col Com and a manual injector system.

Tissue samples were prepared for injection by liquid phase extraction using chilled acetonitrile, to deproteinized the proteins. The mixture was spiked with an internal standard, 3, 4 dihydroxybenzylamine (DHBA) and using a vortex mixer for 1min. The mixture was centrifuged at 10,000g for 10min and the supernatant was collected and injected into the column. A gradient HPLC method was used to separate and quantify the liver and brain serotonin. Chromatographic separations were carried out on a Hypersil ODS C18 reverse phase column (250 x 4.0mm) packed with 5mm particles. The column was maintained at 25[degrees]C. The mobile phase was 0.025M o phosphate buffer containing 200mg 1-octanesulfonate in distilled water (pH 4.3) and C-methanol. The mobile phase was pumped at 70% of the buffer and 30% of methanol. The flow rate was 1.0 ml/min and wavelength detector was 280nm. The stock solutions of serotonin (5HT) and internal standard, DHBA, were prepared in distilled water at a concentration of 50g/ml. The working standard solutions of 5-HT in 5-HT-free protein solutions in situ.

For each run, serotonin and DHBA standards were processed to identify retention times and to confirm the serotonin elution peak from samples. In all cases, 50ml of samples and standards were injected into the column. The signal from the VWD detector was fed directly to the agilent data acquisition system. The serotonin content was determined by comparing serotonin / DHBA peak height ratios of unknown sample chromatograms with those of chromatograms of serotonin standard used as calibrator.

Protein concentrations were assayed by the method of Lowry et al.,[29] using bovine serum albumin as standard. Plasma and tissue cholesterol and triglyceride levels were determined using Synchron CX5 autoanalyzer. The activities of serum aspartate transaminase (AST, EC 2.6.1.1), alanine transaminase (ALT, EC 2.6.1.2), and alkaline phosphatase (EC 3.1.3.1) were assayed at 37 C o according to the recommended principles [34] and using commercial kits manufactured by Baehringer, Mannheim, Germany and Roche, Switzerland.

Results and discussion

Results of the changes in body weight, feed and water intake of rabbits administered (i.p) sertraline, clozapine, amitriptyline, imipramine and saline for 28 days are shown in Table 1. The body weights of the rabbits administered the irrespective drugs or saline significantly (p<0.01) increased irrespective of the drug, as compared to the initial mean body weight of 1.06 [+ or -] 0.031kg/rabbit. However, the body weights of rabbits administered amitriptyline and imipramine wee significantly higher than in rabbits administered sertraline, clozapine or saline. Mean feed and water intake of rabbits administered amitriptyline and imipramine were significantly (p<0.01) higher than in sertraline, clozapine or saline administered rabbit (Table 1). However the mean feed or water intake of rabbits administered saline was significantly (p<0.01) lower than in rabbits administered sertraline, clozapine, amitriptyline and imipramine.

The results of the mean liver and brain weights, and organo-somatic index of livers or brains of rabbits administered the respective drugs and saline are presented in Table 2. The mean liver weight of rabbits administered imipramine was significantly (p < 0.01) higher than in rabbits administered Sertraline or clozapine or amitriptyline or saline . There was no significant difference in the organo-somatic index of the livers of rabbits administered the respective drugs or saline (Table 2).

The mean brain weight of rabbits administered saline was significantly (p<0.01) higher than in rabbits administered sertraline, clozapine, amitriptyline, imipramine and saline. However the mean brain weight of rabbits administered clozapine was significantly the lowest as compared to rabbits administered the other drugs. (Table 2). The organosomatic index of br5ains of rabbits administered saline was significantly (p<0.01) lower than in rabbits administered Sertraline or clozapine, but higher in rabbits administered amitriptyline or imipramine (Table 2 ).

The concentrations of serotonin in serum and brains of rabbits administered (i.p) sertraline, clozapine, amitriptyline, imipramine and saline are shown in Table 3. The serum serotonin and brain serotonin levels in rabbits administered the respective drugs were significantly (p<0.01) higher than in rabbits administered saline. However, rabbits administered imipramine had the highest serum serotonin levels, while brain serotonin levels were highest in sertraline administered rabbits (Table 3).

The concentrations of total protein, cholesterol and triglyceride in the brain of rabbits administered (i.p) sertraline, clozapine, amitriptyline, imipramine and saline are presented in Table 4. Brain protein and cholesterol levels in rabbits administered saline were significantly (p<0.01) lower than in rabbits administered sertraline, clozapine, amitriptyline and imipramine (Table 4). There was no significant (p<0.01) difference in the brain cholesterol levels of rabbits administered the respective drugs. Significant (p<0.01) differences do not exist in brain protein levels of rabbits administered sertraline, amitriptyline and imipramine, but except in clozapine administered rabbits which was significantly (p<0.01) reduced and had the lowest protein level.

The concentrations of total protein, cholesterol and triglyceride in the liver of rabbits administered sertraline, clozapine, amitriptyline, imipramine and saline are presented in Table 5. Liver protein level of rabbits administered saline was significantly (p<0.01) lower than in rabbits administered sertraline, clozapine, amitriptyline or imipramine. There was no significant difference in the liver protein level of the rabbits administered sertraline or clozapine, amitriptyline or imipramine. The liver cholesterol levels of rabbits administered saline was significantly (p<0.01) lower than in rabbits administered sertraline or clozapine, while it was higher in amitriptyline or imipramine administered rabbits (Table 5). Liver triglyceride level of rabbits administered saline was significantly lower than in rabbits administered the respective drugs. (Table 5).

The concentrations of total protein, cholesterol and triglyceride in the serum of rabbits administered (i.p). sertraline, clozapine, amitriptyline, imipramine and saline for 28 days are presented in Table 6. There was no significant (p<0.01) difference in the serum protein levels of rabbits administered sertraline, clozapine, amitriptyline, imipramine and saline. Serum cholesterol level of rabbits administered saline was significantly (p<0.01) lower than in rabbits administered respective drugs. However, rabbits administered amitriptyline and imipramine had significantly higher serum cholesterol levels as compared with those administered sertraline, clozapine or saline. Serum triglyceride levels in the rabbits administered the respective drugs or saline were not significantly different (p<0.01).

Serum alkaline phosphatase (ALP), aspartate transaminase (APT) and alanine transaminase (ALT) activities of rabbits administered sertraline, clozapine, amitriptyline, imipramine or saline for 28 days are presented in Table 7. Serum ALP activities of rabbits administered amitriptyline and imipramine were significantly (p<0.01) higher compared with those administered sertraline, clozapine or saline. However, serum ALP activity of rabbits administered clozapine was significantly the lowest. Serum APT and ALT activities of rabbits administered saline were significantly (p<0.01) lower than in those administered the respective drugs (Table 7). Liver ALP, APT and ALT activities of rabbits administered sertraline, clozapine, amitriptyline, imipramine and saline for 28 days are shown in Table 8. The liver ALP, activity of rabbits administered saline were significantly (p<0.01) lower than in rabbits administered the respective drugs.

Discussion

Behavioural changes were reported in rabbits intraperitoneally administered sertraline, clozapine, amitriptyline and imipramine for 28 days. The rabbits were restless and hyperactive, indicating significant stimulation of spontaneous activity of the nerves. Some of the rabbits demonstrated varying degrees of hair loss, especially around the easy, neck and nose. Other behavioural signs observed in the rabbits, include dry nose and mouth, photosensitivity, frequent urination and disorientation. This observation is in agreement with the previous reports of Karolewick et al., [22,14,15].

The intraperitoneal administration of amitriptyline and imipramine resulted in an increase in body weights of rabbits. This suggest that these drugs may stimulate appetite and protein synthesis and ultimately body growth. Allison et al, [1] reported a little weight gain, while others reported setraline caused weight loss [6]. Wood et al., [37] reported that chronic administration of potent and selective 5-HT antagonists does not induce weight gain in rat. The present findings concur previous results that sertraline administration resulted in body weight loss of rabbit. It is not clear how amitriptyline and imipramine promoted growth. With the exception of the rabbits administered imipramine, the mean liver and brain weights were significantly higher compared to liver, brain weights of other rabbits administered the respective drugs. This may suggest that imipramine promotes organ growth, especially, liver and brain.

The increase in serum and brain serotonin levels of rabbit administered sertraline, clozapine, imipramin and amitryptyline drugs may promote serotonin synthesis in the brain. For example, the antidepressant effect of setraline is presumed to be linked to its ability to inhibit the uptake of serotonin [7,20]. Sertraline potently inhibits the uptake of serotonin into neurons in vitro. Sertraline lowers 5-hydroxy indole acetic acid level in the brain by reducing serotonin (5-HT) turn over [27,35].

This probably accounts for the increase concentration of serotonin in the serum and brain of rabbits. From the wealth of literature, there is no report on whether intraperitoneal administrations of clozapine, imipramine and amitriptyline affects serum and brain serotonin levels. It could be suggested that these antidepressants may also intrasynaptically inactivate serotonin.

Additionally, data of the study obtained in the serum and brain serotonin could also suggest that the transport of these antidepressants or their metabolites across the blood brain barrier (BBB) was not impaired and did not reflect any blockage of serotonin receptors. Previous studies by Cottingham[6], reported that thioridazine, an antipsychotic drug, blocks cholinergic, adreninergic and histamine receptors causing a variety of side effects. The significantly higher levels of serotonin in rabbits administered these respective antidepressants may also mediate neural functions culminating in the behavioural changes observed in rabbits used in this study.

Ebuehi et al., [10,11,12,13,16] previously, reported that malnutrition, marijuana smoking, caffeine and ethanol consumption altered the metabolism of 5-HT in the rat. For instance, caffeine consumption enhanced 5HT levels in plasma and brain, while a decrease in 5-HT level was found in acute and chronic ethanol treated rats. It has been reported that imipramine increases plasma 5-HT level by blocking the re-uptake of 5-HT, more so than most secondary amine tricyclics [38]. Serum, liver and brain protein, cholesterol and triglyceride concentrations were significantly elevated in rabbits administered the respective anti-depressants and these findings may indicate that these drugs potentiate protein and lipid biosyntheses. However, the precise mechanism of action by these drugs remain to be ascertained, viz a viz the roles they play in the biosynthesis of these biomolecules.

Too little is known about the influence of antidepressants on the synthesis of biomolecules. Ebuehi et al., [14] previously reported that sertraline and thioridazine administration potentiated protein levels in the brain, liver and heart of rabbits, but had no effect on brain monoamine oxidase activity. Some of the present findings in this study are in harmony with the data obtained by previous workers [6,15,20,17], but data on the effects of these anti-depressants on cholesterol and triglyceride levels in serum, liver and brain, are relatively new contribution to the existing body of knowledge.

Serum and liver alkaline phosphatase, aspartate transaminase (AST) and alanine transaminase (ALT) activities in rabbits administered sertraline, clozapine, amytriptyline and imipramine were elevated and since they are serum liver derived enzymes , data of this study indicate administration of these drugs posed a threat and prolonged liver damage and disease (Patel and O'Gorman [31], Ebuehi and Asonye [17]. It is important to mention that the severity of liver damage was more pronounced by imipramine or amytriptyline administration, while the least effect was by clozapine. Serum and liver alkaline phosphatase activities of rabbits administered imipramine or amytriptyline were the highest as compared to those administered clozapine or sertraline, which indicate the possibility of abnormal destruction of erythrocytes, leukocytes and other cells [31,34]. However, it is imperative to state that the outcome of the present findings may not necessarily be in agreement with researches carried out on depressed patients, which have the capacity to response in the totally different way from healthy individuals.

In conclusion, data of the present study indicate that intraperitoneal administration of imipramine or amitriptyline produced a more pronounced effect than sertraline or clozapine on brain serotonin, liver enzymes' activities and blood chemistry of rabbits. These antidepressants may affect in varying degrees neural functions mediated by serotoninergic neurotransmission.

References

[1.] Allison, D.B., J.L. Mentore, M. Heo, L.P. Chandler, J.C. Cappelleri, M.C. Infante and P.J. Weiden, 1999. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am. J. Psychiatry, 156: 1686-1696.

[2.] Banki, C.M., 1978. Alterations of CSF, 5HIAA and total blood 5HT content during clozapine treatment. Psychopharmacology, 56: 195-198.

[3.] Bustillo, J.R., R.W. Buchanam, D. Irish and A. Breier, 1996. Differential effect of clozapine on weight: a controlled study. Am. J. Psychiatry, 153: 817-819.

[4.] Cantrell, R., W. Gillespie and L. Altshuter, 1999. Fluoxetirie and sertraline dosages in major depression. Depr. Anxiety, 9: 78-82.

[5.] Cohen, B.M., J.E. Lipinki and D. Waternaux, 1989. A fixed dose study of the plasma concentration and clinical effects of thioridazine and its major metabolites Psychopharmacology, 97: 481-488.

[6.] Cottingham, J., 2000. Thioridazine/Mellaril Parkinson's List Drug Data-base index, pp. 1-4.

[7.] Doorgan, D.P. and V. Caillard, 1988 . Sertaline: a new antidepressant. J. Clin. Psychiatry, 49 (Suppl): 46-47.

[8.] Doss F.W., 1979. The effect of antipsychotic drug on body weight; a retrospect view. J. Clin. Psychiatry (Dec.), 40(12): 528-530.

[9.] Dursun S.M., A. Szemis, H. Andrews, P. Whitaker and M.A. Revelev, 2000. Effect of clozapine and typical anti-psychotic drug on plasma 5HT turnover and impulsivity in patients with schizophrenia: a cross-sectional study. J. Psychiatry Neurosci. Sep, 25(4): 347-352.

[10.] Ebuehi, O.A.T. and A.I. Akinwande, 1993. An indirect evaluation of the effect of material and post weaning protein and tryptophan malnutrition on the central serotoninergic metabolism. Nig. Qt. J. Hosp. Med., 5(1): 48-55.

[11.] Ebuehi, O.A.T., A.O. Adenuga and O.O. Erinle, 1999. Effect of caffeine and ethanol consumption on the metabolism of 5-hydroxy tryptamine in rats J. Med. and Med. Sci., 1(1): 31-38.

[12.] Ebuehi O.A.T. and A.I. Akinwande, 1996. Maternal and post weaning protein and tryptophan malnutrition on serotonin concentration in rat platelets. West Afr. J. Biol. Sci., 4(2): 122-124.

[13.] Ebuehi O.A.T., A.I. Akinwande, O.O. Famuyiwa and E.O. Uzodinma, 2005. Effect of marijuana smoking on blood chemistry and serum biogenic amines concentrations in Humans. Nig. J. of Health and Biomed. Sci. Jan.-June, 4(1): 20-24.

[14.] Ebuehi, O.A.T., A.O. Sanya, and O.A. Lewis, 2004. Sertraline and Thioridazine on the metabolism of serotonin in Rabbit Brain, Liver and Heart. African Scientist, 5(1): 27-33.

[15.] Ebuehi O.A.T., O.Q. Asuni and Y.C. Kayode, 2004. Effect of sertraline and haloperidol on the metabolism of adrenaline and histamine in rabbit brain. African Scientist, 5(1): 21-26.

[16.] Ebuehi O.A.T., S.A. Bishop, O.O. Famuyiwa, A.I. Akinwande and O.A. Ladengan, 2001. Biogenic amines metabolism and blood chemistry of psychiatric patients. Afr. Med. and Medical Sci., 30: 269-273.

[17.] Ebuehi, O.A.T. and C.L. Asonye, 2007 .Gender and Alcohol consumption affect human serum enzymes protein and bilirubin. Asian J. Biochemistry, 2(5): 330-336.

[18.] Fernstrom, J.D. and M.J. Hirsch, 1977. Brain serotonin synthesis. Reduction in coramalnourished rats. J. Neurochem, 28: 877-883.

[19.] Feighner, J.P., 1999. Mechanism of action of antidepressant medications. J. Clin. Psychiatry, 60(Suppl)4: 4-11.

[20.] Frazer, A., 1997. Pharmacology of antidepressants. J. Clin. Psychopharmacology, 17: 125-127.

[21.] Hollister, L.E., J.E. Overall, M. Johnson, et al, 1964. Controlled comparison of amitriptyline, imipramine and placebo in hospitalized depressed patients. J. Nerv. Ment. Dis., 139: 370-375.

[22.] Karolewick, B., L. Antiewiez-Micchaluk, J. Micha, and J.H. Vetulani, 1996. Different effects of chronic administration of haloperidol and primozide on dopamine metabolism in the rat brain. Eur. J. Pharmacol., 313(3): 181-186.

[23.] Kane, J., G. Honigfied and J. Singer, 1989. Clozapine for treatment-resistant schizophrenic. result of a U.S. multi-centre trial. Psychopharmacology, 99: 560-563.

[24.] Klerman, G.L. and J.O.C. Cole, 1976. Clinical pharmacology of imipramine and related antidepressant compounds. Int. J. Psychiatry, 3: 267-304.

[25.] Marken, P.A., 2000. Selecting a selective serotonin reuptake inhibitor: Clinically important distinguishing features. Primary care companion. J. Clin. Psychiatry, 2: 205-210.

[26.] McConaghy, N., A.D. Joffe, W.R. Kingston, et al, 1968. Correlation of clinical features of depressed outpatients with response to amitriptyline and protriptyline. Br. J. Psychiatry, 114: 103-106.

[27.] Laporta, M., G. Chouinard, D. Goldbloom and D. Beaudiar, 1987. Hypomania induce by sertraline, a new serotonin re-uptake inhibitor. Am. J. Psychiatry. 144: 1513-1514.

[28.] Lieberman, J.A., A.Z. Safferman and S. Pollack, 1994. Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcomes. Am J. Psychiatry, 151: 1744-1752.

[29.] Lowry, O.H., N.J. Rosenbrough, A.L. Farr and R.L. Randall, 1951. Protein measurement with Folin phenol reagent. J. Biol. Chem., 193: 265-275.

[30.] Meltzer, H.Y., 1990. Effects of six months clozapine treatment on the quality of life of chronic schizophrenic patients, Hosp Com. Psychiatry, 52: 892-897.

[31.] Patel, S. and P. O'Gorman, 1975. Serum enzyme levels in alcoholism and drug dependency. J. Clin. Pathol., 28: 414-417.

[32.] Ruch, W. and H.R. Asper, 1976. Effect of Clozapine on the metabolism of serotonin in rat brain. Psychopharmacology, 46(1): 103-109.

[33.] Solai L.K., B.H. Mulsant, B.G. Pollock, et al, 1997. The effect of setraline on the pharmacokinetics of desipramine and imipramine. Clin. Pharmacol. Ther., 62: 145-156.

[34.] Steffensen, F.M., H.T. Sorensen, A. Brock, H. Vilstrup and T. Lauritzen, 1997. Alcohol consumption and serum liver derived enzymes in a Danish population aged 30-50 years. Int. J. Epidemiol., 26: 92-99.

[35.] Tremain, L.M., W.M. Wlch and R.A. Ronfield, 1989. Metabolism and deposition of 5HT blocker Sertraline in rat . Drug Metabolism Disposition, 17: 542-552.

[36.] Trujillo, M., 1996. Antidepressants and the brain. California State Univ. Press, USA, pp. 24-36.

[37.] Wood, M.D., C. Reavill, I.B. Trai, A. Wilson, T. Stean, G.A. Kenneth, S. Liughtowler, T.P. Blackburn, D. Thomas, T.L. Gager, G. Riley, V. Hollad, S.M. Bromidge, I.T. Forbes and D.W. Middle, 2001. SB-243213: A selective 2HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety. Neuro Pharmacology, 41: 186-199.

[38.] Wikipedia, 2006. The free encyclopedia, http//en.wikipedia.org/wiki/main. www.en.wikipedia.org/wiki/imipramine/2006.

O.A.T. Ebuehi, C.E.O. Ikanone and A.A. Balogun

Department of Biochemistry, College of Medicine, University of Lagos, P.M.B. 12003, Lagos, Nigeria, W/Africa.

Corresponding Author

O.A.T. EBUEHI, Department of Biochemistry, College of Medicine, University of Lagos, P.M.B. 12003, Lagos, Nigeria, W/Africa. E-mail: ebuehi@yahoo.com
Table 1: Changes in body weight, feed and water intake of rabbits adm
inistered (i.p) sertraline, clozapine, amitriptyline, imipramine and
saline for 28 days. (1,2)

Drug Mean body weight Mean feed intake

Administration (kg/rabbit) (g/rabbit/day)
Setraline 1.16 [+ or -] 0.04 (a) 30.86 [+ or -] 2.14 (a)
Clozapine 1.36 [+ or -] 0.05 (b) 34.22 [+ or -] 3.45 (a)
Amitriptyline 1.60 [+ or -] 0.07 (c) 59.29 [+ or -] 1.62 (b)
Imipramine 1.58 [+ or -] 0.02 (c) 52.67 [+ or -] 4.73 (b)
Saline 1.30 [+ or -] 0.03 (b) 31.51 [+ or -] 1.18 (a)

Drug Mean water intake

Administration (ml/rabbit / day)
Setraline 71.09 [+ or -] 3.06 (a)
Clozapine 72.60 [+ or -] 4.82 (a)
Amitriptyline 95.39 [+ or -] 6.79 (b)
Imipramine 93.71 [+ or -] 3.05 (b)
Saline 75.16 [+ or -] 3.64 (a)

(1) Values are expressed as Mean [+ or -] S.D. (n=10) in
triplicate determ inations.

(2) Values carrying different superscripts vertically are
significantly (p<0.01) different.

Table 2: Liver and brain weights of rabbits administered (i.p)
sertraline, clozapine, amitriptyline, imipramine and saline for 28
days (1,2)

Drug Mean body Organo-somatic
administration weight (g/rabbit) index * {liver(%)}

Setraline 27.64 [+ or -] 2.18 (a) 2.08 [+ or -] 0.16 (a)
Clozapine 28.77 [+ or -] 1.43 (a) 2.10 [+ or -] 0.34 (a)
Amitriptyline 26.21 [+ or -] 1.05 (a) 1.86 [+ or -] 0.28 (b)
Imipramine 33.22 [+ or -] 0.46 (b) 1.92 [+ or -] 0.17 (b)
Saline 26.78 [+ or -] 1.13 (a) 1.81 [+ or -] 0.15 (b)

Drug Mean brain weight Organo-somatic
administration (g/rabbit) index {brain (%)}

Setraline 6.07 [+ or -] 0.18 (a) 0.55 [+ or -] 0.08 (a)
Clozapine 4.81 [+ or -] 0.32 (b) 0.53 [+ or -] 0.14 (a)
Amitriptyline 5.46 [+ or -] 0.47 (c) 0.31 [+ or -] 0.07 (b)
Imipramine 6.14 [+ or -] 0.59 (a) 0.34 [+ or -] 0.05 (b)
Saline 6.46 [+ or -] 0.21 (a) 0.44 [+ or -] 0.06 (c)

* O rgano/som atic index = weight (g) of the organ/Day 28 total body
wt (g) X 100/1

(1) Values are expressed as M ean [+ or -] S.D . (n=10) in triplicate
determinations.

(2) Values carrying different superscripts vertically are
significantly (p<0.01) different.

Table 3: Concentration of serotonin in serum and brain of rabbits
administered (i.p) sertraline, clozapine, amitriptyline, imipramine
and saline for 28 days. (1,2)

 Serum serotonin Brain serotonin
Drug administration ([micro]g/m l) ([micro]g/m l)

Setraline 5.86 [+ or -] 0.43 (a) 7.86 [+ or -] 0.46 (a)
Clozapine 5.05 [+ or -] 0.38 (b) 7.05 [+ or -] 0.54 (b)
Amitriptyline 5.49 [+ or -] 0.52 (a) 6.84 [+ or -] 0.70 (b)
Imipramine 6.23 [+ or -] 0.27 (b) 6.37 [+ or -] 0.43 (c)
Saline 4.20 [+ or -] 0.65 (c) 5.51 [+ or -] 0.38 (d)

(1) Values are expressed as Mean [+ or -] S.D. (n=10) in triplicate
determinations.

(2) Values carrying different superscripts vertically are
significantly (p<0.01) different.

Table 4: Concentrations of total protein, cholesterol and
triglyceride in the brain of rabbits administered (i.p) sertraline,
clozapine, amitriptyline, imipramine and saline for 28 days (1,2).

Drug Brain
administration
 Protein Cholesterol
 (g/l) (mmol/l)

Setraline 41.14 [+ or -] 2.06 (a) 1.60 [+ or -] 0.24 (a)
Clozapine 29.65 [+ or -] 1.14 (b) 1.50 [+ or -] 1.76 (b)
Amitriptyline 38.91 [+ or -] 2.49 (a) 1.69 [+ or -] 0.07 (c)
Imipramine 40.15 [+ or -] 3.62 (b) 1.86 [+ or -] 0.05 (d)
Saline 22.16 [+ or -] 0.84 (b) 0.70 [+ or -] 1.04 (e)

Drug
administration
 Triglyceride
 (mmol/l)

Setraline 8.45 [+ or -] 0.65 (a)
Clozapine 9.03 [+ or -] 0.92 (b)
Amitriptyline 9.75 [+ or -] 0.73 (c)
Imipramine 9.14 [+ or -] 0.52 (b)
Saline 7.78 [+ or -] 0.32 (d)

(1) Values are expressed as Mean [+ or -] S.D. (n=10) in triplicate
determ inations.

(2) Values carrying different superscripts vertically are
significantly (p<0.01) different.

Table 5: Concentrations of total protein, cholesterol and triglyceride
in the liver of rabbits administered (i.p) sertraline, clozapine,
amitriptyline, imipramine and saline for 28 days (1,2).

Drug
administration Liver

 Protein (g/l) Cholesterol (m m ol/l)

Setraline 22.75 [+ or -] 3.16 (a) 3.30 [+ or -] 0.24 (a)
Clozapine 19.98 [+ or -] 2.04 (a) 2.10 [+ or -] 0.41 (b)
Amitriptyline 22.84 [+ or -] 1.16 (a) 0.55 [+ or -] 0.04 (c)
Imipram ine 23.16 [+ or -] 2.95 (a) 0.68 [+ or -] 0.05 (d)
Saline 15.53 [+ or -] 2.48 (b) 0.86 [+ or -] 0.16 (a)

Drug
administration

 Triglyceride (m m ol/l)

Setraline 6.14 [+ or -] 0.42 (a)
Clozapine 7.28 [+ or -] 0.66 (b)
Amitriptyline 8.14 [+ or -] 0.78 (c)
Imipram ine 8.68 [+ or -] 0.60 (d)
Saline 5.02 [+ or -] 0.49 (e)

(1) Values are expressed as Mean [+ or -] S.D. (n=10) in triplicate
determ inations.

(2) Values carrying different superscripts vertically are
significantly (p<0.01) different.

Table 6: Concentrations of protein, cholesterol and triglyceride in
the serum of rabbits administered (i.p) sertraline, clozapine,
amitriptyline, imipramine and saline for 28 days (1,2).

Drug
administration Serum

 Protein (g/l) Cholesterol (m m ol/l)

Setraline 62.18 [+ or -] 4.43 (a) 2.50 [+ or -] 0.06 (a)
Clozapine 62.68 [+ or -] 2.49 (a) 1.78 [+ or -] 0.04 (b)
Amitriptyline 63.37 [+ or -] 3.82 (a) 3.26 [+ or -] 1.02 (c)
Imipramine 64.80 [+ or -] 4.10 (a) 3.66 [+ or -] 1.52 (c)
Saline 64.23 [+ or -] 2.30 (a) 1.58 [+ or -] 0.07 (b)

Drug
administration

 Triglyceride (m m ol/l)

Setraline 4.96 [+ or -] 0.27 (a)
Clozapine 5.10 [+ or -] 0.18 (a)
Amitriptyline 5.48 [+ or -] 0.32 (b)
Imipramine 5.62 [+ or -] 0.61 (b)
Saline 5.02 [+ or -] 0.42 (a)

(1) Values are expressed as Mean [+ or -] S.D. (n=10) in triplicate
determinations.

(2) Values carrying different superscripts vertically are
significantly (p<0.01) different.

Table 7: Serum alkaline phosphatase (ALP), aspartate transaminase
(APT) and alanine transaminase (ALT) activities of rabbits
administered (i.p) sertraline, clozapine, amitriptyline, imipramine
and saline for 28 days (1,2).

Drug
administration Enzyme Activity

 ALP (IU /l) APT (IU /l)

Setraline 24.25 96.18 [+ or -] 4.47 (a) 14.50 [+ or -] 1.62 (a)
 [+ or -] 1.26
Clozapine 10.74 [+ or -] 1.03 (b) 85.26 [+ or -] 2.93 (b)
Amitriptyline 30.67 [+ or -] 2.53 (a) 79.84 [+ or -] 3.53 (c)
Imipramine 46.84 [+ or -] 3.18 (d) 79.57 [+ or -] 4.69 (c)
Saline 26.27 64.75 [+ or -] 5.48 (d) 9.62 [+ or -] 1.70 (d)
 [+ or -] 2.43

Drug
administration

 ALT (IU /l)

Setraline 24.25
 [+ or -] 1.26
Clozapine 13.47 [+ or -] 1.52 (b)
Amitriptyline 14.25 [+ or -] 1.36 (a)
Imipramine 12.43 [+ or -] 1.85 (c)
Saline 26.27
 [+ or -] 2.43

(1) Values are expressed as Mean [+ or -] S.D. (n=10) in triplicate
determ inations.

(2) Values carrying different superscripts vertically are
significantly (p<0.01) different.

Table 8: Liver alkaline phosphatase (ALP), aspartate transaminase
(APT) and alanine transaminase (ALT) activities of rabbits
admnistered (i.p) sertraline, clozapine, amitriptyline, imipram ine
Drug administration and saline for 28 days (1,2).

 Enzyme Activity

 ALP (IU /l) APT (IU /l)

Setraline 83.94 [+ or -] 3.61 (a) 96.18 [+ or -] 5.93 (a)
Clozapine 75.97 [+ or -] 3.32 (b) 87.15 [+ or -] 3.65
Amitriptyline 92.8 [+ or -] 4.43 (c) 92.84 [+ or -] 4.25 (a)
Imipram ine 87.12 [+ or -] 6.80 (a) 89.57 [+ or -] 4.59 (a)
Saline 66.43 [+ or -] 2.40 (d) 77.50 [+ or -] 3.12 (c)

 ALT (IU /l)

Setraline 84.25 [+ or -] 7.60 (a)
Clozapine 80.75 [+ or -] 2.23 (a)
Amitriptyline 88.43 [+ or -] 3.26 (b)
Imipram ine 90.14 [+ or -] 4.87 (b)
Saline 71.75 [+ or -] 3.28 (c)

(1) Values are expressed as Mean [+ or -] S.D. (n=10) in triplicate
determinations.

(2) Values carrying different superscripts vertically are
significantly (p<0.01) different.
COPYRIGHT 2008 American-Eurasian Network for Scientific Information
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2008 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Title Annotation:Original Article
Author:Ebuehi, O.A.T.; Ikanone, C.E.O.; Balogun, A.A.
Publication:Advances in Medical and Dental Sciences
Article Type:Report
Geographic Code:1USA
Date:Sep 1, 2008
Words:5599
Previous Article:Assessment of in Vitro and in Vivo antimicrobial activities of selected Nigerian tootpastes and mouth washes on some oral pathogens.
Next Article:Effect of zinc deficiency on memory, oxidative stress and blood chemistry in rats.
Topics:

Terms of use | Privacy policy | Copyright © 2019 Farlex, Inc. | Feedback | For webmasters