Pharmacological Reports Copyright © 2012 2012, 64, 13161325 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences
Effects of the histamine H3 receptor antagonist ABT-239 on cognition and nicotine-induced memory enhancement in mice
Marta Kruk1, Joanna Miszkiel2, Andrew C. McCreary3, Edmund Przegaliñski2, Ma³gorzata Filip2,4, Gra¿yna Bia³a1
1 Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, ChodŸki 4A, PL 20-093 Lublin, Poland
2 Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland
3 BrainsOn-Line, de Mudden 16, 9747AW Groningen, The Netherlands
4 Department of Toxicology, Faculty of Pharmacy, Jagiellonian University, College of Medicine, Medyczna 9, PL 30-688 Kraków, Poland
Correspondence: Gra¿yna Bia³a, e-mail: [email protected]
Abstract: Background: The strong correlation between central histaminergic and cholinergic pathways on cognitive processes has been re- ported extensively. However, the role of histamine H3 receptor mechanisms interacting with nicotinic mechanisms has not previ- ously been extensively investigated. Methods: The current study was conducted to determine the interactions of nicotinic and histamine H3 receptor systems with regard to learning and memory function using a modified elevated plus-maze test in mice. In this test, the latency for mice to move from the open arm to the enclosed arm (i.e., transfer latency) was used as an index of memory. We tested whether ABT-239 (4-(2-{2-[(2R)-2- methylpyrrolidinyl]ethyl}-benzofuran-5-yl), an H3 receptor antagonist/inverse agonist, had influence on two different stages of memory, i.e., memory acquisition and consolidation (administered prior to or immediately after the first trial, respectively) and whether ABT-239 influenced nicotine-induced memory enhancement. Results: Our results revealed that the acute administration of nicotine (0.035 and 0.175 mg/kg), but not of ABT-239 (0.1–3 mg/kg) reduced transfer latency in the acquisition and consolidation phases. In combination studies, concomitant administration of either ABT-239 (1 and 3 mg/kg) and nicotine (0.035 mg/kg), or ABT-239 (0.1 mg/kg) and nicotine (0.0175 mg/kg) further increased nicotine-induced improvement in both memory acquisition and consolidation. Conclusion: The present data confirm an important role for H3 receptors in regulating nicotine-induced mnemonic effects since in- hibition of H3 receptors augmented nicotine-induced memory enhancement in mice.
Key words: modified elevated plus maze, histamine3 receptor, nicotine, cognition
1316 Pharmacological Reports, 2012, 64, 13161325 H3 receptors in nicotine cognitive effects Marta Kruk et al.
Introduction coupled receptors including H1,H2,H3 and the re- cently discovered H4 subtype [48, for review]. Among them, H3 receptors are constitutively active and highly The strong correlation between central cholinergic expressed in the central nervous system functioning pathways and learning and memory as well as impact as autoreceptors on histaminergic neurons and hetero- of the nicotinic cholinergic system on memory-related receptors on non-histaminergic neurons. Experimen- behavior has been described in the literature [26, 35, tal data suggest that these receptors can influence the 36]. However, with respect to the influence of nico- synthesis and release of variety of different neuro- tine on memory functions, experimental studies in hu- transmitters, i.e., histamine itself, ACh, dopamine, mans and animals have yielded contradictory results. GABA, glutamate, noradrenaline and serotonin [7, In humans, many studies have described deficits or 22, 52] and more importantly, in the context of the improved efficiency of cognitive processing after present manuscript, recent evidence suggests that his- nicotine administration [27, 35]. In animals, some re- taminergic neurotransmission might interact with searchers have argued that nicotine improves memory nicotinic systems [25]. This role of H3 receptors has function, while others have reported no effect or even critical influence on cognition, memory and vigilance negative effects [36, 38]. For example, many studies processes, food intake and a variety of other behav- have demonstrated that nicotine enhances hippocam- iors [22, 25]. Interestingly, blockade of H3 receptors pal-dependent learning and memory, including spatial promotes attention, wakefulness and adjusts short learning in the radial-arm maze and Morris water term and social memory in rodents [40, 43, 47, 49]. maze, avoidance conditioning, and contextual fear H3 receptor antagonists have been shown by some conditioning [15–17, 62]. Interestingly, human and studies to improve cognitive function, but others have animal studies point to attenuated memory and learn- ing capacities during nicotine withdrawal as well as not found this effect and some have found memory improved cognitive function following acute nicotine impairment [19, 47]. Moreover, recent, limited studies administration [35, 39]. indicate that blockade of H3 receptors effectively The central effects of nicotine have been the sub- reverses nicotine choice accuracy impairment in the ject of many experimental studies but the precise radial-arm maze repeated acquisition task [33]. How- mechanisms responsible for the potential enhance- ever, the role of H3 receptors appears not to have been ment of learning and memory induced by nicotine studied in relation to nicotine-induced mnemonic pro- have not been elucidated. It is generally accepted that cesses. nicotine exerts its behavioral effects acting at the The current study was therefore conducted to assess nicotinic acetylcholine (ACh) receptors (nAChRs) whether ABT-239 (4-(2-{2-[(2R)-2-methylpyrrolidi- [61, for review]. Among all central nAChR subtypes, nyl]ethyl}-benzofuran-5-yl), a novel, non-imidazole the heteromeric a4b2 and homomeric a7 receptors H3 receptor antagonist and inverse agonist [14], influ- seem to play the pivotal role in the reinforcing, dis- enced nicotine-induced memory-related behavior in criminative stimulus and locomotor effects [6, 12, 24, mice using a modified elevated plus maze (mEPM) 32, 37, 58, 59] as well as in memory-related responses paradigm, designed to evaluate spatial learning and of nicotine [13]. Nicotine facilitates, via the stimula- memory [28–31, 42, 53]. ABT-239 has already been tion of a4b2 and a7 receptors located presynaptically, shown to improve social memory in aged rats or to the release of a variety of neurotransmitters including partially reverse scopolamine-induced deficits in ACh, dopamine, serotonin, g-aminobutyric acid a spatial navigation test in the water maze [20]. As (GABA), glutamate and histamine [56, 57], all of which may be responsible for the nicotine-evoked ad- pharmacological blockade of central H3 receptors diction and/or cognitive processes. could enhance cognition in rodents, there is growing It is now well-established that histamine (H) acts as interest in such compounds for potential utility in an important neurotransmitter, originating from hypo- treating attentional and cognitive deficits such as thalamic neurons that project widely throughout the those seen in attention deficit-hyperactivity disorder brain to forebrain regions including the cortex, hippo- and attention deficit disorder (ADHD and ADD), Alz- campus, amygdala, and striatum [8]. This biogenic heimer’s disease, mild cognitive impairment, and amine is now known to affect four distinct G protein- schizophrenia etc.
Pharmacological Reports, 2012, 64, 13161325 1317 Materials and Methods terruptions of photocell beams located across two lon- gitudinal axis measured animal movement.
Animals Modified elevated plus maze as a memory test
Male Swiss mice (20–30 g), derived from Farm of Memory and learning responses were measured using Laboratory Animals (Warszawa, Poland), housed un- the modified elevated plus maze (mEPM) test as de- der standard laboratory condition (12 h light/dark cy- scribed previously [4, 5]. The experimental apparatus cle, room temperature 21 ± 1°C, 40–50% humidity), was shaped like a “plus” sign and consisted of a cen- were used. Food and water were available ad libitum. tral platform (5 × 5 cm), two open arms (5 × 30 cm) Animals were habituated to the laboratory conditions and two enclosed arms (5 × 30 × 15 cm) opposite to for at least one week prior to experimentation. All be- each other. The maze was made of dark Plexiglas. The havioral experiments were performed between 8:00 whole apparatus was elevated 50 cm above the floor and 14:00 h, and were conducted according to the Na- and illuminated by a dim red light. tional Institute of Health Guidelines for the Care and Use of Laboratory Animals and to the European Com- Experimental procedure munity Council Directive for the Care and Use of Laboratory Animals of 24 November 1986 (86/609/ EEC), and approved by the local ethics committee. Locomotor activity Each experimental group consisted of 7–10 mice. The In order to measure locomotor effects of ABT-239 animals were drug naive at the start of the studies. and/or nicotine, the animals, naive for any drug treat- ment, were injected with vehicle or ABT-239 (0.1, 1 and Drugs 3 mg/kg), 30 min before vehicle or nicotine (0.0175 and 0.035 mg/kg) administration, and immediately Nicotine bitartrate, reported as freebase nicotine placed in the activity chamber. Locomotor activity, weight (Sigma-Aldrich, St. Louis, USA) was diluted i.e., the number of photocell beam breaks (above) was in saline (0.9% NaCl) with the pH (5–7) adjusted and automatically recorder for 60 min. given subcutaneously (sc) 30 min before behavioral recording. ABT-239 (Solvay Pharmaceuticals Re- mEPM search Laboratories, Weesp, The Netherlands) was suspended in one drop of 1% solution of Tween 80 As described previously [4, 5], mice were placed indi- (Sigma, St. Louis, USA) and dissolved in saline. This vidually at the end of one open arm facing away from diluent also served as vehicle. ABT-239 was adminis- the central platform. Each group was submitted to the tered intraperitoneally (ip), 60 min before behavioral same procedure twice (interval between trials of 24 h). testing or 30 min before nicotine or vehicle injection On the first trial (acquisition trial), the latency to in a volume of 10 ml/kg. Control groups received ve- move from the open arm to either of the enclosed hicle injections at the same volume and by the same arms (transfer latency, TL1) was recorded and ob- route. Fresh drug solutions were prepared on each day served on a monitor through a closed-circuit video of experimentation. Doses of nicotine and ABT-239 camera system. If the mice did not enter the enclosed used were selected according to those commonly re- arm within 90 s, they were placed into the enclosed ported in the literature, including our previous studies arm and permitted to explore this maze for an addi- [4, 5, 19, 20, 59–61]. tional 60 s; in such cases TL1 was recorded as 90 s. On the next trial (retention trial), 24 h later, the test Apparatus was performed in the same manner as the first trial and the TL was recorded (TL2). If the mouse did not Locomotor activity measurements enter the enclosed arm within 90 s, the test was stopped and TL2 was recorded as 90 s. Any animal Locomotor activity in mice was recorded individually that fell off the maze was excluded from the experi- in a round actometer cages (32 cm in diameter) ment. In the mEPM test, we used the TL2 values on housed in a sound-attenuated experimental room. In- the retention trial as an index of memory and learning
1318 Pharmacological Reports, 2012, 64, 13161325 H3 receptors in nicotine cognitive effects Marta Kruk et al.
effects. The improvement of memory was indicated Results by decreases in time which the mice took to move from the open arms to either of enclosed arms on the second, retention trial. The impairment of memory Locomotor activity and learning was characterized by increases in these measures. Entry into one arm was recorded when all It can be noted that neither ABT-239 nor nicotine, at four paws passed the line dividing the central square doses tested, caused any statistically significant from the open arms. The test arena was wiped with changes in the locomotor activity of mice as com- a damp cloth after each trial. pared with the control vehicle-injected group (Tab. 1). Two-way ANOVA of the locomotor response did not reveal any treatment effect [F (1, 90) = 0.42, p = Treatment 0.52), pre-treatment effect [F (4, 90) = 2.21, p = 0.07] or treatment x pre-treatment interaction [F (4, 90) = The first experiment was designed to investigate the in- 0.034, p = 0.99]. fluence of either nicotine or ABT-239 on memory- related responses using the mEPM in mice. Nicotine mEPM – memory acquisition (0.0175, 0.035, 0.175 and 0.35 mg/kg), ABT 239 (0.1, 0.3, 1 and 3 mg/kg), or respective vehicles were admin- In the acquisition trial, there were no significant dif- istered at the appropriate times (above) before or imme- ferences in the TL1 between the drug-treated and con- diately after the first acquisition trial (effect on memory trol groups (approximately, TL1 = 34 ± 7 s). acquisition or consolidation, respectively). Twenty-four Acute nicotine (0.0175–0.35 mg/kg) but not acute hours after, the animals were re-tested in the mEPM dur- ABT-239 (0.1–3 mg/kg) administration evoked a dose- ing the retention trial. This second day, the mice did not dependent reduction in TL2 values compared to the receive any pharmacological intervention. corresponding control groups [one-way ANOVA for Subsequent experiments were designed to investi- nicotine: F (4, 36) = 5.18, p = 0.002; for ABT-239: gate the influence of ABT-239 on the acquisition and F (4, 36) = 0.81, p = 0.53]. Accordingly, the post-hoc consolidation of memory-related responses induced analysis (Tukey’s test) revealed that nicotine (0.035 by an acute nicotine administration. For this purpose, and 0.175 mg/kg; p < 0.01) caused a significant im- ABT-239 (1 and 3 mg/kg) or vehicle were adminis- provement in memory acquisition (Fig. 1A and 2A). tered 30 min prior to nicotine (0.035 mg/kg), and ABT-239 (0.1 mg/kg) or vehicle were administered 30 min prior to nicotine (0.0175 mg/kg); the mice Tab. 1. Effects of nicotine and ABT-239, alone or in combination, on were tested 30 min later and re-tested after 24 h (ac- locomotor activity (the mean ± SEM, photocell beam breaks) of mice quisition). Additional groups of mice were injected measured for 60 min; n = 10 with ABT-239 (1 and 3 mg/kg) or vehicle 30 min prior to nicotine (0.035 mg/kg), and ABT-239 Treatment Mean ± SEM (0.1 mg/kg) or vehicle 30 min prior to nicotine Vehicle + vehicle 648.8 ± 72.43 (0.0175 mg/kg) immediately after the first trial; the Vehicle + nicotine 0.0175 mg/kg 625.9 ± 69.72 animals were then re-tested after 24 h (consolidation). Vehicle + nicotine 0.035 mg/kg 551.2 ± 57.84
Statistical analyses ABT-239 (0.1 mg/kg) + vehicle 599.5 ± 72.97 ABT-239 (0.3 mg/kg) + vehicle 462.5 ± 37.58 The data were expressed as the means ± SEM. The ABT-239 (1.0 mg/kg) + vehicle 579.7 ± 65.23 statistical analyses were performed using the two-way ABT-239 (3.0 mg/kg) + vehicle 490.4 ± 75.11 analyses of variance (ANOVA) with pre-treatment and treatment as factors. Also, one-way ANOVA was ABT-239 (0.1 mg/kg) 461.4 ± 74.23 + nicotine (0.0175 mg/kg) used where appropriate for additional analysis. A post-hoc comparison of means was conducted us- ABT-239 (1.0 mg/kg) 538.7 ± 98.78 + nicotine (0.035 mg/kg) ing the Tukey’s test for multiple comparisons, where appropriate, p < 0.05 was considered statistically sig- ABT -239 (3.0 mg/kg) 460.3 ± 55.19 + nicotine (0.035 mg/kg) nificant.
Pharmacological Reports, 2012, 64, 13161325 1319 A A 40 40
30 30
20 20 ** **
10 10 Transfer latency (TL2) 0 Transfer latency (TL2) 0 VEHICLE 0.0175 0.035 0.175 0.35 mg/kg VEHICLE 0.1 0.3 1.0 3.0 mg/kg
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0 Transfer latency (TL2) Transfer latency (TL2) VEHICLE 0.0175 0.035 0.175 0.35 mg/kg 0 VEHICLE 0.1 0.3 1.0 3.0 mg/kg NICOTINE ABT-239
Fig. 1. Effects of acute nicotine administration on the transfer latency to the enclosed arm in the acquisition trial (A) or consolidation trial Fig. 2. Effects of acute ABT-239 administration on the transfer latency (B) using the mEPM test in mice. Mice were injected with vehicle or to the enclosed arm in the acquisition trial (A) or consolidation trial nicotine (0.0175, 0.035, 0.175 and 0.35 mg/kg, sc) 30 min before the (B) using the mEPM test in mice. Mice were injected with vehicle or first trial (A) or immediately after the first trial (B); n = 7–9/group. Each ABT-239 (0.1, 0.3, 1 and 3 mg/kg, ip) 60 min before the first trial (A) or bar represents the mean ± SEM; * p < 0.05; ** p < 0.01 vs. vehicle immediately after the first trial (B); n = 7–9/group. Each bar repre- control group; Tukey’s test sents the mean ± SEM
Figure 3A shows the effect of ABT-239 administra- nificant effect for pre-treatment [F (1, 28) = 16.26, p < tion (1 and 3 mg/kg) on the nicotine-induced improve- 0.0001], treatment [F (1, 28) = 21.71, p < 0.0001], ment of memory acquisition in the mEPM. Two way without interaction [F (1, 28) = 1.72, p = 0.20]. The ANOVA revealed statistically significant effects of post-hoc analysis revealed that such drug combination pre-treatment [F (2, 43) = 2.72, p = 0.0077], treatment exhibited a significant reduction in TL2 values com- (F (1, 43) = 43.13, p < 0.0001], without interaction pared to the vehicle/control group (p < 0.001) as well [F (2, 43) = 0.30, p = 0.74]. Post-hoc analysis re- as to the groups that received either 0.1 mg/kg of vealed that the nicotine/control group (0.035 mg/kg) ABT-239 (p < 0.001) or 0.0175 mg/kg of nicotine (p < exhibited a significant reduction in TL2 values com- 0.01). Neither ABT-239 (0.1 mg/kg) nor nicotine pared to the vehicle/control group (p < 0.01), and this (0.0175 mg/kg) alone failed to show any affect alone effect was further increased by ABT-239 administra- on memory acquisition (see above). tion at both doses used (1 and 3 mg/kg) (p < 0.001). It should be mentioned, however, that at any dose ABT-239 alone did not show any effect by itself (see mEPM – memory consolidation above). Figure 4A shows the effect of combination of Acute nicotine (0.0175–0.35 mg/kg), but not acute subthreshold doses of ABT-239 (0.1 mg/kg) and nico- ABT-239 (0.1–3 mg/kg) administration evoked tine (0.0175 mg/kg) on memory acquisition in the a dose-dependent reduction in TL2 values compared mEPM. Two-way ANOVArevealed a statistically sig- to the corresponding control groups [one-way
1320 Pharmacological Reports, 2012, 64, 13161325 H3 receptors in nicotine cognitive effects Marta Kruk et al.
A 50 A 40
40 30 30 ### 20 20 ^^ ^^ *** 10 10 Transfer latency (TL2) *** *** Transfer latency (TL2) 0 0 (1) (3) (3) NIC NIC . VEH VEH VEH VEH VEH
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(0.1) (0 035) (0.035)
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(0.0175) NIC (0.035) B 40 ABT (0.1) B NIC (0.0175) 50 30 40 ### 30 20 ^ ^^ 20 * * 10 10 Transfer latency (TL2) Transfer latency (TL2) ** 0 0 (3) (3) (1)
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(0.0175) (0 035) (0.035) ABT (1) ABT ABT ABT
ABT (0.1) NIC (0.035)
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Fig. 3. Influence of ABT-239 on the memory-related response in- Fig. 4. Influence of ABT-239 on the memory-related response duced by acute nicotine administration in the acquisition trial (A) or induced by acute nicotine administration in the acquisition trial (A) or consolidation trial (B) using the mEPM test in mice. ABT-239 (1 or consolidation trial (B) using the mEPM test in mice. ABT-239 3 mg/kg, ip) or vehicle was administered 30 min prior to nicotine (0.1 mg/kg, ip) or vehicle was administered 30 min prior to nicotine (0.035 mg/kg, sc), 30 min before the first trial (A) or immediately after (0.0175 mg/kg, sc), 30 min before the first trial (A) or immediately the first trial (B); n = 8–9/group. Each bar represents the mean after the first trial (B); n = 7–9/group. Each bar represents the mean ± SEM; * p < 0.05; ** p < 0.01; *** p < 0.001 vs. nicotine control group; ± SEM; ^ p < 0.05; ^^ p < 0.01 compared to nicotine control group; ^^ p < 0.01 vs. vehicle control group; Tukey’s test * p < 0.05; *** p < 0.001 vs. ABT-239 control group; ### p < 0.001 vs. vehicle control group; Tukey’s test
ANOVAfor nicotine: F (4, 33) = 3.744, p = 0.013; for post-hoc analysis revealed that the nicotine/control ABT-239: F (4, 39) = 3.05, p = 0.028]. Accordingly, group (0.035 mg/kg) exhibited a significant reduction the post-hoc analysis (Tukey’s test) revealed that in TL2 values compared to the vehicle/control group nicotine (0.035 and 0.175 mg/kg; p < 0.05 and p < (p < 0.01), and this effect was further increased after 0.01, respectively) significantly caused an improve- ABT-239 administration at both doses used (1 and ment in memory consolidation (Fig. 1B and 2B). 3 mg/kg) (p < 0.05 and p < 0.01, respectively). It Figure 3B shows the effect of ABT-239 administra- should be mentioned that at any dose ABT-239 alone tion (1 and 3 mg/kg) on the nicotine-induced im- did not show any effect by itself (see above). provement of memory consolidation in the mEPM. Figure 4B shows the effect of combination of Two way ANOVA revealed a statistically significant subthreshold doses of ABT-239 (0.1 mg/kg) and nico- effect of pre-treatment [F (2, 47) = 11.85, p < 0.0001], tine (0.0175 mg/kg) on memory consolidation in the treatment [F (1, 47) = 18.89, p < 0.0001], and without mEPM. Two-way ANOVArevealed a statistically sig- significant interaction [F (2, 47) = 0.92, p = 0.41]. The nificant effect for a pre-treatment [F (1, 26) = 9.602,
Pharmacological Reports, 2012, 64, 13161325 1321 p = 0.0046], treatment [F (1, 26) = 7.679, p = 0.01], the conclusion that H3 receptor antagonists may have without interaction [F (1, 26) = 0.5545, p = 0.46]. utility for reverse changes in synaptic plasticity and Post-hoc analyses revealed that such drug combina- learning deficits related to this drug [44, 55]. tions exhibited significant reduction in TL2 values Based on previous findings that H3 receptor an- compared to the vehicle/control group (p < 0.001) as tagonists enhance memory performance in rodents well as to the groups that received either 0.1 mg/kg of [20, 40], our present experiments were designed to ABT-239 or 0.0175 mg/kg of nicotine (p < 0.05). Neither further investigate the possible mechanisms of H3 re- ABT-239 (0.1 mg/kg) nor nicotine (0.0175 mg/kg) ceptor modulation of the nicotine-induced memory- alone showed any effect by itself on memory consoli- related behavior in mice using the mEPM test. This dation (see above). test, originally developed to model anxiety in rodents, was modified to evaluate spatial learning and mem- ory. Briefly, this simple method consisted of measur- ing of the time necessary for the animal to move from Discussion the open to the enclosed arm, i.e., the transfer latency (TL). This method has been successfully used in stud- Our findings demonstrate, for the first time, a positive ies investigating the involvement of different neuro- transmitter systems, including cholinergic pathways, interaction between H3 receptors and nicotine in the acquisition and consolidation of memory in mice us- on learning and memory processes [28–31, 42, 53]. ing a modified elevated plus maze procedure. Our re- In line with our previous research [4, 5], we con- firm that acute administration of nicotine (0.0175– sults showed that nicotine, but not H3 receptor antago- nist ABT-239 alone caused improvement in both ac- 0.035 mg/kg) to mice induced a dose-related decrease quisition and consolidation of memory in mice. In in the transfer latency relative to the vehicle-treated combination studies, concomitant administration of group indicating improvement in acquisition and con- ABT-239 and nicotine (in either active or subthresh- solidation of memory. Moreover, we demonstrated old doses) caused further increases in the improve- that various doses of ABT-239 (0.3–3 mg/kg) did not ment in both memory acquisition and consolidation. cause any improvement in memory acquisition and ABT-239 was recently identified [14, 19] as an H3 re- consolidation in mice. These data obtained using the ceptor antagonist/inverse agonist with high affinity mEPM test do not support prior work demonstrating and selectivity for both human and rat H3 receptors that blockade of H3 receptors enhanced memory as with Ki = 0.45 and 1.4, respectively, although some evidenced in place recognition memory [46], novel off-target actions were noted, but at much higher con- object discrimination task [47], repeated acquisition centrations (Ki = 400 nM activity at the human ERK task [33] and the social recognition task [50] as well channel). Good oral bioavailability and excellent as beneficial effects to reverse scopolamine-induced blood brain barrier penetration were also seen. The cognitive deficits in the mEPM test [42, 45], novel data presented in this study indicate that blockade of recognition task [23, 47], passive avoidance test [2, H3 receptors potently enhances the cognitive effects 43] and in spatial learning tasks [10, 34] were seen. of nicotine in mice. Some of the differences in findings may be due to the It has been reported that, in laboratory animals, type of cognitive function modeled in the respective nicotine can affect many aspects of behavior includ- assays, the behavioral tasks used, and the dosing ing reward and dependence, aggression, anxiety, schedules employed, i.e., acute vs. chronic admini- antinociception, psychomotor activation or memory stration. The complex effects seen in the literature may and learning processes [3–6, 59, 60]. In this context, it be due to differential involvement of histamine H3 re- seems important to understand the possible mecha- ceptor in various aspects of cognitive function. Al- nism of nicotine-induced behavioral actions, includ- though there is evidence that pharmacological block- ing its mnemonic effects. The H3 receptor seems to be ade of H3 receptors improves cognitive function [21, valid target to modulate the neurobiology of memory 41, 50], the overall cognitive effects induced by hista- as H3 receptor antagonists may act as cognitive enhan- minergic ligands remain contradictory [8, 11, 31, 54]. cers [19, 47]. Thus, more recent results have suggested Furthermore, the present combination studies with that ABT-239 ameliorates ethanol-induced deficits on ABT-239 and nicotine showed, for the first time, H3 hippocampal long-term potentiation (LTP), leading to receptor and nicotine interactions in the acquisition
1322 Pharmacological Reports, 2012, 64, 13161325 H3 receptors in nicotine cognitive effects Marta Kruk et al.
and consolidation of memory in the mEPM test in should be further investigated, but are out of the scope mice. Either nicotine or ABT-239, at all doses tested, of the present study. had no significant acute effect on locomotor activity Taken together, the present studies confirm an im- indicating that the alterations in transfer latency were portant role for H3 receptors in regulating nicotine- not due to non-specific motor effects, including the induced mnemonic effects. Furthermore, it can be stimulant-like activity of nicotine. suggested that selective H3 receptor blockade with The precise mechanism of ABT-239 – nicotine in- compounds such as ABT-239 with functional antago- teraction was not assessed in this study, however, nist activity at central H3 receptors and potential based on complementary roles in cognitive function cognition-enhancing activity, at doses well below between nicotine and histaminergic systems [7], those inducing adverse effects in locomotion, may a number of hypotheses can be considered. First, therefore represent a novel approach for treatment of nicotine acting via nAChRs has a variety of effects human cognitive disorders. However, this hypothesis mediated through its facilitation of the release of a va- requires further studies with using more specific cog- riety of different neurotransmitters, including dopa- nition tasks as well as using more selective receptor mine, serotonin, ACh, noradrenaline, GABA, gluta- ligands for the H3 receptor or its various isoforms, ac- mate, and histamine [56]. However, the improved cording to receptor subtypes on particular brain re- cognitive function may be due to an action on gions involved in memory regulation. nAChRs in the prefrontal cortex, hippocampus and/or amygdala [39]. Stimulation of these area-specific re- Acknowledgments: ceptor sites provokes the release of a variety neuro- This work was supported by the statutory funds, and received transmitters [above; 57]. Among them, modulation of no special grant from any funding agency in the public, commercial or not-for-profit sectors. All authors declare that they have the histaminergic system is of key interest as a candi- no conflict of interest to disclose. date for complementary or facilitatory interactions with cholinergic (nicotinic) systems. Interestingly, it has been demonstrated that histamine co-administra- tion reduces the improvement in passive avoidance References: learning by nicotine, whereas histamine H1 receptor antagonists enhance nicotine-induced improvements 1. Bacciottini L, Passani MB, Giovannelli L, Cangioli I, [18]. It may be the case that enhancing histamine re- Mannaioni PF, Schunack W, Blandina P: Endogenous lease caused by nicotine may help or hinder nicotinic histamine in the medial septum-diagonal band complex increases the release of acetylcholine from the hippo- actions on learning function. campus: a dual-probe microdialysis study in the freely Secondly, H3 receptors are found in many brain ar- moving rat. 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