Pharmacological Reports Copyright © 2012 2012, 64, 191204 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences
Protective effects of histamine H3-receptor ligands in schizophrenic behaviors in experimental models
Danish Mahmood, Razia Khanam, Krishna Kolappa Pillai, Mohd Akhtar
Department of Pharmacology, Faculty of Pharmacy, Hamdard University, New Delhi-110062, India
Correspondence: Mohd. Akhtar, e-mail: [email protected], [email protected]
Abstract: Schizophrenia (SCZ) afflicts around 1% of the world’s population with characteristic symptoms such as hallucinations, delusions, and cognitive disorders. Several experimental studies in the past have indicted brain histaminergic neuronal system involvement in the pathogenesis of psychotic disorders including SCZ. Present study investigates anti-schizophrenic activity using two histamine H3-receptor (H3R)-antagonists/inverse agonists, ciproxifan (3.0 mg/kg, ip) and clobenpropit (15 mg/kg, ip), on some of the estab- lished animal model of schizophrenia, for example, amphetamine (AMPH) and dizocilpine (MK-801)-induced hyperactivity, apo- morphine (APO)-induced climbing behavior, scopolamine and MK-801-induced learning and memory deficits and haloperidol-induced catalepsy including determination of acetylcholinesterase (AChE) activity. Results of the present study demon- strate that ciproxifan and clobenpropit were able to control AMPH and MK-801-induced hyperlocomotor activities demonstrated as re- duced horizontal activity and reduced number of movements made by rats. Further, there was overall reduction in APO-induced climbing behavior. Learning and memory deficits, as evaluated on elevated plus maze, followed by estimation of brain AChE activity demonstrated positive results with these protypical imidazole H3R-antagonists/inverse agonists. In conclusion, present study demonstrates anti-schizophrenic like activities of ciproxifan and clobenpropit and supports the thera- peutic interest of histamine H3R antagonists/inverse agonists to improve symptomatic treatment of psychotic disorders.
Key words: histamine H3-ligands, schizophrenia, amphetamine, MK-801, learning and memory
Introduction [1] have been established with the help of histidine decarboxylase (HDC) deficient (HDC–/–) mice model [13]. HDC is an enzyme that helps in synthesis of his- Schizophrenia (SCZ) is a severe debilitating mental tamine from L-histidine [27]. Several preclinical and disorder affecting up to 1% of the population world- clinical studies in the past have shown brain histamine wide, presenting itself with characteristic set of symp- neurons involvement in the pathogenesis of SCZ and toms which include positive, negative and cognitive have indicted histaminergic systems in the psychotic derangements. Functional roles of brain histaminergic disorders [23]. Methamphetamine (meth-AMPH), neurons are now well recognized. Histaminergic neu- a psychotogenic and prototypic drug of abuse has rons, in the regulation of basic functions such as sleep been reported to activate histamine neurons [28, 35, wake control [53], learning and memory [22], motor 49]. Hyperactivity of histaminergic transmission is and emotional behaviors [21, 33], energy homeostasis also suggested, since the levels of tele-methylhista- [25], seizure development [14] and circadian rhythm mine (t-MeHA), the major histamine (HA) metabolite
Pharmacological Reports, 2012, 64, 191204 191 in brain, has been found to be significantly elevated in and atypical APDs in the NMDA-model of schizo- the cerebrospinal fluid in schizophrenic patients [56]. phrenic symptoms. Since APDs are known to affect Further, typical APDs decrease while atypical APDs cognitive functioning, the novel APDs are expected to increase the HA release and could be one reason for have memory enhancing effects or if do not have superior therapeutic profile of atypical APDs [48]. them, at least they should not have deleterious effects
H3R was first described as presynaptic autoreceptor on learning and memory. Therefore, it is imperative to regulating synthesis and release of HA from histamin- screen novel APDs displaying antipsychotic activity ergic neurons [5–7, 38] and later demonstrated as het- for effects on learning and memory. eroreceptor. H3Rs apart from modulating HA release, Furthermore, devising experimental models of schizo- also modulate the release of various neurotransmitters phrenia has been challenging since the pathophysiology such as dopamine (DA), acetylcholine (ACh), norepi- of negative symptoms remain less well understood com- nephrine (NE), 5-hydroxytryptamine (5-HT), g-am- pared to positive symptoms and there are more models of inobutyric acid (GABA), glutamate, substance P and positive than negative symptoms. Further, characteriza- tachykinins [59]. H3Rs are present in cerebral cortex, tion of novel compounds with respect to their potential ef- hippocampus, amygdala, nucleus accumbens, globus fects on negative symptoms has been limited to the use of pallidus, striatum and hypothalamus, however, the behavioral models with face validity [19]. highest density of H3Rs are found in basal ganglia However, behavioral models of negative symptoms [55], which is an important seat in the brain involved currently being used in the development of novel antipsy- in coordination of information from sensorimotor, chotic agents include: the social withdrawal model in ro- motivational and cognitive brain areas to control dents and nonhuman primates; and the forced swim test; behaviors such as movement and reward learning. H3R chronic mild stress model of anhedonia, predictive for antagonists/inverse agonists, such as thioperamide compounds with efficacy for negative symptoms. In ro- (THP) and ciproxifan (CPX) [36], potentiate neuro- dents, chronic administration of phencyclidine (PCP) in- chemical and behavioral effects of haloperidol (HAL) creases the duration of immobility in the forced swim test [40, 54] and enhance prepulse inhibition of startle in and has been used as a model of the negative symptoms rats [26] and also modulate the neurochemical and be- of schizophrenia, such as flattening of affect and avolition havioral effects of meth-AMPH [50]. [19]. It is considered that compounds that produce cata- Previous studies have reported discrepancies in the lepsy will have antipsychotic activity as most of the effects of H3-ligands on rat and mice. For example, typical APDs including HAL which produce catalepsy CPX and THP potentiate HAL-induced catalepsy in and therefore, HAL-induced catalepsy is regarded as rat but not in mice [48, 54, 63], and therefore, the a model for putative APDs. Apomorphine (APO)-i- present study utilize both mice and rats as experimen- nduced climbing behavior in mice is a classical animal tal models. Thus, the present study is a further attempt model used to screen APDs [58] and atypical APDs are to investigate anti-schizophrenic potentials of H3R- very effective in this model [18]. antagonists/inverse agonists on some of the estab- Indirect agonist such as amphetamine (AMPH) in- lished animal models of SCZ, which is expected to duces a strong increase in locomotor activity when in- add to the previous works highlighting therapeutic in- jected into rodents and the increased locomotor activ- terests of H3R antagonists/inverse agonists in the ity is due to an increased dopaminergic activity in the treatment of psychiatrical disorders especially SCZ. mesolimbic system particularly the nucleus accum- bens and/or olfactory tubercle [16]. N-methyl-D- aspartate (NMDA) receptor antagonists, phencycli- dine and dizocilpine (MK-801), produce behavioral Materials and Methods syndrome in rodents characterized by increased loco- motor activity, ataxia, head weaving, body rolling, Animals and stereotyped motor patterns and these behavioral syndromes are used as an animal model of the puta- The study was carried on 12-week old Wistar albino tive schizophrenia-like effects of NMDA antagonism. rats and mice of either sex weighing 150–200 g and In particular, NMDA antagonist-induced hyperloco- 25–30 g, respectively, procured from Central Animal motion has been used to compare the effects of typical House Facility, Hamdard University. They were
192 Pharmacological Reports, 2012, 64, 191204 Histamine H3-receptor ligands in schizophrenia Danish Mahmood et al.
housed in a group of 6 animals per cage and main- hour in the home cage for habituation. They were then tained at 20–30°C and 50–55% humidity in a light individually placed in the open field chamber for half and dark cycle, with free access to food and water. an hour prior to recording of the locomotor activity. The experimental protocol was approved by the Insti- All the test recordings were done between 9.00 a.m. tutional Animal Ethics Committee. The animals were and 5.00 p.m. Horizontal locomotion was recorded in maintained under standard conditions in an animal centimeters covered by each individual rat during house approved by the Committee for the Purpose of 20 min test period, beginning 20 min after the injection Control and Supervision of Experiments on Animals of AMPH to AMPH group (n = 6) [42]. Normal con- (CPCSEA). Utmost care was taken to ensure that ani- trol groups (n = 6) were injected with normal saline mals were treated in the most ethically acceptable (1 ml/kg, ip). CPX (3 mg/kg, ip), CBP (15 mg/ kg, ip) manner. Animals were allowed a one week acclimati- and CLZ (3 mg/kg, ip) were administered 1 h, and CPZ zation period before being used in experiments. (3 mg/kg, ip) was administered 30 min before locomo- tor test, while RAMH was administered 15 min before Drugs and treatment locomotor testing [2, 48, 54, 61]. Normal control ani- mals were given normal saline (1 ml/kg, ip). Ciproxifan maleate (CPX), clobenpropit dihydrobromide (CBP), clozapine (CLZ), chlorpromazine (CPZ), dizocil- Antagonism of MK-801 (0.2 mg/kg, ip) induced pine maleate (MK-801), (+)-amphetamine (AMPH), apo- locomotor behaviors in rat morphine (APO), scopolamine (SCOP) and R-a- methylhistamine (RAMH) were procured from Sigma Locomotor activity tests were performed in the simi- Chemicals Co. St. Louis, MO, USA. Drug solutions lar manner as mentioned above in the amphetamine were made in normal saline (0.9% NaCl). HAL was induced locomotor behavior. MK-801 was adminis- administered through oral route while APO and AMPH tered 10 min before locomotor test [62] were administered subcutaneously (sc). The rest of drugs was administered through intraperitoneal (ip) route. Assessment of HAL (2 mg/kg, po) induced RAMH was administered through intra-cerebroventri- catalepsy in mice [2] cular (icv) route in mice only. All the drug solutions were freshly made on the same day of experiment. Catalepsy is the inability of animals to correct its ex- ternally imposed posture. The phenomenon was PROCEDURES measured as the mouse maintained an imposed pos- ture with both fore limbs extended and resting on Open field activity [29] a 4 cm high bar (0.4 cm diameter). The total time dur- ing which animal stayed on the bar with both fore It was measured in open field arenas consisting of an limbs or even if it removed one limb was noted down acrylic box (40.6 × 40.6 × 40.6 cm) fitted with two for a maximum period of 300 s. HAL (2 mg/kg, po) photobeam frames (16 beams/dimensions; 2.5 cm be- was administered 1 h before assessment of catalepsy tween beams; Coulbourn Instruments; Allentown, [2]. CPX (3 mg/kg, ip), CBP (15 mg/kg, ip) and CLZ PA). The lower frame (2.5 cm above the arena floor) (3 mg/kg, ip) were administered 1 h, and CPZ recorded horizontal locomotor activity while the up- (3 mg/kg, ip) was administered 30 min before HAL per frame (15 cm above the floor) records rearing. administration [2,48, 54, 61], while RAMH was ad- Open field chamber was connected to a computer run- ministered 15 min before HAL administration [2]. ning software (TruScan 2.0 version, Coulbourn In- struments) that recorded beam breaks (100 ms sam- APO (1.5 mg/kg, sc) induced climbing behavior pling rate). in mice [2, 17, 57]
Antagonism of AMPH (0.5 mg/kg, sc) induced All the measurements of climbing behavior were car- locomotor behaviors in rat [42] ried out between 9.00 a.m. and 6.00 p.m. in a dif- fusely illuminated room maintained at a temperature On the day of experiments, rats were brought to the of 21 ± 1°C. Each test consisted of half an hour dura- test room from animal house facility and left for half an tion during which two parameters were recorded:
Pharmacological Reports, 2012, 64, 191204 193 1. Climbing index (the percentage of time spent in trial [31] and all the drugs were administered before climbing during the 30 min period following first acquisition trial as mentioned above. climb) and 2. Maximum time (the maximum time spent in a single climb throughout the duration of BIOCHEMICAL STUDIES APO effect). APO was administered immediately be- fore the test [17] while all other drugs were adminis- Estimation of brain acetylcholinesterase tered as mentioned above. (AChE) in mice
Assessment of learning and memory using Mouse brain was harvested by decapitation, immedi- elevated plus maze in mice ately after retention trial on day 2 (SCOP- and MK- 801-induced memory impairment), weighed and kept SCOP (0.5 mg/kg, ip) induced learning and at –70°C until AChE assay. The whole brain AChE memory deficits [51] activity was measured according to the method of Ell- man et al. [24]. A known weight of the brain tissue The plus-maze was constructed of softwood and was homogenized in 0.32 M sucrose solution to get acrylic resin having two open (5 × 30 cm) and two a 10% homogenate that was centrifuged at 3000 rpm closed (5 × 30 × 15 cm) arms opposite each other. The for 15 min followed by centrifugation at 10,000 rpm entire apparatus was kept at a height of 40 cm above for 10 min, at a constant temperature of 4°C. One mil- the floor. The open arms and central platform were liliter of supernatant was mixed with 9 ml of sucrose colored white and covered with cellophane. The ele- solution to get a 1% post mitochondrial supernatant. vated plus-maze test for evaluating learning and Test samples were prepared by mixing 2.7 ml of phos- memory was performed as previously described. In an phate buffer, 0.1 ml of DTNB and 0.1 ml of PMS. Re- acquisition trial, mice were individually placed at the action mixture was preincubated for 5 min and 0.1 ml end of one open arm facing away from the central of acetylthiocholine iodide was added to the mixture platform. “Transfer latency” the time each mouse to initiate the reaction and immediately absorbance took to move from the open arm to either of the en- was taken at 412 nm for 3 min every 1 min interval. closed arms, was noted down. The mice were left to Blank sample was made in the similar manner except explore the plus-maze for a period of 150 s. If the PMS was not added. Protein was determined accord- mice did not enter the enclosed arm within 90 s, they ing to method of Lowry et al. [41]. were pushed gently into the enclosed arm and allowed to explore this maze for an additional 60 s. Transfer Statistical significance latency in this case was noted as 90 s. Twenty four hours later, a retention trial was performed in the The data were expressed as the mean ± SEM (standard same manner and transfer latency was recorded. If the error of the mean). Results were analyzed by ANOVA mice did not enter the enclosed arm within 90 s on the followed by Dunnett’s t-test for multiple comparison retention trial, transfer latency was also recorded as tests, p values < 0.01 were considered significant. 90 s. CPX (3 mg/kg, ip) and CBP (15 mg/kg, ip) were administered 1 h before, while SCOP and RAMH was administered 15 min before acquisition trial [2, 48, 54]. CLZ (3 mg/kg, ip) and CPZ (3 mg/kg, ip) were Results administered 1 h and 30 min [61] prior to acquisition trial, respectively. Effects of histamine H3R-ligands on AMPH- induced locomotor activity in rats MK-801 (0.2 mg/kg, ip) induced learning and memory deficits in mice [30] Administration of AMPH (0.5 mg/kg, sc) signifi- cantly (p < 0.01) increased locomotor activities such Dizocilpine (MK-801)-induced memory impairment as horizontal locomotor activity in centimeters per was performed in the similar manner as mentioned 20 min, average distance per move (cm), mean veloc- above in scopolamine-induced memory impairment. ity (cm/s), locomotor time (s) and the total number of MK-801 was administered 30 min before retention movements made by rat during entire test period com-
194 Pharmacological Reports, 2012, 64, 191204 Histamine H3-receptor ligands in schizophrenia Danish Mahmood et al.
Tab. 1. The effect of histamine H3R-ligands on AMPH-induced locomotor activity in rats
Group Treatments Horizontal activity Move time Rest time Average Mean velocity Total movements (n = 6) (cm) (s) (s) dist./move (cm/s) (#) (cm)
I NS (1 ml/kg, ip) 2411.63 247.32 952.68 2.28 2.69 619.66 ± 127.78 ± 14.98 ± 14.98 ± 0.07 ± 0.11 ± 29.78
II AMPH (0.5 mg/kg, sc) 8864.97 814.7 385.30 4.58 8.86 1898.0 ± 259.01†† ± 17.96†† ± 17.96†† ± 0.15†† ± 0.09†† ± 83.82††
III RAMH (10 mg/kg, ip) 2324.58 193.22 1006.78 1.95 2.88 529.66 ± 93.12 ± 8.94 ± 8.94 ± 0.07 ± 0.07 ± 2 9.99
IV CPX + AMPH 4181.93 316.57 883.43 2.52 3.03 921.67 (3 mg/kg, ip + 0.5 mg/kg, sc) ± 218.99** ± 15.54** ± 15.54** ± 0.15** ± 0.10** ± 28.51**
V CBP + AMPH 5295.38 379.10 820.90 2.72 3.83 1098.33 (15 mg/kg, ip + 0.5 mg/kg, sc) ± 163.93** ± 14.82** ± 14.82** ± 0.09** ± 0.26** ± 43.48**
VI CPX + RAMH + AMPH 7814.65 677.9 522.10 4.39 7.43 1686.33 (3 mg/kg, ip + 10 mg/kg, ± 192.06## ± 10.75## ± 10.75## ± 0.16## ± 0.26## ± 65.45## ip + 0.5 mg/kg, sc)
VII CBP + RAMH + AMPH 7091.58 615.58 584.42 4.55 7.15 1883.66 (15 mg/kg, ip + 10 mg/kg, ± 328.36$$ ± 16.02$$ ± 16.02$$ ± 0.10$$ ± 0.09$$ ± 50.03$$ ip + 0.5 mg/kg, sc)
VIII CLZ + AMPH (3 mg/kg, 4515.26 325.60 874.40 2.85 4.06 961.83 ip + 0.5 mg/kg, sc) ± 263.27** ± 26.89** ± 26.89** ± 0.10†,** ± 0.26** ± 24.28**
IX CPZ + AMPH (3 mg/kg, 4075.23 299.40 900.60 2.62 3.53 817.33 ip + 0.5 mg/kg, sc) ± 269.44** ± 11.06** ± 11.06** ± 0.13 ± 0.24** ± 22.49**
X CPX per se (3 mg/kg, ip) 2176.37 205.68 994.32 2.16 2.37 578.83 ± 175.97 ± 24.02 ± 24.02 ± 0.23 ± 0.21 ± 38.71
XI CBP per se (15 mg/kg, ip) 2452.53 217.75 982.25 1.96 2.35 577.50 ± 133.80 ± 26.02 ± 26.02 ± 0.15 ± 0.09 ± 32.98
Data presented as the mean ± SEM. ANOVA followed by Dunnett’s multiple comparison tests, p < 0.01 vs. Gp I, ** p < 0.01 vs. Gp II. ## p < $$ 0.01 vs. IV, p < 0.01 vs. V. H3R-antagonists and CLZ were administered 1 h before and CPZ was administered 30 min before locomotor activ- ity. AMPH was administered 20 min before recording of locomotor activity
pared with the saline control group. Administration of Effects of histamine H3R-ligands on MK-801- CPX (3.0 mg/kg, ip) and CBP (15 mg/kg, ip) signifi- induced locomotor activity in rats cantly (p < 0.01) controlled AMPH induced hyperac- tive states and increased the rest time. RAMH Horizontal activity of rats was measured in the similar (10 mg/kg, ip) administration significantly (p < 0.01) manner as mentioned above in AMPH-induced hyper counteracted the effects produced by CPX and CBP locomotor activity. MK-801 (0.2 mg/kg, ip) signifi- (Tab. 1). CLZ (3.0 mg/kg, ip) and CPZ (3.0 mg/kg, ip) cantly increased (p < 0.01) the locomotor response were effective in controlling hyperactive response of such as horizontal distance travelled, average distance AMPH. Interestingly, both CPX and CBP displayed per move, mean velocity, time spent travelling and to- comparable efficacy to CLZ and CPZ mediated con- tal movements made by rats. Both CPX (3.0 mg/kg, trol of AMPH response. ip) and CBP (15 mg/kg, ip) significantly decreased
Pharmacological Reports, 2012, 64, 191204 195 Tab. 2. The effect of histamine H3R-ligands on MK-801-induced locomotor hyperactivity in rats
Group Treatments Horizontal activity Move time Rest time (s) Average dist./move Mean velocity Total movements (n = 6) (cm) (s) (cm) (cm/s) (#) I NS (1 ml/kg, ip) 2383.17 216.45 983.55 2.76 2.86 592.5 ± 170.03 ± 6.02 ± 22.75 ± 0.18 ± 0.19 ± 8.57 II MK-801 (0.2 mg/kg, ip) 10720.43 864.63 335.37 7.40 11.40 1481.67 ± 340.66†† ± 40.09†† ± 40.09†† ± 0.39†† ± 0.58†† ± 8.23†† III RAMH (10 mg/kg, ip) 1943.2 179.8 1020.2 2.34 2.53 571.5 ± 165.10 ± 7.39 ± 26.28 ± 0.37 ± 0.58 ± 13.38 IV CPX + MK-801 (3 mg/kg, 3962.42 354.60 845.4 3.37 3.44 898.5 ip + 0.2 mg/kg, ip) ± 398.08** ± 41.06** ± 41.06** ± 0.45** ± 0.26** ± 6.97** V CBP + MK-801 (15 mg/kg, 4219.85 390.95 809.45 3.75 3.69 911.17 ip + 0.2 mg/kg, ip) ± 555.89** ± 28.22** ± 28.22** ± 0.34** ± 0.27** ± 9.79** VI CPX + RAMH + MK-801 6991.48 696.02 503.98 6.42 6.85 1278.17 (3 mg/kg, ip + 10 mg/kg, ± 463.87## ± 44.84## ± 44.84## ± 0.19## ± 0.37## ± 18.93## ip + 0.2 mg/kg, ip) VII CBP + RAMH + MK-801 6588.57 664.62 535.38 6.35 6.54 1219.83 (15 mg/kg, ip + 10 mg/kg, ± 444.78$$ ± 31.95*,$$ ± 31.95$$ ± 0.44$$ ± 0.36$$ ± 18.23$$ ip + 0.2 mg/kg, ip) VIII CLZ + MK-801 (3 mg/kg, 3310.03 321.13 878.87 2.77 3.11 833.17 ip + 0.2 mg/kg, ip) ± 518.78** ± 37.86** ± 17.20** ± 0.33** ± 0.22** ± 19.42** IX CPZ + MK-801 (3 mg/kg, 8826.05 703.83 496.17 5.90 5.82 1014.33 ip + 0.2 mg/kg, ip) ± 553.00* ± 57.49** ± 57.49* ± 0.34* ± 0.46** ± 51.64** X CPX per se (3 mg/kg, ip) 2041.5 191.83 1008.17 2.54 2.56 516.33 ± 245.25 ± 25.95 ± 30.91 ± 0.25 ± 0.17 ± 21.37 XI CBP per se (15 mg/kg, ip) 2321.95 ± 205.87 994.13 2.44 2.80 545.67 149.63 ± 18.48 ± 32.42 ± 0.22 ± 0.27 ± 15.58
Data presented as the mean ± SEM. ANOVA followed by Dunnett’s multiple comparison tests, p < 0.01 vs. Gp I, ** p < 0.01 vs. Gp II. ## p < $$ 0.01 vs. IV, p < 0.01 vs. V. H3R-antagonists and CLZ were administered 1 h before and CPZ was administered 30 min before locomotor activ- ity. MK-801 was administered 10 min before recording of locomotor activity
Tab. 3. The effect of histamine H3R-ligands on HAL-induced catalepsy in mice
Group Treatments Catalepsy duration (n = 6) 1 h 2 h 3 h 4 h I NS (10 ml/kg, ip) 4.97 ± 1.07 4.10 ± 0.27 4.32 ± 0.32** 4.42 ± 0.30 II HAL (2 mg/kg, po) 66.83 ± 2.45†† 174.25 ± 7.74†† 125.09 ± 3.27 122.96 ± 6.33 III RAMH (5 µg/mouse, icv) 9.27 ± 0.90 9.56 ± 0.37 6.24 ± 0.35 5.89 ± 0.40 IV CPX + HAL (3 mg/kg, ip + 2 mg/kg, po) 116.04 ± 3.87** 257.20 ± 7.95** 245.13 ± 6.57** 217.48 ± 3.19** V CBP + HAL (15 mg/kg, ip + 2 mg/kg, po) 118.20 ± 3.37** 241.44 ± 6.01** 231.73 ± 5.30** 156.91 ± 3.70** VI CPX + RAMH + HAL (3 mg/kg, ip + 5 µg, icv + 2 mg/kg, po) 50.20 ± 4.17## 113.59 ± 5.18## 119.17 ± 3.41## 64.26 ± 3.73## VII CBP + RAMH + HAL (15 mg/kg, ip + 5 µg, icv + 2 mg/kg, po) 41.37 ± 2.12$$ 99.72 ± 3.64$$ 107.64 ± 4.16$$ 45.67 ± 3.19$$ VIII CLZ + HAL (3 mg/kg, ip + 2 mg/kg, po) 25.14 ± 1.94** 46.34 ± 2.88** 37.14 ± 4.20** 35.66 ± 2.92** IX CPZ + HAL (3 mg/kg, ip + 2 mg/kg, po) 120.83 ± 4.27** 216.57 ± 10.24** 142.68 ± 4.42* 137.93 ± 6.45* X CPX per se (3 mg/kg, ip) 4.33 ± 0.88 3.91 ± 0.29 3.55 ± 0.53 3.03 ± 0.26 XI CBP per se (15 mg/kg, ip) 4.70 ± 0.77 4.55 ± 0.39 4.33 ± 0.34 4.14 ± 0.31
Data presented as the mean ± SEM. ANOVA followed by Dunnett’s multiple comparison tests, p < 0.01 vs. Gp I, ** p < 0.01 vs. Gp II, * p < 0.05 ## $$ vs. Gp II. p < 0.01 vs. IV, p < 0.01 vs. V. H3R-antagonists were administered 2 h, while CLZ and CPZ were administered 1 h and 30 min, re- spectively, before catalepsy test. HAL was administered 1 h before catalepsy test. RAMH was administered 15 min before catalepsy testing
196 Pharmacological Reports, 2012, 64, 191204 Histamine H3-receptor ligands in schizophrenia Danish Mahmood et al.
MK-801-induced hyperlocomotor response. RAMH (3.0 mg/kg, ip), CBP (15 mg/kg, ip), and CPZ (10 mg/kg, ip) administration significantly (p < 0.01) (3.0 mg/kg, ip) were administered along with HAL. counteracted the hypolocomotor responses of CPX Pretreatment of RAMH (5 µg, icv) decreased (p < and CBP. Interestingly, CLZ (3.0 mg/kg, ip) demon- 0.01) the potentiating effect on catalepsy by these strated better hypolocomotor response than CPZ agents. However, CLZ (3.0 mg/kg, ip) reduced dura- (3.0 mg/kg, ip) in MK-801-induced hyperlocomotor tion of HAL-induced catalepsy (Tab. 3). activity. Hypolocomotor responses of CPX and CBP were somehow comparable to CLZ-mediated hypolo- Effects of histamine H3R-ligands on APO- comotion (Tab. 2). induced climbing behavior in mice
Significant climbing behavior was observed in mice Effects of histamine H3R-ligands on HAL- induced catalepsy in mice administrated with APO (1.5 mg/kg, sc) as demon- strated by significant (p < 0.01) increase in the maxi- HAL (2.0 mg/kg, po) administration produced cata- mum time and climbing index. The increase in both of lepsy in mice after 1 h, however, maximum cataleptic these parameters of climbing behavior was signifi- effect was observed after 2 h. Duration of catalepsy cantly reduced (p < 0.01) by the pretreatment of CPX was significantly (p < 0.01) enhanced when CPX (3.0 mg/kg, ip) and CBP (15 mg/kg, ip), and similar
Fig. 1. The effect of histamine H3-anta- gonists on APO-induced climbing be- havior in mice. Data represented as the mean ± SEM. ANOVA followed by Dunnett’s multiple comparison tests, p < 0.01 vs. Gp NS, ** p < 0.01 vs. ## APO, NS = normal saline. p < 0.01 $$ vs. CPX + APO, p < 0.01 vs. CBP + APO. H3R-antagonists, 1 h before, while CLZ and CPZ were administered 30 min before, while APO was adminis- tered immediately before recording of NS APO CPX CBP the climbing behavior. “Maximum time” RAMH is the maximum time spent in a single CPX + APOCBP + APO CLZ + APOCPZ + APO climb throughout the duration of the APO effect CPX + RAMHCBP +APO + RAMH + APO
Fig. 2. The effect of histamine H3-anta- gonists on APO-induced climbing be- havior in mice. Data represented as the mean ± SEM. ANOVA followed by Dunnett’s multiple comparison tests, p < 0.01 vs. Gp NS, ** p < 0.01 vs. ## APO, NS= normal saline. p < 0.01 $$ vs. CPX+APO, p < 0.01 vs. CBP + APO. H3R-antagonists were admin- istered 1 h before, while CLZ and CPZ 30 min before, while APO was adminis- tered immediately before recording of the climbing behavior. “Climbing index (%)” is the percentage of time spent climbing during the 30 min period fol- lowing the first climb NS APO CPX CBP RAMH CPX + APOCBP + APO CLZ + APO CPZ + APO
CPX + RAMH +APOCBP + RAMH + APO
Pharmacological Reports, 2012, 64, 191204 197 results were also obtained with CLZ (3.0 mg/kg, ip) in the retention trial. CPX and CBP per se had no ef- and CPZ (3.0 mg/kg, ip). However, a decrease of the fect on transfer latency. CPX and CBP mediated climbing behavior observed with the administration effect on SCOP-induced learning and memory defi- of CPX and CBP, respectively, was significantly (p < cits was counteracted (p < 0.01) by RAMH (5 µg, icv) 0.01) counteracted with the pretreatment of RAMH administration. CPZ (3.0 mg/kg, ip) displayed non- (Figs. 1 and 2). significant result on SCOP-induced impairment of learning and memory (Fig. 3).
Effects of histamine H3R-ligands on SCOP- induced learning and memory deficits in mice Effects of histamine H3R ligands on MK-801- induced learning and memory deficits in mice SCOP (0.5 mg/kg, ip) administration significantly (p < 0.01) prolonged transfer latency as compared to MK-801 (0.2mg/kg, ip) was administered half an hour the saline control group. Pretreatment of CPX before retention trial and 24 h after acquisition trial. (3.0 mg/kg, ip) and CBP (15 mg/kg, ip) including MK-801 administration prolonged transfer latency as CLZ (3.0 mg/kg, ip) significantly (p < 0.01) counter- compared to the saline control group (p < 0.01). Pre- acted SCOP-induced prolongation of transfer latency treatment of CPX (3.0 mg/kg, ip) and CBP (15 mg/kg,
Fig. 3. The effect of histamine H3-anta- gonists on SCOP-induced learning and memory deficits in mice. Data rep- resented as the mean ± SEM. ANOVA followed by Dunnett’s multiple com- parison tests. p < 0.01 vs. NS ** p < 0.01 vs. SCOP, * p < 0.05 vs. SCOP, ## $$ p < 0.01 vs. CPX + APO, p < 0.01 vs. CBP + APO, NS= normal saline. All the drugs were administered before acquisition trial. H3R-antagonists, 1 h before, CLZ and CPZ, 30 min before, while SCOP and RAMH, 15 min before acquisition trial. Series 1 (white bars) = acquisition trial, Series 2 (grey bars) = retention NS CPX CBP SCOP RAMH
CPX + SCOPCBP + SCOP CLZ + SCOPCPZ + SCOP
CPX + RAMHCBP + + SCOP RAMH + SCOP
Fig. 4. The effect of histamine H3-anta- gonists on MK-801-induced learning and memory deficits in mice. Data rep- resented as the mean ± SEM. ANOVA followed by Dunnett’s multiple com- parison tests. p < 0.01 vs. NS, ** p ## < 0.01 vs. MK-801, p < 0.01 vs. CPX $$ + APO, p < 0.01 vs. CBP + APO, NS = normal saline. MK-801 was adminis- tered 30 min before retention trial. Rests of the drugs were administered before acquisition trial. H3R-antagonists, 1 h before, while CLZ and CPZ, 30 min NS before, and RAMH, 15 min before ac- CPX CBP MK-801 RAMH quisition trial. Series 1 (white bars) = acquisition trial, Series 2 (grey bars) = CPX + MK-801CBP + MK-801 CLZ + MK-801CPZ + MK-801 retention
CPX + RAMHCBP + + MK-801 RAMH + MK-801
198 Pharmacological Reports, 2012, 64, 191204 Histamine H3-receptor ligands in schizophrenia Danish Mahmood et al.
ip) including CLZ (3.0 mg/kg, ip) before acquisition Discussion trial attenuated MK-801-induced impairment of mem- ory retention as demonstrated by prolongation of the transfer latency. RAMH (5 µg, icv) administration During last two decades, several experimental studies abolished effects mediated by both the CPX and CBP have assessed the effects of histamine H R-antago- on MK-801-induced impairment of memory retention 3 (Fig. 4). nists/inverse agonists on several dimensions of animal behavior using different experimental models, and also alongside the development of selective histamine Effects of histamine H3R-ligands on SCOP- induced elevation of brain AChE-activity in H3R continued with increasing pace. mice Some of the selective H3R agonists developed are imetit and immepip, while antagonists include SCOP (0.5 mg/kg, ip) significantly increased the GT2331, ABT-239, BF2.649, NNC 38-1049, and oth-
AChE activity compared to saline control group. Both ers. Despite development of newer H3R selective ago- CPX and CBP were able to control SCOP mediated nists and antagonists, the prototypical imidazole elevation of AChE activity (p < 0.01) in the drug based compounds continue to be used as experimental treated groups. However, RAMH had a vitiating ef- tool compounds, and probably being most widely fect (p < 0.05) on CPX and CBP mediated control of studied H3-ligands, could be the reason, why they are AChE activity (Fig. 5). still used for experimental studies looking for novel therapeutics. Effects of histamine H R ligands on MK-801- 3 Recently, fourth histamine receptor (H4R) has also induced elevation of brain AChE-activity in mice been cloned by several researchers, which predomi- MK-801 (0.2 mg/kg, ip) elevated AChE activity sig- nantly expresses in the cells of hemopoietic origins, nificantly (p < 0.01) compared to saline control group. where as its expression in the CNS is still poorly de- Both CPX and CBP tended to restore AChE activity fined [15]. Histamine H4 receptors have a role in in- (p < 0.01). However, RAMH tended to counteract flammatory conditions [20]. Some of the previously (p < 0.05) effects produced by both the CPX and CBP reported H3 compounds have appreciable affinity for on AChE activity (Fig. 5). H4 and notably among them is clobenpropit [15].
Fig. 5. The effect of histamine H3-anta- gonists on SCOP and MK-801-induced augmentation of AChE activity in mice whole brain homogenate. Data ex- pressed as the mean ± SEM, ANOVA followed by Dunnett’s multiple com- parison tests, p < 0.01 vs. Group I (NS), ** p < 0.01 vs. Group II (SCOP/ # MK-801). p < 0.05 vs. IV, NS = normal saline group. Group III = R-a-methyl- histamine, Group IV = CPX + SCOP/ CPX + MK-801, Group V = CBP + SCOP/CBP + MK-801, Group VI = CPX + RAMH + SCOP/CPX + RAMH + MK- 801, Group VII = CBP + RAMH + SCOP/CBP + RAMH + MK-801, Group VIII = CPX per se, Group IX = CBP per se. Series 1 (white bars) = effect of his- tamine H3-antagonists on SCOP- induced augmentation of AChE activ- ity in mice whole brain homogenate. Series 2 (grey bars) = effect of hista- mine H3-antagonists on MK-801- induced augmentation of AChE activ- ity in mice whole brain homogenate. “AChE activity” is taken as µmole ace- tylcholine iodide hydrolyzed/min/mg protein
Pharmacological Reports, 2012, 64, 191204 199 Present study has evaluated anti-schizophrenic like their four paws. During periods of climbing, mice did activities of two prototypical imidazole based H3R- not remain in one position but moved constantly ligands, CPX and CBP, keeping similar thoughts in around the sides or the tops of the cages, holding on to mind as discussed before. Further, the present data the wire mesh with their four paws [17]. support previous works claiming anti-schizophrenic APO-induced climbing behavior may be due to ac- like activities of H3R-anatgonists/inverse agonists. tivation of DA-receptors in the striatum, which con- Hypoactivity response has been reported with HA, tains the highest concentrations of H3Rs in the brain reducing spontaneous locomotor activity and inhibit- [4, 57]. However, the major localization of striatal ing meth-AMPH-induced locomotor hyperactivity. H3Rs is postsynaptic, in the GABAergic striatal effer- Further, systemic administration of L-histidine, at doses ent neurons, where they are co-localized with D1 and which elevated brain HA levels, has reduced both D2-receptors in the D1 containing neurons of direct AMPH and meth-AMPH-induced hyperactivity [34]. pathway and D2 containing neurons of indirect path- H3-antagonists/inverse agonists have ameliorated psy- way, respectively, [54, 58] and there apparently exists chostimulant induced hyperlocomotion [2] and im- functional postsynaptic H3-D1 and H3-D2 receptor in- proved deficits in prepulse inhibition (PPI) observed teraction. In spite of this, functional antagonism of be- in DBA/2 [12, 25]. Further, BF2.649, a novel hista- havioral responses exhibited by direct or indirect DA mine H3R-antagonist/inverse agonist has antagonized agonists remains elusive, and direct antagonism at DA meth-AMPH induced locomotor activity [42]. receptor could not be seen. NMDA antagonists-induced behavior is used as The inhibitory response shown by both CPX and a complementary model for screening new antipsy- CBP are abolished by the pretreatment with RAMH, chotic agents. NMDA antagonists cause an array of however, neither H3 antagonists per se nor RAMH behavioral changes such as hyperactivity, deficits in per se influenced locomotor activity indicating their PPI, memory impairment [8]. CPX and THP were re- effect as specific. ported to reduce MK-801-induced hyperlocomotor re- Extrapyramidal symptoms (EPS) have been a limit- sponse in rodents [9, 25], and similar observation was ing factor for the use of typical APDs. Recent experi- also made with BF2.649, a novel histamine H3R- mental study has also demonstrated and confirmed antagonist, which reduced locomotor hyperactivity that CPX potentiates cataleptogenic effect of HAL produced by MK-801 at 0.2 mg/kg dose [39]. Results [54]. Compound displaying potentiation of HAL- of the present study demonstrated hypolocomotor re- induced catalepsy is said to have antipsychotic activ- sponse with both CPX (3.0 mg/kg, ip) and CBP ity by many researchers, because almost all the typi- (15 mg/kg, ip) in MK-801 (0.2 mg/kg, ip) treated rats. cal APDs tend to produce catalepsy. Going by this Hypolocomotor response shown by CPX was higher logic, both CPX and CBP potentiate HAL-induced than that of CBP. This may be due to different phar- catalepsy in the present study, however, this model macokinetic profile of CPX and CBP. Also in vivo po- cannot be relied upon for antipsychotic activity, since tency of CPX was found to be 10–20 times higher both CPX and THP are type II cytochrome P450 inhibi- than that of CBP in rodents [47]. Doses of MK-801 tors, which form complex with the heme iron of P450 higher than 0.2 mg/kg tend to produce ataxia and mo- enzymes and cause potent inhibition of cytochrome tor incoordination, thus we restricted ourselves to us- P450 enzymes. CPX is reported to produce almost 95% ing 0.2 mg/kg of MK-801, ip, since this would unduly inhibition of HAL and risperidone metabolism. Poten- interfere locomotor activity monitoring. Further, both tiation observed with CPX (3 mg/kg, ip) and CBP THP and CPX are reported to attenuate hyperlocomo- (15 mg/kg, ip) could be due to inhibition of HAL me- tion in rats and mice, respectively, induced by differ- tabolism. However, unlike the imidazole containing ent direct and indirect dopaminergic agonists including H3R-antagonists/inverse agonist, the non-imidazole APO [49]. CPX has significantly decreased stereo- H3R-antagonists such as ABT-239 and A-431404 do typies induced by meth-AMPH and APO in previous not show potentiation of cataleptogenic effect of studies. APO-induced climbing behavior is a reliable HAL. Absence of potentiating effects with non imida- test to study post synaptic DA-activity [57]. Mice zole H3R-antagonists and results of in vitro drug me- treated with APO (1.5 mg/kg, sc) exhibited intense tabolism study, suggest that the potentiation of HAL- climbing behavior and displayed a tendency to climb induced catalepsy is a result of pharmacokinetic inter- up the walls of the cages holding the wire mesh with action rather than pharmacological interaction. So the
200 Pharmacological Reports, 2012, 64, 191204 Histamine H3-receptor ligands in schizophrenia Danish Mahmood et al.
blockade of H3R cannot be solely implicated for po- NMDA receptor antagonist, MK-801, induced dose tentiating effects of APDs in rodents [63]. Further, dependent impairment of learning and memory [31]. CLZ does not show augmentation of HAL-induced In the present study, MK-801 at a dose of 0.2 mg/kg, catalepsy and cause reduction of catalepsy. CLZ is re- ip administered 30 min before retention trial, signifi- ported to be a blocker of H3R as well [3, 37]. There- cantly impaired the memory recall and pre-treatment fore, it may be assumed that potentiation of HAL- with CPX and CBP including CLZ has reversed MK- induced catalepsy will not become a roadblock to pur- 801-induced amnesia. However, CPZ do not signifi- suing H3R-antagonists as APDs. cantly affect memory deficits of MK-801.Observa- The central cholinergic system is implicated in tions from present study support previous works re- learning and memory and blockade of cholinergic re- porting amelioration of both working and reference ceptors, particularly muscarinic receptors, is reported memory deficits by CBP and its effect was reversed to cause psychosis and cognitive impairment in nor- by immepip, a selective H3R-agonist [34]. Bernaerts mal human subjects, and also exacerbates schizo- et al. [10] reported neuromodulatory effect on mem- phrenic symptoms similar to those elicited by AMPH. ory consolidation exerted by THP and mobilization of Memory facilitating effect of 2-methyl histamine was interaction of histaminergic, cholinergic and glutama- found to be attenuated by pirenzepine, a muscarinic tergic systems. Further, icv injection of THP or hista- antagonist [11]. Previous studies have reported that mine is reported to improve MK-801-induced spatial activation of central histaminergic system attenuates memory deficits in radial maze task [14]. AChE is an SCOP-induced learning and memory deficits [11, 45, enzyme that degrades ACh. Excessive AChE activity 46, 51, 53]. leads to constant ACh deficiency, which in turn re- SCOP is a nonselective muscarinic cholinergic an- sults in memory and cognitive impairments. Our re- tagonist and has been widely used to disrupt learning sults from AChE activity further supported the ame- and memory in experimental animals. H R-antagonist, liorating effect of CPX and CBP on learning and 3 memory deficits. Furthermore, data from our study THP, probably was the first H -ligand to show im- 3 substantiate previous claim of anti-amnesic effects of provement in learning and memory deficits in passive H R antagonists in neuropsychiatrical conditions. avoidance test [44]. However, THP met with setback 3 The present study supports the therapeutic interest because of its hepatotoxicity liabilities as it contains of histamine H R-antagonists/inverse agonists to im- thiourea moiety. Another imidazole based prototypi- 3 prove symptomatic treatment of schizophrenia. How- cal H R-antagonist, CBP, was reported to alleviate 3 ever, the realization of the H R-antagonists/inverse learning and memory deficits in passive avoidance 3 agonists as anti-schizophrenic agents is far from real- test [32, 46, 52] and later, CPX, a more potent H R- 3 ity and a great deal of additional research work is antagonist than THP, showed increased release of needed to fine-tune previous studies involving H3R- ACh in the hippocampus, entorhinal cortex and pre- antagonists/inverse agonists in psychotic disorders. frontal cortex, in vivo [39, 43]. Present study agrees with previous finding of involvement H3R-antagonists in learning and memory effects, improvement in Acknowledgment: learning and memory by both CPX and CBP, which Authors express thanks and gratitude to The Department of Science and Technology (DST), New Delhi, India, for providing may be due to the blockade of H3Rs, hence, increas- the financial assistance for this research. ing neuronal HA levels, which in turn stimulated H1R and H2R post synaptically. Further, since there is a close association between cholinergic and histamin- ergic system and since H3R-antagonists is reported References: to release ACh through H3-heteroreceptor, therefore, another explanation could be its direct stimulation of cholinergic neurons by released HA. Further, out of 1. Abe H, Honma S, Ohtsu H, Honma K: Circadian two marketed APDs, CLZ and CPZ, only CLZ rhythms in behavior and clock gene expressions in the brain of mice lacking histidine decarboxylase. Brain Res showed improvement in learning and memory, what Mol Brain Res, 2004, 124, 178–187. could be ascribed to ACh releasing activity of CLZ in 2. Akhtar M, Uma DP, Ali A, Pillai KK, Vohora D: cortical areas, which is not reported with CPZ [33]. Antipsychotic like profile of thioperamide, a selective
Pharmacological Reports, 2012, 64, 191204 201 H3-receptor antagonist in mice. Fundam Clin Pharmacol, 17. Costal B, Naylor RJ, Nohria V: Climbing behavior by 2006, 20, 373–378. apomorphine in mice: a potential model for the detection 3. Alves-Rodrigues A, Jansen FP, Leurs R, Timmerman H, of neuroleptic activity. Eur J Pharmacol, 1978, 50, 39–50. 18. Prell D: Interaction of clozapine with the histamine H3 Corbett R, Hartman H, Kerman LL, Woods AT, Strup- receptor in rat brain. Br J Pharmacol, 114, 1523–1524. czewski JT, Helsley GC, Conway PC, Dunn RW: Effects 4. Anichtchik OV, Huotari M, Peitsaro N, Haycock JW, of atypical antipsychotics agents on social behavior in Mannisto PT, Panula P: Modulation of H3 receptors in rodents. Pharmacol Biochem Behav, 1993, 45, 9–17. the brain of 6-hydroxydopamine-lesioned rats: Eur 19. Corbett R. Sorensen SM. Mondadori C: Animal models J Neurosci, 2000, 12, 3823–3832. of negative symptoms: M100907 antagonizes PCP- 5. Arrang JM: Histamine and schizophrenia. Int Rev Neu- induced immobility in a forced swim test in mice. Neu- robiol, 2007, 78, 247–286. ropsychopharmacology, 1999, 21, S211–S218. 20. 6. Arrang JM, Garbarg M, Lancelot JC, Lecomte JM, deEsch IJ, Thurmond RL, Jongejan A, Leurs R: The his- Pollard H, Robba M, Schunack W, Schwartz JC: Highly tamine H4 receptor as a new therapeutic target for in- potent and selective ligands for histamine H -receptors. flammation. Trends Pharmacol Sci, 2005, 26, 462–469. 3 21. Nature, 1987, 327, 117–123. Dere E, De Souza MA, Spieler RE, Lin JS, Ohtsu H, 7. Arrang JM, Garbarg M, Schwartz JC: Auto-inhibition Haas HL, Huston JP: Changes in motoric, exploratory and emotional behaviors and neuronal acetylcholine con- of brain histamine mediated by a novel class (H3) of his- tamine receptor. Nature, 1983, 302, 832–837. tent and 5-HT turnover in histidine decarboxylase-KO mice. Eur J Neuroscience, 2004, 20, 1051–1058. 8. Bardgett ME, Points M, Ramsey-Faulkner C, Topmiller 22. Dere E, De Souza MA, Topic B, Spieler RE, Haas HL, J, Roflow J, McDaniel T, Lamontagne T, Griffith MS: Huston JP: Histidine decarboxylase knockout mice show The effects of clonidine on discrete-trial delayed spatial deficient non-reinforced episodic object memory, im- alternation in two rat models of memory loss. Neuropsy- proved negatively reinforced water maze performance, chopharmacology, 2008, 33, 1980–1991. and increased neo and ventrostriatal dopamine turnover. 9. Bardgett ME, Points M, Roflow J, Blankenship M, Learn Mem, 2003, 10, 510–519. Griffith, MS: Effects of the H receptor antagonist, 3 23. Ellenbroek BA: Treatment of schizophrenia: a clinical thioperamide, on behavioral alterations induced by sys- and preclinical evaluation of neuroleptic of drugs. temic MK-801 administration. Psychopharmacology, Pharmacol Ther, 1993, 57, 1–78. 2009, 205, 589–597. 24. Ellman GL, Courtney KD, Andres VJ, Featherstone RM: 10. Bernaerts P, Lamberty Y, Tirelli E: Histamine H3 antago- A new and rapid colorimetric determination of acetylcho- nist thioperamide dose-dependently enhances memory linesterase activity. Biochem Pharmacol, 1961, 7, 88–95. consolidation and reverses amnesia induced by dizocil- 25. Faucard R, Armand V, Héron A, Cochois V, Schwartz pine or scopolamine in a one-trial inhibitory avoidance JC, Arrang JM: N-methyl-D aspartate receptor antago- task in mice. Behav Brain Res, 2004, 154, 211–219. nists enhance histamine neuron activity in rodent brain. 11. Bhattacharya SK: Central histamine receptors in learning J Neurochem, 2006, 98, 1487–1496. and memory in rats. Eur J Pharmacol, 1990, 183, 925–931. 26. Fox GB, Esbenshade TA, Pan JB, Radek RJ, Krueger 12. Browman KE, Komater VA, Curzon P, Rueter LE, Han- KM, Yao BB, Browman KE et al.: Pharmacological cock AA, Decker MW, Fox GB: Enhancement of pre- properties of ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidi- pulse inhibition of startle in mice by the H3 receptor an- nyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neuro- tagonists, thioperamide and ciproxifan. Behav Brain Res, physiological characterization and broad preclinical effi- 2004, 153, 69–76. cacy in cognition and schizophrenia of a potent and se- 13. Chen Z, Li Z, Sakurai E, Izadi Mobarakeh J, Ohtsu H, lective histamine H3 receptor antagonist. J Pharmacol Watanabe T et al: Chemical kindling induced by pentyle- Exp Ther, 2005, 313, 176–190. netetrazole in histamine H1 receptor gene knock-out 27. Fulop AK, Foldes A, Buzas E, Hegyi K, Miklos IH, –/– mice (H1KO), histidine deficient mice (HDC ) and Romics L, Kleiber M et al.: Hyperlepinemia, visceral mast cell deficient W/Wv mice. Brain Res, 2003, 968, adiposity, and decreased glucose tolerance in mice with 162–166. a targeted disruption of the histidine decarboxylase gene. 14. Chen Z, Zhao Q, Sugimoto Y, Fujii Y, Kamei C: Effects Endocrinology, 2003, 144, 4306–4314. of histamine on MK-801-induced memory deficits in ra- 28. Haas HL, Sergeeva OA, Selbach O: Histamine in nerv- dial maze performance in rats. Brain Res, 1999, 839, ous system. Physiol Rev, 2008, 88, 1184–1241. 186–189. 29. Hall DA, Stain JJ, Merquez HA, Gulley JM: A compari- 15. Connelly WM, Shenton FC, Lethbridge N, Leurs son of amphetamine and methamphetamine induced loco- R, Waldvogel HJ, Faull RL, Lees G, Chazot PL: The his- motor activity in rats: evidence for qualitative differences tamine H4 receptor is functionally expressed on neurons in in behavior. Psychopharmacology, 2008, 195, 469–478. the mammalian CNS. Br J Pharmacol, 2009, 157, 55–63. 30. Hlinak Z, Krejci I: N-methyl-D-aspartate prevented 16. Cool AR: Mesolimbic dopamine and its control of loco- memory deficits induced by MK-801 in mice. Physiol motor activity in rats: differences in pharmacology and Res, 2003, 52, 809–812. light/dark periodicity between the olfactory tubercle and 31. Hlinak Z, Krejci I: Oxiracetam prevents the MK-801 the nucleus accumbens. Psychopharmacology, 1986, 88, induced amnesia for the elevated plus-maze in mice. 451–459. Behav Brain Res, 2000, 117, 147–151.
202 Pharmacological Reports, 2012, 64, 191204 Histamine H3-receptor ligands in schizophrenia Danish Mahmood et al.
32. Huang YW, Hu WW, Chen Z, Zhang LS, Shen HQ, 46. Miyazki S, Onodera K, Imaizumi M, Timmerman H: Timmerman H, Leurs R, Yanai K: Effects of the hista- Effects of clobenpropit (VUF-9153), a histamine mine H3-antagonist clobenpropit on spatial memory deficits H3-receptor on learning and memory, and cholinergic induced by MK-801 as evaluated by radial maze in and monoaminergic systems in mice. Life Sci, 1997, 61, Sprague-Dawley rats. Behav Brain Res, 2004, 151, 355–361. 287–293. 47. Morini G, Grandi D, Stark H, Schunack W: Histamine 33. Ichikawa J, Dai J, O’Laughlin IA, Fower WL, Meltzer H3 receptor antagonists inhibit gastric protection by HY: Atypical, but not typical antipsychotic drugs in- (R)-a-methyl histamine in the rat. Br J Pharmacol, 2000, crease cortical acetylcholine release without an effect in 129, 1597–1600. the nucleus accumbens. Neuropsychopharmacology, 48. Morisset S, Sahm UG, Traiffort E, Tardivel-Lacombe J, 2002, 26, 325–339. Arrang JM, Schwartz JC: Atypical neuroleptics enhance 34. Itoh Y, Nishibori M, Oishi R, Saeki K: Neuronal hista- histamine turnover in brain via 5 HT2A receptor block- mine inhibits methamphetamine-induced locomotor hy- ade. J Pharmacol Exp Ther, 1999, 288, 590–596. peractivity in mice. Neurosci Lett, 1984, 48, 305–309. 49. Morriset S, Pilon C, Tardivel-Lacombe J, Weinstein D, 35. Itoh Y, Onodera K, Sakurai E, Sato M, Watanabe T: Rostene W, Betancur C et al.: Acute and chronic effects Effects of dopamine antagonists on neuronal histamine of methamphetamine on tele-methyl histamine levels in release in the striatum of rats subjected to acute and mouse brain: selective involvement of the D2 and not D3 chronic treatments with methamphetamine. J Pharmacol receptor. J Pharmacol Exp Ther, 2002, 300, 621–628. Exp Ther, 1996, 279, 271–276. 50. Munzar P, Tanda G, Justinova Z, Goldberg SR: Hista- 36. Iwabuchi K, Kubota Y, Ito C, Watanabe T, Yanai K: mine H3 receptor antagonists potentiate methampheta- Methamphetamine and brain histamine: A study using mine self administration and methamphetamine-induced histamine-related gene knockout mice. Ann NY Acad accumbal dopamine release. Neuropsychopharmacology, Sci, 2004, 1025, 129–134. 2004, 29, 705–717. 37. Kathmann M, Schlicker E, Gothert M: Intermediate af- 51. Onodera K, Miyazaki S, Imaizumi M, Stark H, Schunack finity and potency of clozapine and low affinity of other W: Improvement by FUB 181, a novel histamine H3- neuroleptics and of antidepressants at H3 receptors. receptor antagonist, on learning and memory in an ele- Psychopharmacology, 1994, 116, 464–468. vated plus-maze test in mice. Naunyn-Schmiedebergs 38. Leurs R, Bakkar RA, Timmerman H, deEsch IJ: The his- Arch Pharmacol, 1998, 357, 508–513. tamine H receptor: from gene cloning to H receptor 3 3 52. Orsetti M, Ghi P, Carlo GD: Histamine H -receptor im- drugs. Nat Rev Drug Discov, 2005, 4, 107–120. 3 proves memory retention and reverses the cognitive defi- 39. Ligneau X, Landais L, Perrin D, Piriou J, Uguen M, cits induced by scopolamine in a two trial place recogni- Denis E, Robert P et al.: Brain histamine and schizophre- tion task. Behav Brain Res, 2001, 124, 235–242. nia: potential therapeutic applications of H -receptor in- 3 53. Parmentier R, Ohtsu H, Djebbara-Hannas Z, Valatax JL, verse agonists studied with BF2.649. Biochem Pharma- Watanabe T, Lin JS: Anatomical, physiological, and col, 2007, 73, 1215–1224. 40. Ligneau X, Lin J, Vanni-Mercier G, Jouvet M, Muir JL, pharmacological characteristics of histidine decarboxy- Ganellin CR, Stark H et al.: Neurochemical and behav- lase knockout mice: Evidence for the role of brain hista- mine in behavioral and sleep wake control. J Neurosci, ioral effects of ciproxifan, a potent histamine H3 receptor antagonist. J Pharmacol Exp Ther, 1998, 287, 658–666. 2002, 22, 7695–7711. 54. 41. Lowry OH, Roseburgh NJ, Farr AL, Randal RL: Protein Pillot C, Ortiz J, Heron A, Ridray S, Schwartz JC, measurement with the folin phenol reagent. J Biol Chem, Arrang JM: Ciproxifan, a histamine H3-receptor antago- 1951, 193, 205–15. nist/inverse agonist, potentiates neurochemical and be- 42. Marchese G, Casu G, Casti P, Spada GP, Pani L: Evalua- havioral effects of haloperidol in rat. J Neurosci, 2002, tion of amphetamine induced hyperlocomotion and cata- 22, 7272–7280. 55. lepsy following long acting risperidone administration in Pollard H, Moreau J, Arrang JM, Schwartz JC: A de- rats. Eur J Pharmacol, 2009, 620, 36–41. tailed autoradiographic mapping of histamine H3 recep- 43. Medhurst AD, Atkins AR, Beresford IJ, Brackenborough tors in rat brain areas. Neuroscience, 1993, 52, 169–189. K, Briggs MA, Calver AR, Cilia J et al.: GSK189254, 56. Prell GD, Green JP, Kaufmann CA, Khandelwal JK, a novel H3 receptor antagonist that binds to histamine H3 Morrishow AM, Kirch DG, Linnoila M, Wyatt RJ: receptors in Alzheimer’s disease brain and improves Histamine metabolites in cerebrospinal fluid of patients cognitive performance in preclinical models. J Pharma- with chronic schizophrenia: their relationships to levels col Exp Ther, 2007, 321, 1032–1045. of other aminergic transmitters and ratings of symptoms. 44. Meguro K, Yanai K, Sakai N, Sakurai E, Sasaki H, Schizophr Res, 1995, 14, 93–104. 57. Watanabe T: Effects of thioperamide, a histamine H3 an- Protais P, Costentin J, Schwartz JC: Climbing behaviour tagonists on step through passive avoidance response and induced by apomorphine in mice: a simple test for the histidine decarboxylase activity in senescence-accelerated study of dopamine receptors in striatum. Psychopharma- mice. Pharmacol Biochem Behav, 1995, 50, 321–325. cology, 1976, 50, 1–6. 45. Miyazaki S, Imaizumi M, Onodera K: Effects of 58. Ryu JH, Yanai K, Sakurai E, Kim CY, Watanabe T: thioperamide, a histamine H3 receptor antagonist, on Ontogenetic development of histamine receptor subtypes scopolamine induced learning deficits using an elevated in rat brain demonstrated by quantitative autoradiogra- plus maze test in mice. Life Sci, 1995, 57, 2137–2144. phy. Develop Brain Res, 1995, 87, 101–110.
Pharmacological Reports, 2012, 64, 191204 203 59. Schlicker E, Malinowska B, Kathmann M, Gothert M: sponse by the 5-HT2 receptor antagonist ketanserin. Eur Modulation of neurotransmitter release via histamine H3 J Pharmacol, 1995, 287, 201–205. heteroreceptor. Fundam Clin Pharmacol, 1994, 8, 128–137. 63. Zhang M, Ballard ME, Pan L, Roberts S, Faghih R, 60. Silva SR, Futuro-Neto HA, Pires JGP: Effects of 5-HT3 Cowart M, Esbenshade TA et al.: Lack of cataleptogenic receptor antagonists on neuroleptic induced catalepsy in potentiation with non-imidazole H3 receptor antagonists mice. Neuropsychopharmacology, 1995, 34, 97–99. reveals potential drug-drug interactions between 61. ñ Simón VM, Parra A, Mi arro J, Arenas MC, Vinader- imidazole-based H3 receptor antagonists and antipsy- Caerols C, Aguilar MA: Predicting how equipotent doses chotic drugs. Brain Res, 2005, 1045, 142–149. of chlorpromazine, haloperidol, sulpiride, raclopride and clozapine reduce locomotor activity in mice. Eur Neu- ropsychopharmacol, 2000, 10, 159–164. 62. Varty GB, Higgins GA: Reversal of dizocilpine-induced Received: December 13, 2010; in the revised form: August 3, disruption of prepulse inhibition of an acoustic startle re- 2011; accepted: August 31, 2011.
204 Pharmacological Reports, 2012, 64, 191204