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Antipsychotic-like profile of thioperamide, a selective H3-receptor antagonist in mice

Experimental and clinical evidence points to a role of central histaminergic system in the pathogenesis of schizophrenia. The present study was designed to study the effect of histamine H3-receptor ligands on neuroleptic-induced catalepsy,
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  doi: 10.1111/j.1472-8206.2006.00411.x ORIGINALARTICLE Antipsychotic-like profile of thioperamide,a selective H 3 -receptor antagonist in mice Mohd Akhtar, P. Uma Devi, Atif Ali, K.K. Pillai, Divya Vohora* Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, Hamdard University, New Delhi 110062, India INTRODUCTION Schizophrenia afflicts approximately 1% of the popula-tion worldwide. The last decade has seen a tremendousgrowth of research activity and introduction of severalnew generations of antipsychotic drugs. In spite of these advances, a significant number of patients areresistant to treatment. Thus, there is a need to identifynovel targets for the disease. Both experimental andclinical evidence exists implicating the role of centralhistaminergic system in the pathogenesis of schizo-phrenia [1–3]. For instance, Novoa and Cacabelos [4]indicated malfunctioning of the histaminergic systemwith altered histamine levels and number of histaminereceptors in brains of schizophrenic patients. Further,the mean levels of tele-methylhistamine, an index of histaminergic activity, were found to be significantlyelevated in cerebrospinal fluid of schizophrenic pati-ents [5]. In addition to this, differential expression of histaminergic receptors has been reported in schizo-phrenia, e.g. there is H 2 -upregulation [6], while H 1 -downregulation [7] in the brains of such patients.Adding to the scientific evidence is the observationthat antipsychotics especially clozapine and olanzapinetarget histamine receptors, besides blocking dopaminereceptors [8,9]. Keywords amphetamine,apomorphine,catalepsy,haloperidol,histamine H 3 -receptors,( R )- a -methylhistamine,thioperamide Received 23 August 2005;revised 19 October 2005;accepted 20 February 2006*Correspondence and ABSTRACT Experimental and clinical evidence points to a role of central histaminergic system inthe pathogenesis of schizophrenia. The present study was designed to study the effectof histamine H 3 -receptor ligands on neuroleptic-induced catalepsy, apomorphine-induced climbing behavior and amphetamine-induced locomotor activities in mice.Catalepsy was induced by haloperidol (2 mg/kg p.o.), while apomorphine (1.5 mg/kgs.c.) and amphetamine (2 mg/kg s.c.) were used for studying climbing behavior andlocomotor activities, respectively. ( R )- a -methylhistamine (RAMH) (5  l g i.c.v.) andthioperamide (THP) (15 mg/kg i.p.), per se did not cause catalepsy. Administration of THP (3.75, 7.5 and 15 mg/kg i.p.) 1 h prior to haloperidol resulted in a dose-dependent increase in the catalepsy times ( P  < 0.05). However, pretreatment withRAMH significantly reversed such an effect of THP (15 mg/kg i.p.). RAMH per seshowed significant reduction in locomotor time, distance traveled and average speedbut THP (15 mg/kg i.p.) per se had no effect on these parameters. On amphetamine-induced hyperactivity, THP (3.75 and 7.5 mg/kg i.p.) reduced locomotor time,distance traveled and average speed ( P  < 0.05). Pretreatment with RAMH (5  l gi.c.v.) could partially reverse such effects of THP (3.75 mg/kg i.p.). Climbing behaviorinduced by apomorphine was reduced in animals treated with THP. Such an effectwas, however, reversed in presence of RAMH. THP exhibited an antipsychotic-like profile by potentiating haloperidol-induced catalepsy, reducing amphetamine-induced hyperactivity and reducing apomorphine-induced climbing in mice. Sucheffects of THP were reversed by RAMH indicating the involvement of histamineH 3 -receptors. Findings suggest a potential for H 3 -receptor antagonists in improvingthe refractory cases of schizophrenia. ª  2006 The Authors Journal compilation  ª  2006 Blackwell Publishing Ltd.  Fundamental & Clinical Pharmacology   20  (2006) 373–378  373  Histamine H 3 -receptor antagonists have been pro-posed as potentially useful therapeutic agents for thetreatment of a variety of neuropsychiatric disorders. Inview of the occurrence of H 3 -receptors in the centralnervous system and their invariable association in theregulation of other neurotransmitters especially dopam-ine and serotonin [10–12], it becomes worthwhile toinvestigate thioperamide (THP), an H 3 -receptor antag-onist and ( R )- a -methylhistamine (RAMH), an agonist forits effects on various behavioral models of schizophreniaviz. catalepsy, climbing behavior and locomotor activitiesin mice. MATERIALS AND METHODS Animals Swiss strain albino mice of either sex (25–30 g)supplied by the Central Animal House Facility of  Jamia Hamdard, New Delhi were used. All animalswere housed in cages kept at a temperature of 23– 30   C with a natural light–dark cycle. They had freeaccess to standard pellet diet (Amrut Laboratory ratand mice feed, NavMaharastra Chakan Oil Mills Ltd,Pune) and tap water. The study was approved byAnimal Ethics Committee CPCSEA (project no. 134,September 2003). Ethical norms were strictly followedduring all experimental procedures. Drugs and their administration Haloperidol, THP maleate, RAMH, amphetamine sulfateand apomorphine HCl were purchased from Sigma-Aldrich Chemical Pvt. Ltd (St Louis, MO, USA). All drugsolutions were prepared using double distilled water.RAMH was dissolved in sterile water for injection forintracerebroventricular (i.c.v.) administration. Haloper-idol was given per orally (p.o.), THP was administeredintraperitoneally (i.p.) while amphetamine and apomor-phine were given by subcutaneous (s.c.) route. Doses of haloperidol (2 mg/kg p.o.) [1], amphetamine (2 mg/kgs.c.) [13], apomorphine (1.5 mg/kg s.c.) [14], RAMH(5  l g per mouse) and THP (3.75, 7.5, 15 mg/kg i.p.)[15] were based on earlier published reports. All thedrugs were given in a volume of 10 mL/kg exceptRAMH, which was administered in a volume notexceeding 5  l L using Hamilton’s microliter syringe.The site of injection was 2 mm from either side of themidline on a line drawn through the anterior base of theears. Control animals received the appropriate vehicle.Each mouse received only one type of treatment and testand was not reused. Procedures Assessment of catalepsy Catalepsy was induced with haloperidol (2 mg/kg p.o.)and determined every hour up to 4 h by means of astandard bar test [16]. The phenomenon was measuredas the time when the mouse maintained an imposedposition with both front limbs extended and resting on a4 cm high bar (0.4 cm diameter). The total time duringwhich animal stayed on the bar (even if it climbed backup) was recorded for a maximum period of 300 s. THP(3.75, 7.5 and 15 mg/kg i.p.) was injected 1 h beforehaloperidol (2 mg/kg p.o.) administration. RAMH wasgiven i.c.v. (5  l g per mouse) using Hamilton’s microlitersyringe 15 min before haloperidol administration. Amphetamine-induced locomotor activities AnimalswereadministeredTHP(3.75,7.5and15 mg/kgi.p.) 1 h before and RAMH (5  l g i.c.v.) 15 min before D -amphetamine (2 mg/kg s.c.) or vehicle (10 mL/kg).Locomotor activities of the animals were then monitoredin a Videopath analyzer (Coulbourn Instruments, Allen-town, PA, USA) and locomotion time, rest time, distancetraveled and speed of the animal were recorded [17]. Apomorphine-induced climbing behavior  Apomorphine-induced climbing behavior was followedas previously described [14,18]. Briefly, vehicle or THP(3.75, 7.5 and 15 mg/kg i.p.) was injected 1 h before theadministration of apomorphine (1.5 mg/kg s.c.). Imme-diately after injection, the mice were then placed indi-vidually in cylindrical wire mesh cages (height 13 cm,diameter 14 cm, mesh size 3 mm). During the trial, thetime when each mouse climbed on the inside of the wirecage was recorded over a 30-min period. Maximum time(i.e.maximumtimespentinasingleclimbthroughouttheduration of apomorphine effect) and % climbing index(i.e. the % of time spent climbing during 30-min periodfollowing the first climb) were calculated. Statistical analysis The data were expressed as mean ± SEM and resultswere analyzed by  ANOVA  followed by Dunnett’s  t -test. P  values < 0.05 were considered significant. RESULTS Effect of histamine H 3 -receptor ligands oncatalepsy test Haloperidol per se (but not THP and RAMH) pro-duced catalepsy post 2, 3, 4 h, and its peak effect was 374  M. Akhtar  et al. ª  2006 The Authors Journal compilation  ª  2006 Blackwell Publishing Ltd.  Fundamental & Clinical Pharmacology   20  (2006) 373–378  observed at 2 h [ F (7,47)  ¼  12.183,  P  < 0.001]. THP(3.75, 7.5 and 15 mg/kg i.p.) dose-dependently elevatedthe haloperidol-induced increase in catalepsy times( P  < 0.01). Pretreatment with RAMH significantlyreverse such an effect of THP (15 mg/kg i.p.) ( Table I  ). Effect of histamine H 3 -receptor ligands onamphetamine-induced locomotor activity Administration of amphetamine per se produced signi-ficant increase in the locomotor time, distance traveled,and average speed [ F (7,47)  ¼  3.831,  P  < 0.001] butreduction in the rest time. RAMH per se resulted insignificant reduction [ F (7,47)  ¼  4.224,  P  < 0.001) inlocomotor time, distance traveled and average speed.No statistically significant changes in locomotor activitywere observed with THP (15 mg/kg i.p.) per se.However, the latter drug at 3.75 and 7.5 mg/kg i.p.,but not 15 mg/kg i.p., significantly decreased amphet-amine-induced hyperactivity as shown by reduction inlocomotor time, distance traveled and average speed[ F (7,47)  ¼  4.050,  P  < 0.001] and increase in rest time.Pretreatment with RAMH (5  l g i.c.v.) could partiallyreverse such effect of THP (3.75 mg/kg i.p.) ( Table II  ). Effect of H 3 -receptor ligands on apomorphine-induced climbing behavior The climbing behavior was observed with apomorphine(1.5 mg/kg s.c.) per se (although statistically insignifi-cant). Pretreatment with THP (7.5 and 15 mg/kg i.p.)reduced the climbing behavior. Such an effect, was Table I  Effect of H 3 -receptor ligands on catalepsy test. Group Treatment ( n  ¼  6)Catalepsy duration (s)1 h 2 h 3 h 4 h1 Control 1.36 ± 0.15 1.20 ± 0.06 1.29 ± 0.08 1.23 ± 0.072 Haloperidol (2 mg/kg p.o.) 27.99 ± 7.72 159.45 ± 22.37** 92.54 ± 14.93* 95.72 ± 31.38*3 Thioperamide (15 mg/kg i.p.) 18.78 ± 5.13 39.91 ± 11.65 33.80 ± 8.81 58.71 ± 19.334 RAMH (5  l g i.c.v.) 58.32 ± 38.62 38.53 ± 11.54 29.92 ± 11.45 51.30 ± 20.785 Thioperamide (3.75 mg/kg i.p.) + haloperidol(2 mg/kg p.o.)87.63 ± 17.01* 156.34 ± 10.83**   80.46 ± 4.76**   65.70 ± 14.156 Thioperamide (7.5 mg/kg i.p.) + haloperidol(2 mg/kg p.o.)146.72 ± 21.31**   168.18 ± 12.80**   254.91 ± 14.84**   237.27 ± 30.68**  7 Thioperamide (15 mg/kg i.p.) + haloperidol(2 mg/kg p.o.)189.18 ± 26.4**   273.64 ± 7.10**   280.18 ± 2.41**   295.35 ± 2.55**  8 Thioperamide (15 mg/kg i.p.) + RAMH (5  l g i.c.v.) +haloperidol (2 mg/kg p.o.)64.80 ± 8.80 118.25 ± 7.09**   109.02 ± 8.04**   100.07 ± 8.87**Data represented as mean ± SEM.  n  ¼  no of animals  ¼  6. * P   < 0.05, ** P   < 0.01 vs. group 1;   P   < 0.01 vs. group 2;   P   < 0.01 vs. group 3. Significance byone-way  ANOVA  followed by Dunnett’s  t  -test. Table II  Effect of H 3 -receptor ligands on locomotor activity in a Videopath analyzer. Group Treatments ( n  ¼  6)Locomotortime (s)Resttime (s)Distancetraveled (cm)Averagespeed (cm/s)1 Control 172.16 ± 24.82 722.83 ± 25.63 3389.33 ± 538.9 220.67 ± 34.632 Amphetamine (2 mg/kg s.c.) 256.33 ± 18.89** 643.66 ± 18.89* 4823.16 ± 364.76** 310.67 ± 21.93*3 RAMH (5  l g i.c.v.) 165.83 ± 14.22   707.16 ± 17.53 2974.5 ± 236.5   201.66 ± 14.41  4 Thioperamide (15 mg/kg i.p.) 204.33 ± 6.79 668.33 ± 19.83 3836.66 ± 256.17 241.5 ± 19.875 Thioperamide (3.75 mg/kg i.p.) + amphetamine (2 mg/kg s.c.) 160.33 ± 12.11   770.66 ± 19.99   2876.5 ± 68.00   190.50 ± 7.92  6 Thioperamide (7.5 mg/kg i.p.) + amphetamine (2 mg/kg s.c.) 189.66 ± 7.82** 740.00 ± 14.90   3045.66 ± 64.28   206.16 ± 10.67  7 Thioperamide (15 mg/kg i.p.) + amphetamine (2 mg/kg s.c.) 202.83 ± 8.36 717.66 ± 19.59 3450.5 ± 385.73   229.5 ± 25.59  8 THP (3.75 mg/kg i.p.) + RAMH (5  l g i.c.v.) + amphetamine(2 mg/kg s.c.)192.16 ± 20.87   722.66 ± 17.48   3257.5 ± 292.76   204.66 ± 16.86  Data represented as mean ± SEM.  n  ¼  no of animals  ¼  6. * P   < 0.05; ** P   < 0.01 vs. group 1;   P   < 0.05;   P   < 0.01 vs. group 2. Significance by one-way ANOVA  followed by Dunnett’s  t  -test. Antipsychotic-like profile of thioperamide  375 ª  2006 The Authors Journal compilation  ª  2006 Blackwell Publishing Ltd.  Fundamental & Clinical Pharmacology   20  (2006) 373–378  however, reversed in presence of RAMH (5  l g i.c.v.)( Table III  ). DISCUSSION The present study evaluated the effects of histamineH 3 -receptor ligands on neuroleptic-induced catalepsy,apomorphine-induced climbing behavior and amphet-amine-induced locomotor activity in mice. THP andRAMH per se did not affect the catalepsy times. However,THP dose-dependently increased the catalepsy timeswhen co-administered with haloperidol. Further, pre-treatment with RAMH suppressed this effect indicatingthe involvement of H 3 -receptors. Our result is in agree-ment with Pillot et al. reporting the potentiation of haloperidol-induced catalepsy by ciproxifan, another H 3 -receptor antagonist [1]. Our results on catalepsy are,however, in contrast with the earlier report of Morisset etal. [19] who failed to detect the potentiation of halop-eridol-induced catalepsy by THP in mice but demon-strated the same in rats. However, they have useda 0.25 mg/kg i.p. dose of haloperidol in mice. Thissuggests that the potentiation of catalepsy is alsodependent on the dose of haloperidol.It has been reported that catalepsy induced byneuroleptic is associated with a concomitant increasein brain histamine content in mice [20]. Further, i.c.v.histamine and  L -histidine has been reported to potentiatehaloperidol-induced catalepsy in mice while H 1 -receptorblockers or histamine synthesis inhibitors antagonizeit [20,21]. Thus, the potentiation of histamine-inducedcatalepsy by THP could be related to an H 3 -receptor-mediated increase of histamine release in brain [22].Recently, THP also potentiated the effect of risperidoneon catalepsy [23]. The potentiation of neuroleptic-induced catalepsy by H 3 -receptor antagonists has beensuggested to result from a direct synergistic interactionbetween H 3  and D 2  receptors leading to enhancedactivation of striatopallidal neurons [1,24]. Anotherpossible mechanism by which this potentiation can beexplained is that H 3 -receptors besides regulating therelease of histamine, also regulate the release of otherneurotransmitters especially 5-HT. Increased availabilityof brain 5-HT due to the blockade of H 3 -receptors couldhave resulted in worsening of catalepsy as 5-HT reup-take blockade (by e.g. fluoxetine) is known to exacerbateextrapyramidal side effects of antipsychotics [25]. Severalclinical reports support this hypothesis, for example,fluoxetine can produce Parkinson-like extrapyramidalside effects [26–30]. While the pharmacodynamic inter-action at the histaminergic, dopaminergic and seroton-ergic system could play an important role, the existenceof a pharmacokinetic interaction may not be ruled out.Both ciproxifan and THP are inhibitors of the cyto-chrome P450 enzymes, responsible for metabolizingrisperidone and haloperidol [23]. It has been reportedrecently that imidazole H 3 -receptor antagonists poten-tially inhibited the metabolism of haloperidol andrisperidone. Thus, a pharmacokinetic interaction couldpartly contribute to such a potentiation by THP. How-ever, the reversal of THP on catalepsy by RAMH stronglysuggests the involvement of pharmacodynamic interac-tion involving H 3 -receptors.Thioperamide inhibitory effect on amphetamine-induced hyperactivity has already been documentedby other workers [31,32]. Reversal of amphetamine-induced hyperactivity has been routinely used as ascreening model to assess the antipsychotic activity of a compound [13]. In our study, THP per se did notaffect the locomotor activity of mice. THP, however Table III  Effect of H 3 -receptor ligandson apomorphine-induced climbingbehavior. Group Treatments ( n  ¼  6) Max time (s) % Climbing index1 Control 14.58 ± 1.69 7.85 ± 1.932 Apomorphine (1.5 mg/kg s.c.) 382.54 ± 142.56 35.33 ± 13.603 Thioperamide (3.75 mg/kg i.p.) +apomorphine (1.5 mg/kg s.c.)418.29 ± 187.68* 29.35 ± 11.634 Thioperamide (7.5 mg/kg i.p.) +apomorphine (1.5 mg/kg s.c.)268.98 ± 87.29 24.02 ± 7.965 Thioperamide (15 mg/kg i.p.) +apomorphine (1.5 mg/kg s.c.)3.59 ± 1.48 0.61 ± 0.13  6 Thioperamide (15 mg/kg i.p.) +RAMH (5  l g i.c.v.) + apomorphine(1.5 mg/kg s.c.)94.62 ± 24.36 8.39 ± 1.54Data represented as mean ± SEM.  n  ¼  no of animals  ¼  6. * P   < 0.05;   P   < 0.05. Significance by one-way ANOVA  followed by Dunnett’s  t  -test. 376  M. Akhtar  et al. ª  2006 The Authors Journal compilation  ª  2006 Blackwell Publishing Ltd.  Fundamental & Clinical Pharmacology   20  (2006) 373–378  significantly reduced amphetamine-induced locomotoractivity (the lower dose being more effective). However,the inhibition by RAMH of the promoting effect of THPon haloperidol-induced catalepsy strongly suggests theinvolvement of H 3 -receptors. The mechanism for thisreduction was attributed to the increase in levels of histamine by THP, which could further reduce thedopamine stores. As dopaminergic neurons are involvedin locomotor activity, the relative deficiency of dopam-ine could eventually lead to reduction of amphetamine-induced locomotor activity.Apomorphine, a dopamine receptor agonist, exhibitedclimbing behavior. The climbing behavior is known to beelicited by stimulation of dopamine receptors in thestriatum [33]. THP at 15 mg/kg i.p. but not 3.75 and7.5 mg/kg i.p. reduced apomorphine-induced climbing.This suggests that the histaminergic mechanisms maybe closely related to the dopaminergic systems, and playan important modulatory role in behaviors induced bydopaminergic agents. Further, as such a reduction byTHP was at least partially reversed in presence of anH 3 -receptor agonist, a role of H 3 -receptor mechanismis likely in the modulation of the climbing behaviorinduced by apomorphine.Taken together, our results indicate an antipsychotic-like profile of THP, a selective histamine H 3 -receptorantagonist, in mice. While the potentiation of haloper-idol-induced catalepsy may result from both pharmaco-dynamic and pharmacokinetic interaction, its effects onother models viz. apomorphine-induced climbing andamphetamine-induced locomotor activity is suggestive of an interaction mainly at a pharmacodynamic level. It isinteresting to note that atypical antipsychotic drugs alsoenhance histamine turnover in the brain [19]. Ourresults suggest a potential for H 3 -receptor antagonists inimproving the refractory cases of schizophrenia. AsH 3 -receptor antagonists are known to improve cognitiveand vigilance deficits [12] and have antidepressanteffects [34,35], their use in schizophrenia may alleviatesome of the negative symptoms observed in suchpatients. However, our observations are preliminaryand further experimental investigations including anexact biochemical correlation with histamine and dop-amine levels, are warranted to provide a more conclusiveview. ACKNOWLEDGEMENT The authors are thankful to UGC, New Delhi forproviding the financial assistance. REFERENCES 1 Pillot C., Ortiz J., Heron A., Ridray S., Schwartz J.C., Arrang J.M.Ciproxifan, a histamine H 3 -receptor antagonists/inverse agonistpotentiates neurochemical and behavioral effects of haloperidolin the rat. J. Neurosci. 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Decreasedhistamine H 1 -receptors in the frontal cortex of brains frompatients with chronic schizophrenia. Biol. Psychiatry (1993) 30  349–356.8 Kathmann M., Schlicker E., Gothert M. Intermediate affinityand potency of clozapine and low affinity of other neurolepticsand antidepressants at H 3 -receptors. Psychopharmacology(1994)  116  464–468.9 Rodrigues A.A., Jansen F.P., Leurs R., Timmerman H., PrellG.D. Interaction of clozapine with the histamine H 3 -receptors inrat brain. Br. J. Pharmacol. (1995)  114  1523–1524.10 Fox G.B., Pan J.B., Esbenshade T.A. et al. Effects of histamineH 3 -receptor ligands GT-2331 and ciproxifan in a repeatedacquisition avoidance response in the spontaneously hyper-tensive rat pup. Behav. Brain Res. (2002)  131  151–161.11 Vohora D., Pal S.N., Pillai K.K. Histamine and selectivehistamine H 3 -receptor ligands: a possible role in the mechanismand epilepsy. Pharmacol. Biochem. Behav. (2001)  68  735– 741.12 Vohora D., Pal S.N., Pillai K.K. 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