Effects of the histamine H 3 receptor antagonist ABT-239 on cognition and nicotine-induced memory enhancement in mice

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1 Pharmacological Reports 12, 64, ISSN Copyright 12 by Institute of Pharmacology Polish Academy of Sciences Effects of the histamine H 3 receptor antagonist ABT-239 on cognition and nicotine-induced memory enhancement in mice Marta Kruk 1, Joanna Miszkiel 2, Andrew C. McCreary 3, Edmund Przegaliñski 2, Ma³gorzata Filip 2,4, Gra yna Bia³a 1 1 Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, ChodŸki 4A, PL -93 Lublin, Poland 2 Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 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 -688 Kraków, Poland Correspondence: Gra yna Bia³a, grazyna.biala@umlub.pl Abstract: Background: The strong correlation between central histaminergic and cholinergic pathways on cognitive processes has been reported extensively. However, the role of histamine H 3 receptor mechanisms interacting with nicotinic mechanisms has not previously been extensively investigated. Methods: The current study was conducted to determine the interactions of nicotinic and histamine H 3 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 H 3 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 (.35 and.175 mg/kg), but not of ABT-239 (.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 (.35 mg/kg), or ABT-239 (.1 mg/kg) and nicotine (.175 mg/kg) further increased nicotine-induced improvement in both memory acquisition and consolidation. Conclusion: The present data confirm an important role for H 3 receptors in regulating nicotine-induced mnemonic effects since inhibition of H 3 receptors augmented nicotine-induced memory enhancement in mice. Key words: modified elevated plus maze, histamine3 receptor, nicotine, cognition 1316 Pharmacological Reports, 12, 64,

2 H 3 receptors in nicotine cognitive effects Marta Kruk et al. Introduction The strong correlation between central cholinergic pathways and learning and memory as well as impact of the nicotinic cholinergic system on memory-related behavior has been described in the literature [26, 35, 36]. However, with respect to the influence of nicotine on memory functions, experimental studies in humans and animals have yielded contradictory results. In humans, many studies have described deficits or improved efficiency of cognitive processing after nicotine administration [27, 35]. In animals, some researchers have argued that nicotine improves memory function, while others have reported no effect or even negative effects [36, 38]. For example, many studies have demonstrated that nicotine enhances hippocampal-dependent learning and memory, including spatial learning in the radial-arm maze and Morris water maze, avoidance conditioning, and contextual fear conditioning [15 17, 62]. Interestingly, human and animal studies point to attenuated memory and learning capacities during nicotine withdrawal as well as improved cognitive function following acute nicotine administration [35, 39]. The central effects of nicotine have been the subject of many experimental studies but the precise mechanisms responsible for the potential enhancement of learning and memory induced by nicotine have not been elucidated. It is generally accepted that nicotine exerts its behavioral effects acting at the nicotinic acetylcholine (ACh) receptors (nachrs) [61, for review]. Among all central nachr subtypes, the heteromeric 4 2 and homomeric 7 receptors seem to play the pivotal role in the reinforcing, discriminative stimulus and locomotor effects [6, 12, 24, 32, 37, 58, 59] as well as in memory-related responses of nicotine [13]. Nicotine facilitates, via the stimulation of 4 2 and 7 receptors located presynaptically, the release of a variety of neurotransmitters including ACh, dopamine, serotonin, -aminobutyric acid (GABA), glutamate and histamine [56, 57], all of which may be responsible for the nicotine-evoked addiction and/or cognitive processes. It is now well-established that histamine (H) acts as an important neurotransmitter, originating from hypothalamic neurons that project widely throughout the brain to forebrain regions including the cortex, hippocampus, amygdala, and striatum [8]. This biogenic amine is now known to affect four distinct G proteincoupled receptors including H 1, H 2, H 3 and the recently discovered H 4 subtype [48, for review]. Among them, H 3 receptors are constitutively active and highly expressed in the central nervous system functioning as autoreceptors on histaminergic neurons and heteroreceptors on non-histaminergic neurons. Experimental data suggest that these receptors can influence the synthesis and release of variety of different neurotransmitters, i.e., histamine itself, ACh, dopamine, GABA, glutamate, noradrenaline and serotonin [7, 22, 52] and more importantly, in the context of the present manuscript, recent evidence suggests that histaminergic neurotransmission might interact with nicotinic systems [25]. This role of H 3 receptors has critical influence on cognition, memory and vigilance processes, food intake and a variety of other behaviors [22, 25]. Interestingly, blockade of H 3 receptors promotes attention, wakefulness and adjusts short term and social memory in rodents [, 43, 47, 49]. H 3 receptor antagonists have been shown by some studies to improve cognitive function, but others have not found this effect and some have found memory impairment [19, 47]. Moreover, recent, limited studies indicate that blockade of H 3 receptors effectively reverses nicotine choice accuracy impairment in the radial-arm maze repeated acquisition task [33]. However, the role of H 3 receptors appears not to have been studied in relation to nicotine-induced mnemonic processes. The current study was therefore conducted to assess whether ABT-239 (4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl), a novel, non-imidazole H 3 receptor antagonist and inverse agonist [14], influenced nicotine-induced memory-related behavior in mice using a modified elevated plus maze (mepm) paradigm, designed to evaluate spatial learning and memory [28 31, 42, 53]. ABT-239 has already been shown to improve social memory in aged rats or to partially reverse scopolamine-induced deficits in a spatial navigation test in the water maze []. As pharmacological blockade of central H 3 receptors could enhance cognition in rodents, there is growing interest in such compounds for potential utility in treating attentional and cognitive deficits such as those seen in attention deficit-hyperactivity disorder and attention deficit disorder (ADHD and ADD), Alzheimer s disease, mild cognitive impairment, and schizophrenia etc. Pharmacological Reports, 12, 64,

3 Materials and Methods Animals Male Swiss mice ( g), derived from Farm of Laboratory Animals (Warszawa, Poland), housed under standard laboratory condition (12 h light/dark cycle, room temperature 21 ± 1 C, 5% humidity), were used. Food and water were available ad libitum. Animals were habituated to the laboratory conditions for at least one week prior to experimentation. All behavioral experiments were performed between 8: and 14: h, and were conducted according to the National Institute of Health Guidelines for the Care and Use of Laboratory Animals and to the European Community Council Directive for the Care and Use of Laboratory Animals of 24 November 1986 (86/69/ EEC), and approved by the local ethics committee. Each experimental group consisted of 7 1 mice. The animals were drug naive at the start of the studies. Drugs Nicotine bitartrate, reported as freebase nicotine weight (Sigma-Aldrich, St. Louis, USA) was diluted in saline (.9% NaCl) with the ph (5 7) adjusted and given subcutaneously (sc) min before behavioral recording. ABT-239 (Solvay Pharmaceuticals Research Laboratories, Weesp, The Netherlands) was suspended in one drop of 1% solution of Tween 8 (Sigma, St. Louis, USA) and dissolved in saline. This diluent also served as vehicle. ABT-239 was administered intraperitoneally (ip), 6 min before behavioral testing or min before nicotine or vehicle injection in a volume of 1 ml/kg. Control groups received vehicle injections at the same volume and by the same route. Fresh drug solutions were prepared on each day of experimentation. Doses of nicotine and ABT-239 used were selected according to those commonly reported in the literature, including our previous studies [4, 5, 19,, 59 61]. Apparatus Locomotor activity measurements Locomotor activity in mice was recorded individually in a round actometer cages (32 cm in diameter) housed in a sound-attenuated experimental room. Interruptions of photocell beams located across two longitudinal axis measured animal movement. Modified elevated plus maze as a memory test Memory and learning responses were measured using the modified elevated plus maze (mepm) test as described previously [4, 5]. The experimental apparatus was shaped like a plus sign and consisted of a central platform (5 5 cm), two open arms (5 cm) and two enclosed arms (5 15 cm) opposite to each other. The maze was made of dark Plexiglas. The whole apparatus was elevated 5 cm above the floor and illuminated by a dim red light. Experimental procedure Locomotor activity In order to measure locomotor effects of ABT-239 and/or nicotine, the animals, naive for any drug treatment, were injected with vehicle or ABT-239 (.1, 1 and 3 mg/kg), min before vehicle or nicotine (.175 and.35 mg/kg) administration, and immediately placed in the activity chamber. Locomotor activity, i.e., the number of photocell beam breaks (above) was automatically recorder for 6 min. mepm As described previously [4, 5], mice were placed individually at the end of one open arm facing away from the central platform. Each group was submitted to the same procedure twice (interval between trials of 24 h). On the first trial (acquisition trial), the latency to move from the open arm to either of the enclosed arms (transfer latency, TL1) was recorded and observed on a monitor through a closed-circuit video camera system. If the mice did not enter the enclosed arm within 9 s, they were placed into the enclosed arm and permitted to explore this maze for an additional 6 s; in such cases TL1 was recorded as 9 s. On the next trial (retention trial), 24 h later, the test was performed in the same manner as the first trial and the TL was recorded (TL2). If the mouse did not enter the enclosed arm within 9 s, the test was stopped and TL2 was recorded as 9 s. Any animal that fell off the maze was excluded from the experiment. In the mepm test, we used the TL2 values on the retention trial as an index of memory and learning 1318 Pharmacological Reports, 12, 64,

4 H 3 receptors in nicotine cognitive effects Marta Kruk et al. effects. The improvement of memory was indicated 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 and learning was characterized by increases in these measures. Entry into one arm was recorded when all four paws passed the line dividing the central square from the open arms. The test arena was wiped with a damp cloth after each trial. Treatment The first experiment was designed to investigate the influence of either nicotine or ABT-239 on memoryrelated responses using the mepm in mice. Nicotine (.175,.35,.175 and.35 mg/kg), ABT 239 (.1,.3, 1 and 3 mg/kg), or respective vehicles were administered at the appropriate times (above) before or immediately after the first acquisition trial (effect on memory acquisition or consolidation, respectively). Twenty-four hours after, the animals were re-tested in the mepm during the retention trial. This second day, the mice did not receive any pharmacological intervention. Subsequent experiments were designed to investigate the influence of ABT-239 on the acquisition and consolidation of memory-related responses induced by an acute nicotine administration. For this purpose, ABT-239 (1 and 3 mg/kg) or vehicle were administered min prior to nicotine (.35 mg/kg), and ABT-239 (.1 mg/kg) or vehicle were administered min prior to nicotine (.175 mg/kg); the mice were tested min later and re-tested after 24 h (acquisition). Additional groups of mice were injected with ABT-239 (1 and 3 mg/kg) or vehicle min prior to nicotine (.35 mg/kg), and ABT-239 (.1 mg/kg) or vehicle min prior to nicotine (.175 mg/kg) immediately after the first trial; the animals were then re-tested after 24 h (consolidation). Statistical analyses The data were expressed as the means ± SEM. The statistical analyses were performed using the two-way analyses of variance (ANOVA) with pre-treatment and treatment as factors. Also, one-way ANOVA was used where appropriate for additional analysis. A post-hoc comparison of means was conducted using the Tukey s test for multiple comparisons, where appropriate, p <.5 was considered statistically significant. Results Locomotor activity It can be noted that neither ABT-239 nor nicotine, at doses tested, caused any statistically significant changes in the locomotor activity of mice as compared with the control vehicle-injected group (Tab. 1). Two-way ANOVA of the locomotor response did not reveal any treatment effect [F (1, 9) =.42, p =.52), pre-treatment effect [F (4, 9) = 2.21, p =.7] or treatment x pre-treatment interaction [F (4, 9) =.34, p =.99]. mepm memory acquisition In the acquisition trial, there were no significant differences in the TL1 between the drug-treated and control groups (approximately, TL1 = 34 ± 7 s). Acute nicotine ( mg/kg) but not acute ABT-239 (.1 3 mg/kg) administration evoked a dosedependent reduction in TL2 values compared to the corresponding control groups [one-way ANOVA for nicotine: F (4, 36) = 5.18, p =.2; for ABT-239: F (4, 36) =.81, p =.53]. Accordingly, the post-hoc analysis (Tukey s test) revealed that nicotine (.35 and.175 mg/kg; p <.1) caused a significant improvement in memory acquisition (Fig. 1A and 2A). Tab. 1. Effects of nicotine and ABT-239, alone or in combination, on locomotor activity (the mean ± SEM, photocell beam breaks) of mice measured for 6 min; n = 1 Treatment Mean ± SEM Vehicle + vehicle ± Vehicle + nicotine.175 mg/kg ± Vehicle + nicotine.35 mg/kg ± ABT-239 (.1 mg/kg) + vehicle ± ABT-239 (.3 mg/kg) + vehicle ± ABT-239 (1. mg/kg) + vehicle ± ABT-239 (3. mg/kg) + vehicle 49.4 ± ABT-239 (.1 mg/kg) + nicotine (.175 mg/kg) ABT-239 (1. mg/kg) + nicotine (.35 mg/kg) ABT -239 (3. mg/kg) + nicotine (.35 mg/kg) ± ± ± Pharmacological Reports, 12, 64,

5 A A 1 ICLE ** ** mg/kg 1 ICLE mg/kg B 5 OTINE B ABT ICLE * ** mg/kg OTINE 1 ICLE mg/kg 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 (B) using the mepm test in mice. Mice were injected with vehicle or nicotine (.175,.35,.175 and.35 mg/kg, sc) min before the first trial (A) or immediately after the first trial (B); n = 7 9/group. Each bar represents the mean ± SEM; * p <.5; ** p <.1 vs. vehicle control group; Tukey s test Fig. 2. Effects of acute ABT-239 administration on the transfer latency to the enclosed arm in the acquisition trial (A) or consolidation trial (B) using the mepm test in mice. Mice were injected with vehicle or ABT-239 (.1,.3, 1 and 3 mg/kg, ip) 6 min before the first trial (A) or immediately after the first trial (B); n = 7 9/group. Each bar represents the mean ± SEM Figure 3A shows the effect of ABT-239 administration (1 and 3 mg/kg) on the nicotine-induced improvement of memory acquisition in the mepm. Two way ANOVA revealed statistically significant effects of pre-treatment [F (2, 43) = 2.72, p =.77], treatment (F (1, 43) = 43.13, p <.1], without interaction [F (2, 43) =., p =.74]. Post-hoc analysis revealed that the nicotine/control group (.35 mg/kg) exhibited a significant reduction in TL2 values compared to the vehicle/control group (p <.1), and this effect was further increased by ABT-239 administration at both doses used (1 and 3 mg/kg) (p <.1). It should be mentioned, however, that at any dose ABT-239 alone did not show any effect by itself (see above). Figure 4A shows the effect of combination of subthreshold doses of ABT-239 (.1 mg/kg) and nicotine (.175 mg/kg) on memory acquisition in the mepm. Two-way ANOVA revealed a statistically significant effect for pre-treatment [F (1, 28) = 16.26, p <.1], treatment [F (1, 28) = 21.71, p <.1], without interaction [F (1, 28) = 1.72, p =.]. The post-hoc analysis revealed that such drug combination exhibited a significant reduction in TL2 values compared to the vehicle/control group (p <.1) as well as to the groups that received either.1 mg/kg of ABT-239 (p <.1) or.175 mg/kg of nicotine (p <.1). Neither ABT-239 (.1 mg/kg) nor nicotine (.175 mg/kg) alone failed to show any affect alone on memory acquisition (see above). mepm memory consolidation Acute nicotine ( mg/kg), but not acute ABT-239 (.1 3 mg/kg) administration evoked a dose-dependent reduction in TL2 values compared to the corresponding control groups [one-way 13 Pharmacological Reports, 12, 64,

6 H 3 receptors in nicotine cognitive effects Marta Kruk et al. A 5 A 1 ^^ *** *** 1 ### *** ^^ B 5 (.35) ABT (1) ABT (3) ABT (1) ( 35). ABT (3) (.35) B (.175) ABT (.1) ABT (.1) (.175) 1 ^^ (.35) ABT (1) ABT (3) * ABT (1) ( 35) ** ABT (3) (.35) 1 (.175) ABT (.1) ### ^ * ABT (.1) (.175) Fig. 3. Influence of ABT-239 on the memory-related response induced by acute nicotine administration in the acquisition trial (A) or consolidation trial (B) using the mepm test in mice. ABT-239 (1 or 3 mg/kg, ip) or vehicle was administered min prior to nicotine (.35 mg/kg, sc), min before the first trial (A) or immediately after the first trial (B); n = 8 9/group. Each bar represents the mean ± SEM; * p <.5; ** p <.1; *** p <.1 vs. nicotine control group; ^^ p <.1 vs. vehicle control group; Tukey s test Fig. 4. Influence of ABT-239 on the memory-related response induced by acute nicotine administration in the acquisition trial (A) or consolidation trial (B) using the mepm test in mice. ABT-239 (.1 mg/kg, ip) or vehicle was administered min prior to nicotine (.175 mg/kg, sc), min before the first trial (A) or immediately after the first trial (B); n = 7 9/group. Each bar represents the mean ± SEM; ^ p <.5; ^^ p <.1 compared to nicotine control group; * p <.5; *** p <.1 vs. ABT-239 control group; ### p <.1 vs. vehicle control group; Tukey s test ANOVA for nicotine: F (4, 33) = 3.744, p =.13; for ABT-239: F (4, 39) = 3.5, p =.28]. Accordingly, the post-hoc analysis (Tukey s test) revealed that nicotine (.35 and.175 mg/kg; p <.5 and p <.1, respectively) significantly caused an improvement in memory consolidation (Fig. 1B and 2B). Figure 3B shows the effect of ABT-239 administration (1 and 3 mg/kg) on the nicotine-induced improvement of memory consolidation in the mepm. Two way ANOVA revealed a statistically significant effect of pre-treatment [F (2, 47) = 11.85, p <.1], treatment [F (1, 47) = 18.89, p <.1], and without significant interaction [F (2, 47) =.92, p =.41]. The post-hoc analysis revealed that the nicotine/control group (.35 mg/kg) exhibited a significant reduction in TL2 values compared to the vehicle/control group (p <.1), and this effect was further increased after ABT-239 administration at both doses used (1 and 3 mg/kg) (p <.5 and p <.1, respectively). It should be mentioned that at any dose ABT-239 alone did not show any effect by itself (see above). Figure 4B shows the effect of combination of subthreshold doses of ABT-239 (.1 mg/kg) and nicotine (.175 mg/kg) on memory consolidation in the mepm. Two-way ANOVA revealed a statistically significant effect for a pre-treatment [F (1, 26) = 9.62, Pharmacological Reports, 12, 64,

7 p =.46], treatment [F (1, 26) = 7.679, p =.1], without interaction [F (1, 26) =.5545, p =.46]. Post-hoc analyses revealed that such drug combinations exhibited significant reduction in TL2 values compared to the vehicle/control group (p <.1) as well as to the groups that received either.1 mg/kg of ABT-239 or.175 mg/kg of nicotine (p <.5). Neither ABT-239 (.1 mg/kg) nor nicotine (.175 mg/kg) alone showed any effect by itself on memory consolidation (see above). Discussion Our findings demonstrate, for the first time, a positive interaction between H 3 receptors and nicotine in the acquisition and consolidation of memory in mice using a modified elevated plus maze procedure. Our results showed that nicotine, but not H 3 receptor antagonist ABT-239 alone caused improvement in both acquisition and consolidation of memory in mice. In combination studies, concomitant administration of ABT-239 and nicotine (in either active or subthreshold doses) caused further increases in the improvement in both memory acquisition and consolidation. ABT-239 was recently identified [14, 19] as an H 3 receptor antagonist/inverse agonist with high affinity and selectivity for both human and rat H 3 receptors with Ki =.45 and 1.4, respectively, although some off-target actions were noted, but at much higher concentrations (Ki = nm activity at the human ERK channel). Good oral bioavailability and excellent blood brain barrier penetration were also seen. The data presented in this study indicate that blockade of H 3 receptors potently enhances the cognitive effects of nicotine in mice. It has been reported that, in laboratory animals, nicotine can affect many aspects of behavior including reward and dependence, aggression, anxiety, antinociception, psychomotor activation or memory and learning processes [3 6, 59, 6]. In this context, it seems important to understand the possible mechanism of nicotine-induced behavioral actions, including its mnemonic effects. The H 3 receptor seems to be valid target to modulate the neurobiology of memory as H 3 receptor antagonists may act as cognitive enhancers [19, 47]. Thus, more recent results have suggested that ABT-239 ameliorates ethanol-induced deficits on hippocampal long-term potentiation (LTP), leading to the conclusion that H 3 receptor antagonists may have utility for reverse changes in synaptic plasticity and learning deficits related to this drug [44, 55]. Based on previous findings that H 3 receptor antagonists enhance memory performance in rodents [, ], our present experiments were designed to further investigate the possible mechanisms of H 3 receptor modulation of the nicotine-induced memoryrelated behavior in mice using the mepm test. This test, originally developed to model anxiety in rodents, was modified to evaluate spatial learning and memory. Briefly, this simple method consisted of measuring of the time necessary for the animal to move from the open to the enclosed arm, i.e., the transfer latency (TL). This method has been successfully used in studies investigating the involvement of different neurotransmitter systems, including cholinergic pathways, on learning and memory processes [28 31, 42, 53]. In line with our previous research [4, 5], we confirm that acute administration of nicotine ( mg/kg) to mice induced a dose-related decrease in the transfer latency relative to the vehicle-treated group indicating improvement in acquisition and consolidation of memory. Moreover, we demonstrated that various doses of ABT-239 (.3 3 mg/kg) did not cause any improvement in memory acquisition and consolidation in mice. These data obtained using the mepm test do not support prior work demonstrating that blockade of H 3 receptors enhanced memory as evidenced in place recognition memory [46], novel object discrimination task [47], repeated acquisition task [33] and the social recognition task [5] as well as beneficial effects to reverse scopolamine-induced cognitive deficits in the mepm test [42, 45], novel recognition task [23, 47], passive avoidance test [2, 43] and in spatial learning tasks [1, 34] were seen. Some of the differences in findings may be due to the type of cognitive function modeled in the respective assays, the behavioral tasks used, and the dosing schedules employed, i.e., acute vs. chronic administration. The complex effects seen in the literature may be due to differential involvement of histamine H 3 receptor in various aspects of cognitive function. Although there is evidence that pharmacological blockade of H 3 receptors improves cognitive function [21, 41, 5], the overall cognitive effects induced by histaminergic ligands remain contradictory [8, 11, 31, 54]. Furthermore, the present combination studies with ABT-239 and nicotine showed, for the first time, H 3 receptor and nicotine interactions in the acquisition 1322 Pharmacological Reports, 12, 64,

8 H 3 receptors in nicotine cognitive effects Marta Kruk et al. and consolidation of memory in the mepm test in mice. Either nicotine or ABT-239, at all doses tested, had no significant acute effect on locomotor activity indicating that the alterations in transfer latency were not due to non-specific motor effects, including the stimulant-like activity of nicotine. The precise mechanism of ABT-239 nicotine interaction was not assessed in this study, however, based on complementary roles in cognitive function between nicotine and histaminergic systems [7], a number of hypotheses can be considered. First, nicotine acting via nachrs has a variety of effects mediated through its facilitation of the release of a variety of different neurotransmitters, including dopamine, serotonin, ACh, noradrenaline, GABA, glutamate, and histamine [56]. However, the improved cognitive function may be due to an action on nachrs in the prefrontal cortex, hippocampus and/or amygdala [39]. Stimulation of these area-specific receptor sites provokes the release of a variety neurotransmitters [above; 57]. Among them, modulation of the histaminergic system is of key interest as a candidate for complementary or facilitatory interactions with cholinergic (nicotinic) systems. Interestingly, it has been demonstrated that histamine co-administration reduces the improvement in passive avoidance learning by nicotine, whereas histamine H 1 receptor antagonists enhance nicotine-induced improvements [18]. It may be the case that enhancing histamine release caused by nicotine may help or hinder nicotinic actions on learning function. Secondly, H 3 receptors are found in many brain areas where they act as autoreceptors or heteroreceptors [48, for review]. Their blockade results in stimulation of histamine release, modulation of ACh release and in increases in dopamine, serotonin and noradrenaline release [1, 49, 51]. An increase in ACh release in the prefrontal cortex or hippocampus of freely moving adult rats following systemic or intra-nucleus basalismagnocellularis [9] or intra-septal [1] infusions of H 3 receptor antagonists, including ABT-239, have been correlated with memory enhancement [19,, 46]. Thus, microdialysis studies report increased release of ACh and dopamine in the prefrontal cortex, but no change in extracellular dopamine in the striatum following systemic administration of ABT-239 []. Whether actions on independent neurotransmitter systems or their combined effects plays a role in the improvement of transfer latency in the mepm should be further investigated, but are out of the scope of the present study. Taken together, the present studies confirm an important role for H 3 receptors in regulating nicotineinduced mnemonic effects. Furthermore, it can be suggested that selective H 3 receptor blockade with compounds such as ABT-239 with functional antagonist activity at central H 3 receptors and potential cognition-enhancing activity, at doses well below those inducing adverse effects in locomotion, may therefore represent a novel approach for treatment of human cognitive disorders. However, this hypothesis requires further studies with using more specific cognition tasks as well as using more selective receptor ligands for the H 3 receptor or its various isoforms, according to receptor subtypes on particular brain regions involved in memory regulation. Acknowledgments: This work was supported by the statutory funds, and received no special grant from any funding agency in the public, commercial or not-for-profit sectors. All authors declare that they have no conflict of interest to disclose. References: 1. Bacciottini L, Passani MB, Giovannelli L, Cangioli I, Mannaioni PF, Schunack W, Blandina P: Endogenous histamine in the medial septum-diagonal band complex increases the release of acetylcholine from the hippocampus: a dual-probe microdialysis study in the freely moving rat. Eur J Neurosci, 2, 15, Bernaerts P, Lamberty Y, Tirelli E: Histamine H 3 antagonist thioperamide dose-dependently enhances memory consolidation and reverses amnesia induced by dizocilpine or scopolamine in a one-trial inhibitory avoidance task in mice. Behav Brain Res, 4, 154, Biala G, Budzynska B: Calcium-dependent mechanisms of the reinstatement of nicotine-conditioned place preference by drug priming in rats. Pharmacol Biochem Behav, 8, 89, Biala G, Kruk M: Cannabinoid receptor ligands suppress memory-related effects of nicotine in the elevated plus maze in mice. Behav Brain Res, 8, 192, Bia³a G, Kruk M: Influence of bupropion and calcium channel antagonists on the nicotine-induced memoryrelated response of mice in the elevated plus maze. Pharmacol Rep, 9, 61, Biala G, Staniak N, Budzynska B: Effects of varenicline and mecamylamine on the acquisition, expression, and reinstatement of nicotine-conditioned place preference by drug priming in rats. Naunyn Schmiedebergs Arch Pharmacol, 1, 381, Pharmacological Reports, 12, 64,

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