Neuroscience Letters

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1 Neuroscience Letters 587 (2015) Contents lists available at ScienceDirect Neuroscience Letters journal homepage: Research article Dorsal hippocampal microinjection of chlorpheniramine reverses the anxiolytic-like effects of l-histidine and impairs emotional memory in mice L. Canto-de-Souza a,c, D.C. Garção b, F. Romaguera d, R. Mattioli a, a Laboratório de Neurociências, Universidade Federal de São Carlos, Brazil b Universidade Tiradentes, Rua Lagarto, 264, Aracaju, Brazil c Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, , Ribeirão Preto, Brazil d Universidade do Estado de Santa Catarina, Rua Pascoal Simone, 358, Florianópolis, Brazil highlights l-histidine has an anxiolytic-like effect on mice exposed to the elevated plus-maze test. CPA reverses the anxiolytic-like effect caused by l-histidine. The dorsal hippocampus s H1 receptors are involved in emotional memory of mice. article info abstract Article history: Received 30 July 2014 Received in revised form 27 November 2014 Accepted 11 December 2014 Available online 15 December 2014 Keywords: Anxiety Emotional memory Chlorpheniramine Dorsal hippocampus Elevated plus-maze Mice Several findings have pointed to the role of histaminergic neurotransmission in the modulation of anxietylike behaviors and emotional memory. The elevated plus-maze (EPM) test has been widely used to investigate the process of anxiety and also has been used to investigate the process of learning and memory. Visual cues are relevant to the formation of spatial maps, and as the hippocampus is involved in this task, experiment 1 explored this issue. Experiment 2 investigated the effects of intraperitoneal (i.p.) injections of l-histidine (LH, a precursor of histamine) and of intra-dorsal hippocampus (intra-dh) injections of chlorpheniramine (CPA, an H 1 receptor antagonist) on anxiety and emotional memory in mice re-exposed to the EPM. Mice received saline (SAL) or LH i.p. and SAL or CPA (0.016, 0.052, and 0.16 nmol/0.1 l) intra-dh prior to Trial 1 (T1) and Trial 2 (T2). No significant changes were observed in the number of enclosed-arm entries (EAE) in T1, an EPM index of general exploratory activity. LH had an anxiolytic-like effect that was reversed by intra-dh injections of CPA. T2 versus T1 analysis revealed that only the lower dose of CPA resulted in impaired emotional memory. Combined injections of LH and CPA revealed that higher doses of CPA impair emotional memory. Taken together, these results suggest that LH and H 1 receptors present in the dorsal hippocampus are involved in anxiety-related behaviors and emotional memory in mice submitted to EPM Elsevier Ireland Ltd. All rights reserved. 1. Introduction Emotional memory may be modulated by experiences occurring at the time when it is learned (acquisition), consolidated, or Corresponding author at: Departamento de Fisioterapia, Universidade Federal de São Carlos, Rodovia Washington Luiz, 235, São Carlos, SP, Brazil. Tel.: ; fax: addresses: lucascanto@gmail.com (L. Canto-de-Souza), diogoufscar@yahoo.com.br (D.C. Garção), feromaguera@gmail.com (F. Romaguera), mattioli@ufscar.br (R. Mattioli). retrieved [3] and a modulatory system involved in these memory processes may be the histaminergic system [2]. The actions of histamine are mediated by four distinct subtypes of G-protein-coupled receptors: H 1 H 4 [15,30]. The central histaminergic nervous system originates from the tuberomammillary nucleus of the posterior hypothalamus, and it innervates almost the whole brain, including the hippocampus, which is innervated by two histaminergic fiber bundles through the fornix and caudal route [15]. Histamine also regulates a variety of neurobiological functions and behavioral responses [for review see [2,15]], including anxiety [33]. When histaminergic agents are microinjected into the hiphttp://dx.doi.org/ /j.neulet / 2014 Elsevier Ireland Ltd. All rights reserved.

2 12 L. Canto-de-Souza et al. / Neuroscience Letters 587 (2015) pocampus of a rat, they may modulate anxiety via the H 1 and H 2 receptors in an elevated plus-maze (EPM) test of anxiety [26,33], and they enhance memory consolidation through the activation of H 2 in an inhibitory avoidance test [8]. The EPM test is an animal model of anxiety based on rodents natural aversion to open spaces [18,25]. Further, the EPM has been used to investigate the process of learning and memory based on exploratory behavior during EPM re-exposure [6,10,12,13,27,28]. After being confronted with evidence of the involvement of the dorsal hippocampus (DH) of rats in anxiety and memory, which has histaminergic projections [15,33], the present study was designed to investigate the role of the histaminergic system on anxiety and emotional memory of mice via i.p. injections of l-histidine and intra-dorsal hippocampus (intra-dh) injections of chlorpheniramine using a Trial 1/2 protocol in the EPM. The present study investigated if l-histidine would have anxiolytic and/or memory impairment and if these putative effects would be reversed by chlorpheniramine. 2. Materials and methods 2.1. Animals Male Swiss mice (UFSCar SP, Brazil), weighing g were maintained under a 12 h light cycle in a controlled environment at 23 ± 1 C. The experimental sessions were conducted during the light period of the cycle (11:00 15:00 h) Drugs l-histidine monohydrochloride monohydrate (LH) and the H 1 receptor antagonist chlorpheniramine maleate salt (CPA) (Sigma, MO, USA) were prepared in vehicle of physiological saline (SAL). The doses were based on previous study [28] First experiment Once our experimental room included the presence of different visual cues, such as windows and laboratory benches, we investigated if animals use environmental cues to remember and avoid the open arms of the EPM. In this context, we exposed and re-exposed two naïve independent groups of animals to the EPM under different conditions: without (n = 12) or with (n = 15) an opaque black curtain placed around the EPM. The illumination levels in the central area of the EPM were 86 (without) and 50 (with curtain) lux. The apparatus consisted of two open arms ( cm) and two enclosed arms ( cm) connected to a common central platform (5 5 cm). The maze was made of crystal acrylic and was raised to a height of 38.5 cm above floor level Second experiment stereotaxic surgery and microinjections Mice were anesthetized by i.p. injection of ketamine hydrochloride (50 mg/kg) plus xylazine (5 mg/kg) and were then placed in a stereotaxic instrument. The stereotaxic coordinates for injection into the DH were as follows: 1.8 mm anterior to the bregma, ±1.6 mm lateral to the midline, and 1.5 ventral to skull surface, according to brain atlas [23]. The stainless steel guide cannula (25-gauge) was implanted bilaterally in the DH, 1 mm above the injection site. It was then fixed to the skull with acrylic dental cement. Postoperative analgesic was provided according to Messier et al. [20]. Intra-DH injections were performed by means of an internal cannula (33-gauge) terminating 1 mm below the tip of the guides and connected by polyethylene tubing (PE-10) to a 5- l Hamilton syringe. Administration was controlled by an infusion pump programmed to deliver a volume of 0.1 l over a 60-s period (0.2 l/mouse). The microinjection procedure was followed according to previous studies [11,27] Evaluation of anxiety (T1) and evaluation of emotional memory (T2) On the fifth day after surgery, the animals were submitted to the EPM test. For T1, mice were pre-treated i.p. with SAL or LH. Two hours after the systemic injection [27], the animals were treated with intra-dh microinjections of SAL or CPA (0.016, and 0.16 nmol/0.1 l). Five minutes after the central microinjections, the mice were individually placed on the central platform of the maze facing the open arm and were allowed to explore the maze for 5 min. Twenty-four hours after T1, the mice were submitted to the same protocol described above (Fig. 2B) Behavioral analysis The behavioral parameters [24] were the following: the frequency of open- and enclosed-arm entries (EAE) and the total times spent in the open arms and central area. These data were used to calculate the percentage of: open-arm entries (%OAE), time spent in the open arms (%OAT) and time spent in the central area (%CT). The number of stretched-attend postures (SAP) and the frequency of head dipping (exploratory movement of head/shoulders over the sides of the maze) were also scored. The total SAP was considered to be a primary index of risk assessment, and head dipping was considered to be an index of exploratory behavior [25]. EAE were used as a locomotor activity measure [7]. Data for the above measures are reported both as behavior totals (e.g., SAP) and as percent protected scores (e.g., %psap) [24]. Anxiety-related behaviors and emotional memory were evaluated by the T1/T2 paradigm [1,12,28]. Anxiety was evaluated through open-arm exploration measures in T1. Reduction in openarm exploration in T2 was used as a learning and memory response [4,6,12,13,27,28] Histology At the end of testing, animals received a 0.1- l infusion of 1% methylene blue according to the microinjection procedure described above. The animals received an anesthetic overdose, their brains were removed, and the injection sites were verified histologically according to the mouse brain atlas [23] Statistical analysis For the first experiment, the data were analyzed using a twoway ANOVA with repeated measures [Factor 1 (F 1 ): without or with curtain; Factor 2 (F 2 ): T1 and T2]. The second experiment was analyzed with a three-way ANOVA with repeated measures (F 1 : i.p. administration of SAL or LH; F 2 : central microinjections of SAL or CPA; Factor 3 (F 3 ): T1 and T2). When differences were indicated by significant F values, they were identified by Duncan s test. A p 0.05 was required to indicate significance. 3. Results 3.1. First experiment ANOVA demonstrated a significant difference between the two conditions (F 1 (1,25) = 12.80), trials (F 2 (1,25) = 4.62) and a tendency of interaction between factors (F 1 F 2 (1,25) = 3.57, p = 0.07) for %OAE. Duncan s test pointed to an increase in %OAE of mice exposed to the EPM with a curtain in T1 as compared with animals exposed

3 L. Canto-de-Souza et al. / Neuroscience Letters 587 (2015) to the EPM without curtain (Fig. 1 ). Duncan s test also revealed a decrease in the %OAE for mice submitted to the EPM with a curtain in T2 as compared with T1 under the same conditions. Similar results were demonstrated by statistical analysis of %OAT (F 1 (1,25) = 19.64; F 2 (1,25) = 2.36 and F 1 F 2 (1,25) = 10.66) (Fig. 1B). ANOVA revealed no significant differences of EAE between the two conditions (F 1 (1,25) = 0.19) and factor interactions (F 1 F 2 (1,25) = 2.08). However, a significant difference was found between trials (F 2 (1,25) = 8.26), as shown by an increase in EAE in T2 for mice submitted to the EPM with a curtain (Fig. 1C). Based on these data, we adopted the use of the curtain for the second experiment Second experiment Histology confirmed that a total of 66 mice had accurate bilateral cannula placements in the DH (Fig. 2A). Therefore, the final sample sizes were as follows: SAL/SAL (n = 8), SAL/CPA1 (n = 9), SAL/CPA2 (n = 10), SAL/CPA3 (n = 8), LH/SAL (n = 7), LH/CPA1 (n = 8), LH/CPA2 (n = 7), and LH/CPA3 (n = 9) Evaluation of the effects of l-histidine and chlorpheniramine on anxiety (Trial 1) ANOVA indicated an interaction between i.p. and intra-dh injections for %OAE [F 1 F 2 (3,58) = 3.48] and %OAT [F 1 F 2 (3,58) = 3.46]. The Duncan s test indicated that i.p. administration of LH (LH/SAL group) increased both the %OAE and %OAT as compared with the SAL/SAL group (Fig. 2C and D). ANOVA also indicated interactions between treatments for %CT [F 1 F 2 (3,58) = 2.84] and %pdips [F 1 F 2 (3,58) = 4.79] (Fig. 2F and G). The Duncan s test indicated that LH reduced %CT (a trend, p = 0.052) and %pdips (Fig. 2F and G) as compared with the control group. It is important to note that these effects were observed in the absence of any significant change in the frequency of EAE [F 1 F 2 (3,58) = 1.54] (Fig. 2E). Microinfusions of CPA into the DH did not alter the anxiety indexes per se. However, when mice were previously treated with LH, the three doses of CPA decreased %OAT (Fig. 2D) and increased %pdips (at doses of and 0.16 nmol) and %CT (at dose of 0.16 nmol) (Fig. 2F and G) as compared with the LH/SAL group Evaluation of the effects of l-histidine and chlorpheniramine on emotional memory (Trial 2 versus Trial 1) ANOVA revealed significant differences between trials for %OAE [F 3 (1,58) = 40.51]; however, no interaction between the factors was found [F 1 F 2 F 3 (3,58) = 0.31]. In contrast, ANOVA indicated significant differences for %OAT [F 3 (1,58) = 50.46] and an interaction between the factors [F 1 F 2 F 3 (3,58) = 4.39]. The Duncan s test indicated a reduction in T2 for %OAE for the groups SAL/SAL, SAL/CPA2, SAL/CPA3, LH/SAL and LH/CPA2 (Fig. 2C). For %OAT, post hoc test indicated a reduction in T2 for the groups SAL/SAL, SAL/CPA2, SAL/CPA3, LH/SAL and LH/CPA2 (Fig. 2D). As shown in Fig. 2(E and G), ANOVA revealed significant differences for EAE [F 3 (1,58) = 26.76] and %pdips [F 3 (1,58) = 69.35], although no interaction between the factors was observed (F 1 F 2 F 3 (3,58) = 0.32; F 1 F 2 F 3 (3,58) = 1.89, respectively). Significant differences and interactions between factors were revealed for %CT ([F 3 (1,58) = 19.91]; [F 1 F 2 F 3 (3,58) = 2.92) and %psap ([F 3 (1,58) = 15.38]; [F 1 F 2 F 3 (3,58) = 3.59]). The Duncan s test indicated that the control group exhibited increased %pdips, and the administration of LH (LH/SAL) resulted in increased %CT, %psap, and %pdips (Fig. 2F H). Animals that received i.p. injections of SAL, only microinfusions of the lower dose of CPA (SAL/CPA1) did not decrease %OAE or %OAT (Fig. 2C and D). Intermediate and higher doses of CPA increased %pdips (Fig. 2G); the SAL/CPA3 group displayed increased EAE (Fig. 2E) and %psap (Fig. 2H). However, in animals previously Fig. 1. Mice submitted to the EPM under different conditions: without or with an opaque black curtain placed around the EPM. Data are reported as mean + SEM of the percentage of: open arm entries (%OAE) (a), open arm time (%OAT); (b) and enclosed arm entries (EAE) during Trial 1 (T1) and Trial 2 (T2). *p < 0.05 for T2 compared to T1 of respective group; #p < 0.05 for T1 versus T1 of without curtain group (Two-way ANOVA test, followed by Duncan s test). treated with LH, the lower dose of CPA decreased %OAT (Fig. 2D) and increased %pdips, whereas the intermediate dose decreased %OAE (Fig. 2C) and increased EAE (Fig. 2E), %CT and %ddips (Fig. 2F and G). 4. Discussion It has been described in the literature that rodents may use vision for spatial navigation and avoid open spaces [19]. Therefore, the aim of the first experiment was to investigate if animals associate the aversiveness of the open arms of the EPM with environmental cues and then use these to remember/avoid the open arms on a second trial. In this sense, our data demonstrated that the absence of environmental cues increased the exploration of the open arms on T1. The presence of a curtain placed around the EPM might have decreased the aversiveness of the open arms, although animals could still distinguish between open and enclosed arms,

4 14 L. Canto-de-Souza et al. / Neuroscience Letters 587 (2015) Fig. 2. Schematic representation of sites of intra-dorsal hippocampus (intra-dh) infusions (adapted from Paxinos and Franklin, 2001). Sites outside the DH are represented by black dots. (A) Experimental procedure. (B) Effects of i.p. LH injection (500 mg/kg) and intra-dh infusion of SAL or CPA (0.016, and 0.16 nmol/0.1 l). Data are represented as mean + SEM on the percentage of: open arm entries (%OAE) (C) and open arm time (%OAT) (D); the enclosed arm entries (EAE) (E); the percentages of: center time (%CT) (F), protected head dipping (%pdips) (G) and protected stretched-attend postures (%psap) (H) during Trial 1 (T1) and Trial 2 (T2). *p < 0.05 for T2 compared to T1; #p < 0.05 for T1 versus Tl of p < 0.05 for T1 versus T1 of LH/SAL (Three-way ANOVA test, followed by Duncan s test). as they decreased open-arm exploration in T2. A different result was observed for animals exposed to the non-curtain condition. It is possible that the open arms of the EPM were too aversive, which may have inhibited the open-arm exploration levels in T1, impairing the comparison with the exploration levels in T2. Based on these data, we adopted the use of the curtain for the second experiment. Several studies have demonstrated that drugs that increase open-arm activity are anxiolytic, whereas drugs that reduce openarm activity are anxiogenic [4,18]. In our study, mice treated with LH (i.p.) and SAL (intra-dh) exhibited increased open-arm exploration of the EPM in T1 as compared with the control group. Open-arm activity was accompanied by a decrease in the risk assessment behaviors; thus, displaying an anxiolytic-like effect for LH. However, the anxiolytic-like effect was not observed when mice were treated with LH and chlorpheniramine in the DH. An allocentric strategy may facilitate associations between the environmental cues and the risks represented by the open arms. As egocentric strategies encode locations related to the current position of the subject and rely on idiothetic cues [17], in the present study, the black curtain increases exploration of the open arms through egocentric strategies. This may justify the higher number of open-arm entries. However, the open-arm exploration is still lower than the enclosed arms, as the percentage of time spent in the open arms was 36.49%. Furthermore, control mice spent almost 63% of the time in protected areas in T1, which indicates that they identify the open arms as an aversive location. Our findings diverge from studies on anxiety-like behaviors performed by our research group demonstrating that different doses of LH had no effects on the anxiety-like behaviors of mice during exposure to the EPM [12,27,28]. These contradictory effects can be explained because mice were studied under different experimental conditions. It is possible that under a higher emotional situation, such as in the standard EPM [12,27,28], LH may not have an anxiolytic-like effect. On the other hand, in a moderate emotional state, as we observed in our first experiment, LH has an anxiolytic-like effect. The results of the present paper demonstrate that animals treated with LH and CPA displayed decreased open-arm exploration time. Furthermore, the higher dose increased the %CT and %pdips compared with the LH/SAL group, which indicates the reversal of the anxiolytic-like effects caused by l-histidine. It has been demonstrated that histamine microinjected into the ventral hippocampus of rats has an anxiogenic-like effect [26], and when it is microinjected into the DH of rats, histamine has an anxiolytic-like effect that is mediated by H 1 receptors [33]. According to our data, the doses of chlorpheniramine used did not change the anxiety-like behavior indices per se. However, higher doses of CPA reversed the anxiolytic-like behavior of LH in a robust manner, which demonstrates that this effect may also be mediated by the H 1 DH receptors of mice during exposure to the EPM. An interesting feature of the EPM concerns the influence of prior test experience with the apparatus on subsequent behavioral and pharmacological responses related to memory derived from prior experience [4]. Upon re-exposure to the EPM, the animals of the control group decreased open-arm exploration; thus, demonstrating that they were able to remember the aversive characteristics of the open arms, but animals treated with the lower dose of CPA explored the open arms at a level similar to the T1, indicating emotional memory impairment. However, the same behavioral profile was not observed when subjects were treated with CPA at doses of and 0.16 nmol/0.1 l.

5 L. Canto-de-Souza et al. / Neuroscience Letters 587 (2015) Different effects have been reported in the literature concerning the involvement of H 1 antagonists in mnemonic processes. Gianlorenço et al. [12] revealed that i.p. CPA reversed the statedependent memory deficits induced by l-histidine in mice during re-exposure to the EPM. However, previous results demonstrated that learning and memory in passive avoidance and active avoidance tests were improved by histamine H 1 agonists and were inhibited by histamine H 1 receptor antagonists, such as pyrilamine and CPA [16]. Furthermore, Nakazato et al. [22] observed that pyrilamine impaired the working memory performance of rats when administered to the DH, and the effects of intra-hippocampal pyrilamine were prevented by histamine H 1 receptor agonist. It is known that CPA possess antimuscarinic effects [32] as well as binding affinity to the serotonin (5-HT) transporter [31] and inhibits the uptake of 5-HT [29]. Thus, the CPA memory impairment would be expected in the highest doses of CPA. However, in our data, only the lower dose of CPA impaired emotional memory. In mice, stimulation of 5-HT2A receptors facilitates consolidation and extinction of fear memory [34]. Considering the dense distribution of 5-HT2A receptors in the hippocampus [5], it is conceivable that activation of the 5-HT2A receptors facilitates information transmission and retention and thereby influences memory consolidation [34]. According to this theory, we propose that when higher doses of CPA are microinjected intra-dh, in addition to binding to H 1 receptors, the CPA molecules may bind to 5-HT transporters; thus, increasing the extracellular 5-HT levels in the DH and blocking the impairment effects of higher doses of CPA. Future study will be performed to test this hypothesis. Different effects of the action of histamine on memory have been reported. De Almeida and Izquierdo [9] demonstrated that post-training intracerebroventricular administration of histamine improved the retention test performance of step-down inhibitory avoidance behavior in rats. In addition, histamine elicited an ameliorating effect on scopolamine-induced learning and memory deficits via histamine H 1 receptors in mice subjected to the EPM [21]. Recently, our group reported that histamine may act differently on memory according to the emotional component, anxiety or fear. An impairment of the emotional memory consolidation via H 1 receptors was observed when histamine was microinjected into the vermis cerebellar of mice re-exposed to the EPM [13,14].Onthe other hand, intra-cerebellar microinjection of histamine enhanced memory consolidation of inhibitory avoidance learning in mice via H 2 receptors [11]. In the present work, our results demonstrated that LH did not impair emotional memory. It is possible that, as in the cerebellum, hippocampal histamine may act distinctly according to the emotional situation. This hypothesis will be tested in a future study. Thus, the lack of environmental cues together with the evidence of hippocampal histamine involvement in the processing of emotional memory may be the factors responsible for the difference in our results compared with those reported by previous studies conducted in our laboratory [27,28]. The DH would be responsible for the spatial component in the processing of emotional memory. In conclusion, our results indicate an anxiolytic effect of LH that is mediated by the H 1 receptors present in the DH of mice. In addition to this finding, we suggest that this type of histaminergic receptor in the DH is involved in the disruption of emotional memory. Acknowledgements We would like to thank Canto-de-Souza, A. for providing her laboratory for histological analysis. 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