- Email: [email protected]
Role of hippocampal H1 receptors in radial maze performance and hippocampal theta activity in rats
Brain Research Bulletin 73 (2007) 231–237
Research report
Role of hippocampal H1 receptors in radial maze performance and hippocampal theta activity in rats Takayoshi Masuoka, Chiaki Kamei ∗ Department of Medicinal Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8530, Japan Received 8 November 2006; received in revised form 17 February 2007; accepted 14 March 2007 Available online 5 April 2007
Abstract Histamine H1 antagonists impaired the spatial memory performance. On the other hand, it is well recognized that the hippocampal theta rhythm plays a critical role in spatial memory. However, little work has been done the effect of H1 antagonists on the hippocampal theta rhythm which was associated with the memory performance. We investigated the effect of pyrilamine, a selective H1 receptor antagonist, on spatial memory performance as well as hippocampal theta rhythm during the memory task in rats. Effect of pyrilamine on spatial memory was measured using eight-arm radial maze with four arms baited. Hippocampal theta rhythm during the radial maze task was recorded with a polygraph system with a telemetric technique. Intraperitoneal injection of pyrilamine resulted in impairments of both reference and working memory on the radial maze task. The working memory deficit induced by pyrilamine was antagonized by the intrahippocampal injection of histamine and 6-[2-(4imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptanecarboxamide (HTMT), a histamine H1 agonist. Intraperitoneal injection of pyrilamine decreased the hippocampal theta power at a dose that impaired reference and working memory. This effect was antagonized by the intrahippocampal injection of histamine and HTMT at a dose that ameliorated the working memory deficit. Intrahippocampal injection of pyrilamine impaired working memory and simultaneously decreased the hippocampal theta power. These results suggest that: (i) the hippocampal H1 receptors play an important role in the working memory processes on the radial maze performance and (ii) the decrease in the hippocampal theta power is associated with the working memory deficit induced by the blocking of H1 receptors. © 2007 Elsevier Inc. All rights reserved. Keywords: Pyrilamine; H1 receptor; Radial maze task; Hippocampal theta power; Theta peak frequency; Hippocampus
1. Introduction Histamine plays an important role in learning and memory via histamine H1 receptors. For instance, H1 antagonists, such as diphenhydramine, ketotifen and pyrilamine, impaired the memory performance, such as step-through active avoidance, the three-panel runway task and the radial maze task, in rats [6,13,22]. In association with this, Taga et al. [22] suggested that the antimuscarinic properties of H1 antagonists are responsible for memory deficit, because many H1 antagonists have potent antimuscarinic properties [10]. On the other hand, although pyrilamine had less antimuscarinic activity, the drug showed a potent memory deficit [7]. Therefore, it seems likely
∗
Corresponding author. Tel.: +81 86 251 7939; fax: +81 86 251 7939. E-mail address: [email protected] (C. Kamei).
0361-9230/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2007.03.005
that the antimuscarinic properties of pyrilamine are not involved in memory deficit. It is well known that the intrahippocampal injection of various kinds of amnesic drugs impairs the memory performance [4,5,18]. Nakazato et al. [13] reported that pyrilamine also caused an impairment of working memory performance of rats when administrated into the dorsal hippocampus on the threepanel runway task. Therefore, it was thought at the time that the histaminergic activity in the hippocampus via histamine H1 receptors is quite important for working memory processes. However, literature dealing with the participation of hippocampal H1 receptors on the spatial memory performance using the radial maze test is scanty. On the other hand, the hippocampal theta rhythm recorded from CA1 is considered to play a critical role in memory function [3,16]. In a previous report, we also reported that the hippocampal theta activity during the eight-arm radial maze per-
232
T. Masuoka, C. Kamei / Brain Research Bulletin 73 (2007) 231–237
formance is closely correlated with memory/learning function [11]. However, little work has been done to study the hippocampal electroencephalographic activity after pyrilamine, which is reported to impair the memory performance. Therefore, the changes in the hippocampal theta rhythm during an impairment of working memory of the radial maze task induced by pyrilamine administration were studied.
computer (PC-9801 BX-2, NEC, Tokyo, Japan). In this system, data sampling was carried out at a rate of 50 Hz for 2.56 s. The power spectrum densities and peak frequencies of the hippocampal theta rhythm were integrated and averaged for a whole task. In the present study, the hippocampal theta rhythm was defined as a 5–12 Hz band. The power spectrum from 5 to 12 Hz in the group-administrated saline was defined as 100% in each rat.
2. Materials and methods
Stainless steel injection cannulas (o.d. 300 m, length 14.0 mm) were connected using a polyethylene tube to a Hamilton syringe. Drug solution or saline (0.5 l) was injected into the intrahippocampus through the injection cannula. The rate of injection was 0.5 l/min with an injection pump (Bee Syringe Pump MF-9090; Bioanalytical System Inc., USA). The injection cannulas were left in place for 2 min after the completion of injection to facilitate diffusion of the drug.
2.1. Animals Male Wistar rats, 7 weeks old (body weight, 200–220 g), were purchased from Japan SLC, Shizuoka, Japan. Animals were maintained in an air-conditioned room with controlled temperature (24 ± 2 ◦ C) and humidity (55 ± 15%). They were housed in aluminum cages with sawdust and kept under a light–dark cycle (lights on from 07:00 to 19:00). The animals were allowed free access to food and water except during the experiments. All procedures involving animals were carried out in accordance with the Guidelines of the Animal Experiments at Okayama University Advanced Science Research Center.
2.2. Surgery The rats were anesthetized with pentobarbital sodium (Nembutal® , 35 mg/kg, i.p., Abbott Laboratories, North Chicago, IL, USA) then fixed to a stereotaxic apparatus (SR-5, Narishige, Tokyo, Japan). Stainless steel wire electrodes (200 m) and guide cannulas made of stainless steel tubing (o.d. 550 m) were chronically implanted into the bilateral dorsal hippocampus (A: 3.0, L: ±2.5, H: 2.5 and A: 2.5, L: ±2.5, H: 2.5), respectively, according to the atlas of de Groot [2]. Electrodes were connected to a miniature receptacle and the whole assembly was fixed to the skull with dental cement. One week was allowed for recovery from the surgery.
2.3. Eight-arm radial maze The apparatus used was described in our previous paper [1]. The procedure was as follows [14,22]. To familiarize them with the radial maze, rats received one daily habituation session for 3 days prior to training. On the first day, food pellets (45 mg, each, Bio-Serv, A Holton Industries, Frenchtown, NJ, USA) were scattered over the entire maze surface, and three or four rats were simultaneously placed on the radial maze and allowed to take pellets freely. Over the next 2 days, a pellet was placed in the food cup in each of the eight arms, and the rat was allowed to explore freely until it had taken all the pellets. After adaptation, all rats were trained with 1 trial/day. In each trial, only four arms were baited, and the sequence was not changed throughout the experiment. The rat was placed on the center platform, which was closed off by a door. After 20 s, the door was opened and the rat was allowed to make an arm choice to obtain food pellets until all four pellets had been eaten or 10 min had elapsed. Rats were trained until reaching the criterion of at most 1 error/trial for five successive trials. The number of entries into the unbaited arms was scored as the total error. The first entry into never-baited arms was scored as a reference memory error, while reentry into arms where the pellet had already been taken was scored as a working memory error.
2.4. Electroencephalographic measurement and analysis The electroencephalogram of the rat was recorded with a polygraph system (RM-6000, Nihon Kohoden, Tokyo, Japan) with a telemetric technique during the eight-arm radial maze task. Twenty seconds before each task, the telemetry transmitter (ZB-701J) was connected to a miniature receptacle on the head. The electroencephalographic signals were transmitted to the telemetry receiver (ZR-701J) and recorded with a thermal recorder (WT-645G). The analogue signals were converted into digital values using a multi-channel A–D converter (GENIUS, Medical Research Equipment, Tokyo, Japan) and fast Fourier transformer (FFT); spectral powers were calculated in real time using a personal
2.5. Intrahippocampal injection
2.6. Drugs The following drugs were used: pyrilamine maleate (Sigma, St. Louis, MO., USA), histamine dihydrochloride (Wako, Osaka, Japan), HTMT (6-[2(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptanecarboxamide) dimaleate (Tocris Cookson Ltd., Bristol, UK). All drugs were dissolved in saline.
2.7. Histology The rats were anesthetized with pentobarbital sodium (Nembutal® , 35 mg/kg, i.p., Abbott Laboratories) and perfused transcardially with 10% formaldehyde neutral buffered solution (Wako). The brains were removed and placed in 10% formaldehyde neutral buffer solution for 3 days, and the lesion area was coronally removed. The sections were embedded in paraffin and sectioned (10 m) coronally. The sections were stained with hematoxylin and eosin. The lesion positions were checked under the microscope and reconstructed according to the atlas of Paxinos and Watson [17].
2.8. Statistical analysis One-way analysis of variance (ANOVA) with Dunnett’s test was used for the statistical analysis of the eight-arm radial maze performance and theta power and peak frequency. Correlations were examined according to the method of Pearson.
3. Results 3.1. Histology Fig. 1 shows the histological location of the hippocampal injection cannula. All tips of cannulas were inserted in the dorsal hippocampus accurately and the infusions were not penetrated into the ventricle. 3.2. Effect of pyrilamine on radial maze performance Intraperitoneal injection of pyrilamine caused a significant increase in total errors (F(3, 56) = 5.16, p < 0.01), reference memory errors (F(3, 56) = 3.96, p < 0.05) and working memory errors (F(3, 56) = 4.35, p < 0.01). Pyrilamine at doses of 20 and 25 mg/kg showed no significant effect on the number of total errors, reference memory errors and working memory errors. However, pyrilamine at a dose of 35 mg/kg caused a significant increase in the number of total errors (p < 0.01), reference
T. Masuoka, C. Kamei / Brain Research Bulletin 73 (2007) 231–237
233
Table 1 Effect of pyrilamine on the running time per choice during the radial maze task in rats Drugs
Dose
n
Running time per choice (s)
Pyrilamine (i.p.)
Control 20 mg/kg 25 mg/kg 35 mg/kg
15 15 15 15
12.8 30.5 29.4 46.2
± ± ± ±
1.7 11.2 9.7 9.7*
Pyrilamine (i.h.)
Control 100 g/side 150 g/side 200 g/side
12 12 12 12
15.1 10.5 11.0 13.8
± ± ± ±
1.9 1.7 0.8 2.8
Pyrilamine (35 mg/kg, i.p.)
Control
13
50.5 ± 9.2
+Histamine (i.h.)
0.1 g/side 1 g/side
13 13
78.8 ± 11.4 77.7 ± 16.1
+HTMT (i.h.)
1 g/side 10 g/side
13 13
60.2 ± 13.8 74.3 ± 16.0
Each value represents the mean ± S.E.M. * Significantly different from the control group at p < 0.05.
HTMT showed no significant effect on the number of reference memory errors induced by pyrilamine (F(2, 36) = 2.87, n.s.) (Fig. 3). Fig. 1. Histological location of the hippocampal cannulas. (A) Representative photomicrograph of hematoxylin and eosin-stained tissue. (B) Anatomical diagram adapted from Paxinos and Watson [17].
3.4. Effects of pyrilamine on locomotor activity during radial maze performance
memory errors (p < 0.01) and working memory errors (p < 0.01) (Fig. 2A–C). Intrahippocampal injection of pyrilamine caused a significant increase in total errors (F(3, 44) = 3.22, p < 0.05) and working memory errors (F(3, 44) = 3.56, p < 0.05), but not reference memory errors (F(3, 44) = 2.25, n.s.). Pyrilamine at doses of 100 and 150 g/side showed no significant effect on the number of total errors and working memory errors. However, at a dose of 200 g/side, pyrilamine caused a significant increase in the number of total errors (p < 0.01) and working memory errors (p < 0.01) (Fig. 2D–F).
Table 1 shows the changes in running time per choice measured as an index of the locomotor activity. Intraperitoneal injection of pyrilamine dose-dependently increased the running time per choice (F(3, 56) = 2.79, p < 0.05), and a significant increase was observed at a dose of 35 mg/kg (p < 0.05). The intrahippocampal injection of pyrilamine showed no significant effects on running time per choice (F(3, 44) = 1.58, n.s.). The intraperitoneal injection of pyrilamine with histamine (i.h.) or HTMT (i.h.) also show no significant effects (F(3, 56) = 0.15, n.s. and F(3, 56) = 0.29, n.s., respectively).
3.3. Effects of intrahippocampal injection of histamine and HTMT on the memory deficit induced by the intraperitoneal injection of pyrilamine
3.5. Effect of pyrilamine on the hippocampal theta power during radial maze performance
Intrahippocampal injection of histamine antagonized the increase in total errors (F(2, 36) = 7.98, p < 0.01) and working memory errors (F(2, 36) = 6.24, p < 0.01) induced by the intraperitoneal injection of pyrilamine, a significant antagonizing effect was observed at a dose of 1 g/side on the number of total errors (p < 0.01) and working memory errors (p < 0.01). In contrast, histamine showed no significant effect on the number of reference memory errors induced by pyrilamine (F(2, 36) = 2.03, n.s.). Similar findings were observed with HTMT, a histamine H1 agonist. HTMT at a dose of 10 g/side produced a significant effect on the number of total errors (p < 0.01) and working memory errors (p < 0.05) induced by pyrilamine. In contrast,
Intraperitoneal injection of pyrilamine dose-dependently decreased the hippocampal theta power (F(3, 56) = 5.00, p < 0.01) and a significant decrease was observed at a dose of 35 mg/kg (p < 0.01), which produced working memory deficit. The intrahippocampal injection of pyrilamine also showed a significant decrease of the hippocampal theta power (F(3, 44) = 2.56, p < 0.05) at a dose of 200 g/side (p < 0.05), which produced a working memory deficit (Fig. 4). The intrahippocampal injection of histamine (1 g/side) and HTMT (10 g/side), which significantly ameliorated the working memory deficit, significantly increased the hippocampal theta power (p < 0.05) (Fig. 5).
234
T. Masuoka, C. Kamei / Brain Research Bulletin 73 (2007) 231–237
Fig. 2. Effect of pyrilamine on radial maze performance in rats. Test trials were performed 30 min after the intraperitoneal injection of pyrilamine (A–C) and 5 min after the intrahippocampal (i.h.) injection of pyrilamine (D–F). (A and D) Total errors, (B and E) reference memory errors and (C and F) working memory errors. Columns and vertical bars represent the mean ± S.E.M. (n = 12–15). *,** Significantly different from the control group at p < 0.05 and p < 0.01, respectively.
3.6. Effects of pyrilamine on the peak frequency of the hippocampal theta rhythm during radial maze performance The intraperitoneal injection of pyrilamine decreased the peak frequency of the hippocampal theta rhythm dosedependently (F(3, 56) = 10.59, p < 0.01), and a significant decrease was observed at all doses used (20 mg/kg, p < 0.01; 25 mg/kg, p < 0.01; 35 mg/kg, p < 0.01). On the other hand, the intrahippocampal injection of pyrilamine showed no significant effect on the peak frequency of the hippocampal theta rhythm (F(3, 44) = 1.40, n.s.). The intraperitoneal injection of pyrilamine with histamine (i.h.) (F(2, 36) = 0.14, n.s.) and HTMT (i.h.) (F(2, 36) = 0.08, n.s.) also showed no significant effect on the peak frequency of the hippocampal theta rhythm (Table 2). 3.7. Relationship between radial maze performance and hippocampal theta rhythm Fig. 6 shows the relationship between reference memory errors or working memory errors and the hippocampal theta power or theta peak frequency. There was a significant correlation between reference memory errors and the hippocampal theta power (r = −0.626, t11 = −2.66, p < 0.05), reference memory errors and the theta peak frequency (r = −0.588, t11 = −2.41,
Table 2 Effect of pyrilamine on the peak frequency of the hippocampal theta rhythm during the radial maze task in rats Drugs
Dose
n
Peak frequency (Hz)
Pyrilamine (i.p.)
Control 20 mg/kg 25 mg/kg 35 mg/kg
15 15 15 15
7.35 6.98 6.80 6.78
± ± ± ±
0.07 0.08** 0.11** 0.06**
Pyrilamine (i.h.)
Control 100 g/side 150 g/side 200 g/side
12 12 12 12
7.45 7.34 7.33 7.45
± ± ± ±
0.06 0.07 0.13 0.11
Pyrilamine (35 mg/kg, i.p.)
Control
13
6.71 ± 0.10
+Histamine (i.h.)
0.1 g/side 1 g/side
13 13
6.70 ± 0.11 6.75 ± 0.11
+HTMT (i.h.)
1 g/side 10 g/side
13 13
6.79 ± 0.12 6.73 ± 0.13
Each value represents the mean ± S.E.M. ** Significantly different from the control group at p < 0.01.
T. Masuoka, C. Kamei / Brain Research Bulletin 73 (2007) 231–237
Fig. 3. Effects of histamine and HTMT on memory deficit induced by intraperitoneal injection of pyrilamine in rats. Pyrilamine was injected 30 min before the test trial, and histamine or HTMT was injected 5 min before the test trial. (A) Total errors, (B) reference memory errors and (C) working memory errors. Columns and vertical bars represent the mean ± S.E.M. (n = 13). ** Significantly different from the control group at p < 0.01.
p < 0.05), working memory errors and the hippocampal theta power (r = −0.803, t11 = −4.47, p < 0.01), while there was no significant correlation between working memory errors and the theta peak frequency (r = −0.316, t11 = −1.10, n.s.). These results clearly indicate that there is the highest correlation between the working memory errors and hippocampal theta power. 3.8. Relationship between locomotor activity and hippocampal theta rhythm
235
Fig. 4. Effect of pyrilamine on the hippocampal theta power during radial maze task in rats EEG were recorded 30 min after the intraperitoneal injection of pyrilamine (A) and 5 min after the intrahippocampal (i.h.) injection of pyrilamine (B). Columns and vertical bars represent the mean ± S.E.M. (n = 12–15). *,** Significantly different from the control group at p < 0.05 and p < 0.01, respectively.
observed by Taga et al. [22]. On the other hand, the intrahippocampal injection of histamine at a dose of 1 g/side and HTMT, a selective histamine H1 agonist, at a dose of 10 g/side only antagonized the working memory errors induced by the intraperitoneal injection of pyrilamine. In addition, the intrahippocampal injection of pyrilamine at a dose of 200 g/side only impaired working memory. These results indicate that the inhibition of hippocampal H1 receptor resulted in the impairment of working memory in the radial maze task. Almost the same findings were demonstrated by Nakazato et al. [13]. That is, pyrilamine at a dose of 32 g/side impaired the working mem-
Fig. 7 shows the relationship between the hippocampal theta power or theta peak frequency and running time per choice. There was no correlation between the hippocampal theta power and running time per choice (r = 0.036, t11 = 0.12, n.s.), while the theta peak frequency and running time per choice showed a significant correlation (r = −0.804, t11 = −3.14, p < 0.01). 4. Discussion It was found in the present study that the intraperitoneal injection of pyrilamine at a dose of 35 mg/kg impaired both reference memory and working memory. The same findings were
Fig. 5. Effects of histamine and HTMT on the hippocampal theta power during radial maze task in rats. Columns and vertical bars represent the mean ± S.E.M. (n = 13). * Significantly different from the control group at p < 0.05.
236
T. Masuoka, C. Kamei / Brain Research Bulletin 73 (2007) 231–237
Fig. 6. Correlation between the memory performance and hippocampal theta rhythm. (A) Reference memory errors and hippocampal theta power, (B) reference memory errors and theta peak frequency, (C) working memory errors and hippocampal theta power and (D) working memory errors and theta peak frequency. Each point represents the averaged value in the group administrated each drug (13 groups).
ory task with the three-panel runway task when administered into the dorsal hippocampus, and the effects were antagonized by the concurrent injection of 2-pyridylethylamine, a histamine H1 agonist. Therefore, it is certain that hippocampal histamine H1 receptors play an important role in spatial working memory. It is well recognized that H1 antagonists produced significant sedative effects such as sleepiness, dizziness and incordination. For instance, Kaneko et al. [8] reported that pyrilamine (20 and 50 mg/kg, p.o.) showed a drowsy EEG pattern at the frontal cortex and the hippocampus in rats. The sedative effect of pyrilamine on hippocampal neuronal activity may participate in pyrilamine-induced spatial memory deficit to some extent. It was also demonstrated that pyrilamine decreased the hippocampal theta power at a dose that impaired working memory when injected both intraperitoneally and intrahippocampally. In addition, histamine and HTMT at doses that significantly ameliorated the working memory deficit increased the hippocampal theta power. Segal [19,20] demonstrated that histamine elevated the hippocampal activity via the H1 receptor, because histamine causes the depolarization of pyramidal neurons and prometazine, a histamine H1 antagonist, antagonized the histamine effects. From these findings, it can be concluded that the H1 receptor regulates the hippocampal neuronal activity. In this study, it was revealed that the decrease of hippocampal theta power was parallel to pyrilamine-induced working memory deficit. It is well recognized that the hippocampus plays a
critical role in working memory performance, since hippocampal lesions resulted in an impairment of working memory, but not reference memory [15]. Therefore, it is easy to understand that the decrease of hippocampal activity induced by pyrilamine and the working memory deficit by pyrilamine take place at the same time. The intraperitoneal injection of pyrilamine at doses of 20, 25 and 35 mg/kg decreased the peak frequency of the hippocampal theta rhythm. In addition, the intrahippocampal injection of histamine and HTMT at doses that ameliorated the working memory deficit showed no significant effect on the peak frequency of the hippocampal theta rhythm. Furthermore, pyrilamine also showed no significant effect when administrated into the hippocampus. These findings suggest that there is no participation between hippocampal H1 receptor and the peak frequency of the theta rhythm. In fact, there were few reports that the theta peak frequency was regulated in the hippocampus. On the other hand, the other brain areas, such as the supramammillary nucleus and the midbrain, were identified as the modulation site of the theta peak frequency [9]. There exists a close relationship between the hippocampal theta rhythm and running speed in the rat. For instance, McFarland et al. [12] reported that an increase of locomotor activity resulted in an induction of the hippocampal theta activity. Sławinska and Kasicki [21] also demonstrated that there was a strong relationship between the speed of locomotion and the theta frequency. Therefore, we examined the relation-
T. Masuoka, C. Kamei / Brain Research Bulletin 73 (2007) 231–237
237
References
Fig. 7. Correlation between the theta power (A) or the peak frequency (B) of the hippocampal theta rhythm and the running time per choice. Each point represents the averaged value in the group administrated each drug (13 groups).
ship between the hippocampal theta rhythm and the locomotor activity. As a result, there was no correlation between the hippocampal theta power and the locomotor activity. This finding clearly indicated that the changes in the theta power have no relation to the locomotion in the radial maze task. The same findings were also reported by Olvera-C´ortes et al. [16] using the Morris water maze in rats. On the other hand, it was demonstrated in the study that there is a close relationship between the theta peak frequency and the locomotor activity. This finding is also confirmed by Sławinska and Kasicki [21] that an increase of locomotion speed shifted the hippocampal theta activity to a higher peak frequency. Therefore, the changes in locomor activity induced by the drugs may participate in the changes in the peak frequency. In conclusion, the H1 receptor in the dorsal hippocampus may be responsible for working memory processes on radial maze performance. Furthermore, the decrease in the hippocampal theta power might be associated with the working memory deficit induced by the inhibition of hippocampal histamine H1 receptors.
[1] Z. Chen, Y. Sugimoto, C. Kamei, Effect of intracerebroventricular injection of ␣-fluoromethylhistidine on radial maze performance in rats, Pharmacol. Biochem. Behav. 64 (1999) 513–518. [2] J. de Groot, The rat forebrain in stereotaxic coordinates, Verh. K. Nat. Acad. Wet. Natuurkund. 52 (1959) 1–40. [3] Z. Elazar, W.R. Adey, Spectral analysis of low frequency components in the electrical activity of the hippocampus during learning, Electroencephalogr. Clin. Neurophysiol. 23 (1967) 225–240. [4] Y.W. Huang, Z. Chen, W.W. Hu, L.S. Zhang, W. Wu, L.Y. Ying, E.Q. Wei, Facilitating effect of histamine on spatial memory deficits induced by dizocilpine as evaluated by eight-arm radial maze in SD rats, Acta Pharmacol. Sin. 24 (2003) 1270–1276. [5] J.Z. Ji, X.M. Wang, B.M. Li, Deficit in long-term contextual fear memory induced by blockade of beta-adrenoceptors in hippocampal CA1 region, Eur. J. Neurosci. 17 (2003) 1947–1952. [6] C. Kamei, Y.H. Chung, K. Tasaka, Influence of certain H1 -blockers on the step-through active avoidance response in rats, Psychopharmacology 102 (1990) 312–318. [7] C. Kamei, K. Tasaka, Participation of histamine in the step-through active avoidance response and its inhibition by H1 -blockers, Jpn. J. Pharmacol. 57 (1991) 473–482. [8] Y. Kaneko, K. Shimada, K. Saitou, Y. Sugimoto, C. Kamei, The mechanism responsible for the drowsiness caused by first generation H1 antagonists on the EEG pattern, Methods Find. Exp. Clin. Pharmacol. 22 (2000) 163–168. [9] I.J. Kirk, N. McNaughton, Mapping the differential effects of procaine on frequency and amplitude of reticularly elicited hippocampal rhythmical slow activity, Hippocampus 3 (1993) 517–525. [10] N. Kubo, O. Shirakawa, T. Kuno, C. Tanaka, Antimuscarinic effects of antihistamines: quantitative evaluation by receptor-binding assay, Jpn. J. Pharmacol. 43 (1987) 277–282. [11] T. Masuoka, Y. Fujii, C. Kamei, Participation of the hippocampal theta rhythm in memory formation for an eight-arm radial maze task in rats, Brain Res. 1103 (2006) 159–163. [12] W.L. McFarland, H. Teitelbaum, E.K. Hedges, Relationship between hippocampal theta activity and running speed in the rat, J. Comp. Physiol. Psychol. 88 (1975) 324–328. [13] E. Nakazato, T. Yamamoto, M. Ohno, S. Watanabe, Cholinergic and glutamatergic activation reverses working memory failure by hippocampal histamine H1 receptor blockade in rats, Life Sci. 67 (2000) 1139–1147. [14] M. Nishiga, C. Kamei, Ameliorative effects of histamine on 7chlorokynurenic acid-induced spatial memory deficits in rats, Psychopharmacology 166 (2003) 360–365. [15] D.S. Olton, Hippocampal function and memory for temporal context, in: R.L. Issacson, K.H. Pribram (Eds.), The Hippocampus, vol. 4, Plenum, New York, 1986, pp. 281–298. [16] E. Olvera-C´ortes, M.A. Guevara, I. Gonzalez-Burgos, Increase of the hippocampal theta activity in the Morris water maze reflects learning rather than motor activity, Brain Res. Bull. 62 (2004) 379–384. [17] G. Paxinos, C. Watson, The Rat Brain in Stereotaxic Coordinates, 4th ed., Academic Press, San Diego, 1997. [18] J.K. Robinson, J.B. Mao, Differential effects on delayed non-matchingto-position in rats of microinjections of muscarinic receptor antagonist scopolamine or NMDA receptor antagonist MK-801 into the dorsal or ventral extent of the hippocampus, Brain Res. 765 (1997) 51–60. [19] M. Segal, Histamine produces a Ca2+ -sensitive depolarization of hippocampal pyramidal cells in vitro, Neurosci. Lett. 19 (1980) 67–71. [20] M. Segal, Histamine modulates reactivity of hippocampal CA3 neurons to afferent stimulation in vitro, Brain Res. 213 (1981) 443–448. [21] U. Sławinska, S. Kasicki, The frequency of rat’s hippocampal theta rhythm is related to the speed of locomotion, Brain Res. 796 (1998) 327–331. [22] C. Taga, Y. Sugimoto, M. Nishiga, Y. Fujii, C. Kamei, Effects of vasopressin on histamine H1 receptor antagonist-induced spatial memory deficits in rats, Eur. J. Pharmacol. 423 (2001) 167–170.
Research report
Role of hippocampal H1 receptors in radial maze performance and hippocampal theta activity in rats Takayoshi Masuoka, Chiaki Kamei ∗ Department of Medicinal Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8530, Japan Received 8 November 2006; received in revised form 17 February 2007; accepted 14 March 2007 Available online 5 April 2007
Abstract Histamine H1 antagonists impaired the spatial memory performance. On the other hand, it is well recognized that the hippocampal theta rhythm plays a critical role in spatial memory. However, little work has been done the effect of H1 antagonists on the hippocampal theta rhythm which was associated with the memory performance. We investigated the effect of pyrilamine, a selective H1 receptor antagonist, on spatial memory performance as well as hippocampal theta rhythm during the memory task in rats. Effect of pyrilamine on spatial memory was measured using eight-arm radial maze with four arms baited. Hippocampal theta rhythm during the radial maze task was recorded with a polygraph system with a telemetric technique. Intraperitoneal injection of pyrilamine resulted in impairments of both reference and working memory on the radial maze task. The working memory deficit induced by pyrilamine was antagonized by the intrahippocampal injection of histamine and 6-[2-(4imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptanecarboxamide (HTMT), a histamine H1 agonist. Intraperitoneal injection of pyrilamine decreased the hippocampal theta power at a dose that impaired reference and working memory. This effect was antagonized by the intrahippocampal injection of histamine and HTMT at a dose that ameliorated the working memory deficit. Intrahippocampal injection of pyrilamine impaired working memory and simultaneously decreased the hippocampal theta power. These results suggest that: (i) the hippocampal H1 receptors play an important role in the working memory processes on the radial maze performance and (ii) the decrease in the hippocampal theta power is associated with the working memory deficit induced by the blocking of H1 receptors. © 2007 Elsevier Inc. All rights reserved. Keywords: Pyrilamine; H1 receptor; Radial maze task; Hippocampal theta power; Theta peak frequency; Hippocampus
1. Introduction Histamine plays an important role in learning and memory via histamine H1 receptors. For instance, H1 antagonists, such as diphenhydramine, ketotifen and pyrilamine, impaired the memory performance, such as step-through active avoidance, the three-panel runway task and the radial maze task, in rats [6,13,22]. In association with this, Taga et al. [22] suggested that the antimuscarinic properties of H1 antagonists are responsible for memory deficit, because many H1 antagonists have potent antimuscarinic properties [10]. On the other hand, although pyrilamine had less antimuscarinic activity, the drug showed a potent memory deficit [7]. Therefore, it seems likely
∗
Corresponding author. Tel.: +81 86 251 7939; fax: +81 86 251 7939. E-mail address: [email protected] (C. Kamei).
0361-9230/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2007.03.005
that the antimuscarinic properties of pyrilamine are not involved in memory deficit. It is well known that the intrahippocampal injection of various kinds of amnesic drugs impairs the memory performance [4,5,18]. Nakazato et al. [13] reported that pyrilamine also caused an impairment of working memory performance of rats when administrated into the dorsal hippocampus on the threepanel runway task. Therefore, it was thought at the time that the histaminergic activity in the hippocampus via histamine H1 receptors is quite important for working memory processes. However, literature dealing with the participation of hippocampal H1 receptors on the spatial memory performance using the radial maze test is scanty. On the other hand, the hippocampal theta rhythm recorded from CA1 is considered to play a critical role in memory function [3,16]. In a previous report, we also reported that the hippocampal theta activity during the eight-arm radial maze per-
232
T. Masuoka, C. Kamei / Brain Research Bulletin 73 (2007) 231–237
formance is closely correlated with memory/learning function [11]. However, little work has been done to study the hippocampal electroencephalographic activity after pyrilamine, which is reported to impair the memory performance. Therefore, the changes in the hippocampal theta rhythm during an impairment of working memory of the radial maze task induced by pyrilamine administration were studied.
computer (PC-9801 BX-2, NEC, Tokyo, Japan). In this system, data sampling was carried out at a rate of 50 Hz for 2.56 s. The power spectrum densities and peak frequencies of the hippocampal theta rhythm were integrated and averaged for a whole task. In the present study, the hippocampal theta rhythm was defined as a 5–12 Hz band. The power spectrum from 5 to 12 Hz in the group-administrated saline was defined as 100% in each rat.
2. Materials and methods
Stainless steel injection cannulas (o.d. 300 m, length 14.0 mm) were connected using a polyethylene tube to a Hamilton syringe. Drug solution or saline (0.5 l) was injected into the intrahippocampus through the injection cannula. The rate of injection was 0.5 l/min with an injection pump (Bee Syringe Pump MF-9090; Bioanalytical System Inc., USA). The injection cannulas were left in place for 2 min after the completion of injection to facilitate diffusion of the drug.
2.1. Animals Male Wistar rats, 7 weeks old (body weight, 200–220 g), were purchased from Japan SLC, Shizuoka, Japan. Animals were maintained in an air-conditioned room with controlled temperature (24 ± 2 ◦ C) and humidity (55 ± 15%). They were housed in aluminum cages with sawdust and kept under a light–dark cycle (lights on from 07:00 to 19:00). The animals were allowed free access to food and water except during the experiments. All procedures involving animals were carried out in accordance with the Guidelines of the Animal Experiments at Okayama University Advanced Science Research Center.
2.2. Surgery The rats were anesthetized with pentobarbital sodium (Nembutal® , 35 mg/kg, i.p., Abbott Laboratories, North Chicago, IL, USA) then fixed to a stereotaxic apparatus (SR-5, Narishige, Tokyo, Japan). Stainless steel wire electrodes (200 m) and guide cannulas made of stainless steel tubing (o.d. 550 m) were chronically implanted into the bilateral dorsal hippocampus (A: 3.0, L: ±2.5, H: 2.5 and A: 2.5, L: ±2.5, H: 2.5), respectively, according to the atlas of de Groot [2]. Electrodes were connected to a miniature receptacle and the whole assembly was fixed to the skull with dental cement. One week was allowed for recovery from the surgery.
2.3. Eight-arm radial maze The apparatus used was described in our previous paper [1]. The procedure was as follows [14,22]. To familiarize them with the radial maze, rats received one daily habituation session for 3 days prior to training. On the first day, food pellets (45 mg, each, Bio-Serv, A Holton Industries, Frenchtown, NJ, USA) were scattered over the entire maze surface, and three or four rats were simultaneously placed on the radial maze and allowed to take pellets freely. Over the next 2 days, a pellet was placed in the food cup in each of the eight arms, and the rat was allowed to explore freely until it had taken all the pellets. After adaptation, all rats were trained with 1 trial/day. In each trial, only four arms were baited, and the sequence was not changed throughout the experiment. The rat was placed on the center platform, which was closed off by a door. After 20 s, the door was opened and the rat was allowed to make an arm choice to obtain food pellets until all four pellets had been eaten or 10 min had elapsed. Rats were trained until reaching the criterion of at most 1 error/trial for five successive trials. The number of entries into the unbaited arms was scored as the total error. The first entry into never-baited arms was scored as a reference memory error, while reentry into arms where the pellet had already been taken was scored as a working memory error.
2.4. Electroencephalographic measurement and analysis The electroencephalogram of the rat was recorded with a polygraph system (RM-6000, Nihon Kohoden, Tokyo, Japan) with a telemetric technique during the eight-arm radial maze task. Twenty seconds before each task, the telemetry transmitter (ZB-701J) was connected to a miniature receptacle on the head. The electroencephalographic signals were transmitted to the telemetry receiver (ZR-701J) and recorded with a thermal recorder (WT-645G). The analogue signals were converted into digital values using a multi-channel A–D converter (GENIUS, Medical Research Equipment, Tokyo, Japan) and fast Fourier transformer (FFT); spectral powers were calculated in real time using a personal
2.5. Intrahippocampal injection
2.6. Drugs The following drugs were used: pyrilamine maleate (Sigma, St. Louis, MO., USA), histamine dihydrochloride (Wako, Osaka, Japan), HTMT (6-[2(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptanecarboxamide) dimaleate (Tocris Cookson Ltd., Bristol, UK). All drugs were dissolved in saline.
2.7. Histology The rats were anesthetized with pentobarbital sodium (Nembutal® , 35 mg/kg, i.p., Abbott Laboratories) and perfused transcardially with 10% formaldehyde neutral buffered solution (Wako). The brains were removed and placed in 10% formaldehyde neutral buffer solution for 3 days, and the lesion area was coronally removed. The sections were embedded in paraffin and sectioned (10 m) coronally. The sections were stained with hematoxylin and eosin. The lesion positions were checked under the microscope and reconstructed according to the atlas of Paxinos and Watson [17].
2.8. Statistical analysis One-way analysis of variance (ANOVA) with Dunnett’s test was used for the statistical analysis of the eight-arm radial maze performance and theta power and peak frequency. Correlations were examined according to the method of Pearson.
3. Results 3.1. Histology Fig. 1 shows the histological location of the hippocampal injection cannula. All tips of cannulas were inserted in the dorsal hippocampus accurately and the infusions were not penetrated into the ventricle. 3.2. Effect of pyrilamine on radial maze performance Intraperitoneal injection of pyrilamine caused a significant increase in total errors (F(3, 56) = 5.16, p < 0.01), reference memory errors (F(3, 56) = 3.96, p < 0.05) and working memory errors (F(3, 56) = 4.35, p < 0.01). Pyrilamine at doses of 20 and 25 mg/kg showed no significant effect on the number of total errors, reference memory errors and working memory errors. However, pyrilamine at a dose of 35 mg/kg caused a significant increase in the number of total errors (p < 0.01), reference
T. Masuoka, C. Kamei / Brain Research Bulletin 73 (2007) 231–237
233
Table 1 Effect of pyrilamine on the running time per choice during the radial maze task in rats Drugs
Dose
n
Running time per choice (s)
Pyrilamine (i.p.)
Control 20 mg/kg 25 mg/kg 35 mg/kg
15 15 15 15
12.8 30.5 29.4 46.2
± ± ± ±
1.7 11.2 9.7 9.7*
Pyrilamine (i.h.)
Control 100 g/side 150 g/side 200 g/side
12 12 12 12
15.1 10.5 11.0 13.8
± ± ± ±
1.9 1.7 0.8 2.8
Pyrilamine (35 mg/kg, i.p.)
Control
13
50.5 ± 9.2
+Histamine (i.h.)
0.1 g/side 1 g/side
13 13
78.8 ± 11.4 77.7 ± 16.1
+HTMT (i.h.)
1 g/side 10 g/side
13 13
60.2 ± 13.8 74.3 ± 16.0
Each value represents the mean ± S.E.M. * Significantly different from the control group at p < 0.05.
HTMT showed no significant effect on the number of reference memory errors induced by pyrilamine (F(2, 36) = 2.87, n.s.) (Fig. 3). Fig. 1. Histological location of the hippocampal cannulas. (A) Representative photomicrograph of hematoxylin and eosin-stained tissue. (B) Anatomical diagram adapted from Paxinos and Watson [17].
3.4. Effects of pyrilamine on locomotor activity during radial maze performance
memory errors (p < 0.01) and working memory errors (p < 0.01) (Fig. 2A–C). Intrahippocampal injection of pyrilamine caused a significant increase in total errors (F(3, 44) = 3.22, p < 0.05) and working memory errors (F(3, 44) = 3.56, p < 0.05), but not reference memory errors (F(3, 44) = 2.25, n.s.). Pyrilamine at doses of 100 and 150 g/side showed no significant effect on the number of total errors and working memory errors. However, at a dose of 200 g/side, pyrilamine caused a significant increase in the number of total errors (p < 0.01) and working memory errors (p < 0.01) (Fig. 2D–F).
Table 1 shows the changes in running time per choice measured as an index of the locomotor activity. Intraperitoneal injection of pyrilamine dose-dependently increased the running time per choice (F(3, 56) = 2.79, p < 0.05), and a significant increase was observed at a dose of 35 mg/kg (p < 0.05). The intrahippocampal injection of pyrilamine showed no significant effects on running time per choice (F(3, 44) = 1.58, n.s.). The intraperitoneal injection of pyrilamine with histamine (i.h.) or HTMT (i.h.) also show no significant effects (F(3, 56) = 0.15, n.s. and F(3, 56) = 0.29, n.s., respectively).
3.3. Effects of intrahippocampal injection of histamine and HTMT on the memory deficit induced by the intraperitoneal injection of pyrilamine
3.5. Effect of pyrilamine on the hippocampal theta power during radial maze performance
Intrahippocampal injection of histamine antagonized the increase in total errors (F(2, 36) = 7.98, p < 0.01) and working memory errors (F(2, 36) = 6.24, p < 0.01) induced by the intraperitoneal injection of pyrilamine, a significant antagonizing effect was observed at a dose of 1 g/side on the number of total errors (p < 0.01) and working memory errors (p < 0.01). In contrast, histamine showed no significant effect on the number of reference memory errors induced by pyrilamine (F(2, 36) = 2.03, n.s.). Similar findings were observed with HTMT, a histamine H1 agonist. HTMT at a dose of 10 g/side produced a significant effect on the number of total errors (p < 0.01) and working memory errors (p < 0.05) induced by pyrilamine. In contrast,
Intraperitoneal injection of pyrilamine dose-dependently decreased the hippocampal theta power (F(3, 56) = 5.00, p < 0.01) and a significant decrease was observed at a dose of 35 mg/kg (p < 0.01), which produced working memory deficit. The intrahippocampal injection of pyrilamine also showed a significant decrease of the hippocampal theta power (F(3, 44) = 2.56, p < 0.05) at a dose of 200 g/side (p < 0.05), which produced a working memory deficit (Fig. 4). The intrahippocampal injection of histamine (1 g/side) and HTMT (10 g/side), which significantly ameliorated the working memory deficit, significantly increased the hippocampal theta power (p < 0.05) (Fig. 5).
234
T. Masuoka, C. Kamei / Brain Research Bulletin 73 (2007) 231–237
Fig. 2. Effect of pyrilamine on radial maze performance in rats. Test trials were performed 30 min after the intraperitoneal injection of pyrilamine (A–C) and 5 min after the intrahippocampal (i.h.) injection of pyrilamine (D–F). (A and D) Total errors, (B and E) reference memory errors and (C and F) working memory errors. Columns and vertical bars represent the mean ± S.E.M. (n = 12–15). *,** Significantly different from the control group at p < 0.05 and p < 0.01, respectively.
3.6. Effects of pyrilamine on the peak frequency of the hippocampal theta rhythm during radial maze performance The intraperitoneal injection of pyrilamine decreased the peak frequency of the hippocampal theta rhythm dosedependently (F(3, 56) = 10.59, p < 0.01), and a significant decrease was observed at all doses used (20 mg/kg, p < 0.01; 25 mg/kg, p < 0.01; 35 mg/kg, p < 0.01). On the other hand, the intrahippocampal injection of pyrilamine showed no significant effect on the peak frequency of the hippocampal theta rhythm (F(3, 44) = 1.40, n.s.). The intraperitoneal injection of pyrilamine with histamine (i.h.) (F(2, 36) = 0.14, n.s.) and HTMT (i.h.) (F(2, 36) = 0.08, n.s.) also showed no significant effect on the peak frequency of the hippocampal theta rhythm (Table 2). 3.7. Relationship between radial maze performance and hippocampal theta rhythm Fig. 6 shows the relationship between reference memory errors or working memory errors and the hippocampal theta power or theta peak frequency. There was a significant correlation between reference memory errors and the hippocampal theta power (r = −0.626, t11 = −2.66, p < 0.05), reference memory errors and the theta peak frequency (r = −0.588, t11 = −2.41,
Table 2 Effect of pyrilamine on the peak frequency of the hippocampal theta rhythm during the radial maze task in rats Drugs
Dose
n
Peak frequency (Hz)
Pyrilamine (i.p.)
Control 20 mg/kg 25 mg/kg 35 mg/kg
15 15 15 15
7.35 6.98 6.80 6.78
± ± ± ±
0.07 0.08** 0.11** 0.06**
Pyrilamine (i.h.)
Control 100 g/side 150 g/side 200 g/side
12 12 12 12
7.45 7.34 7.33 7.45
± ± ± ±
0.06 0.07 0.13 0.11
Pyrilamine (35 mg/kg, i.p.)
Control
13
6.71 ± 0.10
+Histamine (i.h.)
0.1 g/side 1 g/side
13 13
6.70 ± 0.11 6.75 ± 0.11
+HTMT (i.h.)
1 g/side 10 g/side
13 13
6.79 ± 0.12 6.73 ± 0.13
Each value represents the mean ± S.E.M. ** Significantly different from the control group at p < 0.01.
T. Masuoka, C. Kamei / Brain Research Bulletin 73 (2007) 231–237
Fig. 3. Effects of histamine and HTMT on memory deficit induced by intraperitoneal injection of pyrilamine in rats. Pyrilamine was injected 30 min before the test trial, and histamine or HTMT was injected 5 min before the test trial. (A) Total errors, (B) reference memory errors and (C) working memory errors. Columns and vertical bars represent the mean ± S.E.M. (n = 13). ** Significantly different from the control group at p < 0.01.
p < 0.05), working memory errors and the hippocampal theta power (r = −0.803, t11 = −4.47, p < 0.01), while there was no significant correlation between working memory errors and the theta peak frequency (r = −0.316, t11 = −1.10, n.s.). These results clearly indicate that there is the highest correlation between the working memory errors and hippocampal theta power. 3.8. Relationship between locomotor activity and hippocampal theta rhythm
235
Fig. 4. Effect of pyrilamine on the hippocampal theta power during radial maze task in rats EEG were recorded 30 min after the intraperitoneal injection of pyrilamine (A) and 5 min after the intrahippocampal (i.h.) injection of pyrilamine (B). Columns and vertical bars represent the mean ± S.E.M. (n = 12–15). *,** Significantly different from the control group at p < 0.05 and p < 0.01, respectively.
observed by Taga et al. [22]. On the other hand, the intrahippocampal injection of histamine at a dose of 1 g/side and HTMT, a selective histamine H1 agonist, at a dose of 10 g/side only antagonized the working memory errors induced by the intraperitoneal injection of pyrilamine. In addition, the intrahippocampal injection of pyrilamine at a dose of 200 g/side only impaired working memory. These results indicate that the inhibition of hippocampal H1 receptor resulted in the impairment of working memory in the radial maze task. Almost the same findings were demonstrated by Nakazato et al. [13]. That is, pyrilamine at a dose of 32 g/side impaired the working mem-
Fig. 7 shows the relationship between the hippocampal theta power or theta peak frequency and running time per choice. There was no correlation between the hippocampal theta power and running time per choice (r = 0.036, t11 = 0.12, n.s.), while the theta peak frequency and running time per choice showed a significant correlation (r = −0.804, t11 = −3.14, p < 0.01). 4. Discussion It was found in the present study that the intraperitoneal injection of pyrilamine at a dose of 35 mg/kg impaired both reference memory and working memory. The same findings were
Fig. 5. Effects of histamine and HTMT on the hippocampal theta power during radial maze task in rats. Columns and vertical bars represent the mean ± S.E.M. (n = 13). * Significantly different from the control group at p < 0.05.
236
T. Masuoka, C. Kamei / Brain Research Bulletin 73 (2007) 231–237
Fig. 6. Correlation between the memory performance and hippocampal theta rhythm. (A) Reference memory errors and hippocampal theta power, (B) reference memory errors and theta peak frequency, (C) working memory errors and hippocampal theta power and (D) working memory errors and theta peak frequency. Each point represents the averaged value in the group administrated each drug (13 groups).
ory task with the three-panel runway task when administered into the dorsal hippocampus, and the effects were antagonized by the concurrent injection of 2-pyridylethylamine, a histamine H1 agonist. Therefore, it is certain that hippocampal histamine H1 receptors play an important role in spatial working memory. It is well recognized that H1 antagonists produced significant sedative effects such as sleepiness, dizziness and incordination. For instance, Kaneko et al. [8] reported that pyrilamine (20 and 50 mg/kg, p.o.) showed a drowsy EEG pattern at the frontal cortex and the hippocampus in rats. The sedative effect of pyrilamine on hippocampal neuronal activity may participate in pyrilamine-induced spatial memory deficit to some extent. It was also demonstrated that pyrilamine decreased the hippocampal theta power at a dose that impaired working memory when injected both intraperitoneally and intrahippocampally. In addition, histamine and HTMT at doses that significantly ameliorated the working memory deficit increased the hippocampal theta power. Segal [19,20] demonstrated that histamine elevated the hippocampal activity via the H1 receptor, because histamine causes the depolarization of pyramidal neurons and prometazine, a histamine H1 antagonist, antagonized the histamine effects. From these findings, it can be concluded that the H1 receptor regulates the hippocampal neuronal activity. In this study, it was revealed that the decrease of hippocampal theta power was parallel to pyrilamine-induced working memory deficit. It is well recognized that the hippocampus plays a
critical role in working memory performance, since hippocampal lesions resulted in an impairment of working memory, but not reference memory [15]. Therefore, it is easy to understand that the decrease of hippocampal activity induced by pyrilamine and the working memory deficit by pyrilamine take place at the same time. The intraperitoneal injection of pyrilamine at doses of 20, 25 and 35 mg/kg decreased the peak frequency of the hippocampal theta rhythm. In addition, the intrahippocampal injection of histamine and HTMT at doses that ameliorated the working memory deficit showed no significant effect on the peak frequency of the hippocampal theta rhythm. Furthermore, pyrilamine also showed no significant effect when administrated into the hippocampus. These findings suggest that there is no participation between hippocampal H1 receptor and the peak frequency of the theta rhythm. In fact, there were few reports that the theta peak frequency was regulated in the hippocampus. On the other hand, the other brain areas, such as the supramammillary nucleus and the midbrain, were identified as the modulation site of the theta peak frequency [9]. There exists a close relationship between the hippocampal theta rhythm and running speed in the rat. For instance, McFarland et al. [12] reported that an increase of locomotor activity resulted in an induction of the hippocampal theta activity. Sławinska and Kasicki [21] also demonstrated that there was a strong relationship between the speed of locomotion and the theta frequency. Therefore, we examined the relation-
T. Masuoka, C. Kamei / Brain Research Bulletin 73 (2007) 231–237
237
References
Fig. 7. Correlation between the theta power (A) or the peak frequency (B) of the hippocampal theta rhythm and the running time per choice. Each point represents the averaged value in the group administrated each drug (13 groups).
ship between the hippocampal theta rhythm and the locomotor activity. As a result, there was no correlation between the hippocampal theta power and the locomotor activity. This finding clearly indicated that the changes in the theta power have no relation to the locomotion in the radial maze task. The same findings were also reported by Olvera-C´ortes et al. [16] using the Morris water maze in rats. On the other hand, it was demonstrated in the study that there is a close relationship between the theta peak frequency and the locomotor activity. This finding is also confirmed by Sławinska and Kasicki [21] that an increase of locomotion speed shifted the hippocampal theta activity to a higher peak frequency. Therefore, the changes in locomor activity induced by the drugs may participate in the changes in the peak frequency. In conclusion, the H1 receptor in the dorsal hippocampus may be responsible for working memory processes on radial maze performance. Furthermore, the decrease in the hippocampal theta power might be associated with the working memory deficit induced by the inhibition of hippocampal histamine H1 receptors.
[1] Z. Chen, Y. Sugimoto, C. Kamei, Effect of intracerebroventricular injection of ␣-fluoromethylhistidine on radial maze performance in rats, Pharmacol. Biochem. Behav. 64 (1999) 513–518. [2] J. de Groot, The rat forebrain in stereotaxic coordinates, Verh. K. Nat. Acad. Wet. Natuurkund. 52 (1959) 1–40. [3] Z. Elazar, W.R. Adey, Spectral analysis of low frequency components in the electrical activity of the hippocampus during learning, Electroencephalogr. Clin. Neurophysiol. 23 (1967) 225–240. [4] Y.W. Huang, Z. Chen, W.W. Hu, L.S. Zhang, W. Wu, L.Y. Ying, E.Q. Wei, Facilitating effect of histamine on spatial memory deficits induced by dizocilpine as evaluated by eight-arm radial maze in SD rats, Acta Pharmacol. Sin. 24 (2003) 1270–1276. [5] J.Z. Ji, X.M. Wang, B.M. Li, Deficit in long-term contextual fear memory induced by blockade of beta-adrenoceptors in hippocampal CA1 region, Eur. J. Neurosci. 17 (2003) 1947–1952. [6] C. Kamei, Y.H. Chung, K. Tasaka, Influence of certain H1 -blockers on the step-through active avoidance response in rats, Psychopharmacology 102 (1990) 312–318. [7] C. Kamei, K. Tasaka, Participation of histamine in the step-through active avoidance response and its inhibition by H1 -blockers, Jpn. J. Pharmacol. 57 (1991) 473–482. [8] Y. Kaneko, K. Shimada, K. Saitou, Y. Sugimoto, C. Kamei, The mechanism responsible for the drowsiness caused by first generation H1 antagonists on the EEG pattern, Methods Find. Exp. Clin. Pharmacol. 22 (2000) 163–168. [9] I.J. Kirk, N. McNaughton, Mapping the differential effects of procaine on frequency and amplitude of reticularly elicited hippocampal rhythmical slow activity, Hippocampus 3 (1993) 517–525. [10] N. Kubo, O. Shirakawa, T. Kuno, C. Tanaka, Antimuscarinic effects of antihistamines: quantitative evaluation by receptor-binding assay, Jpn. J. Pharmacol. 43 (1987) 277–282. [11] T. Masuoka, Y. Fujii, C. Kamei, Participation of the hippocampal theta rhythm in memory formation for an eight-arm radial maze task in rats, Brain Res. 1103 (2006) 159–163. [12] W.L. McFarland, H. Teitelbaum, E.K. Hedges, Relationship between hippocampal theta activity and running speed in the rat, J. Comp. Physiol. Psychol. 88 (1975) 324–328. [13] E. Nakazato, T. Yamamoto, M. Ohno, S. Watanabe, Cholinergic and glutamatergic activation reverses working memory failure by hippocampal histamine H1 receptor blockade in rats, Life Sci. 67 (2000) 1139–1147. [14] M. Nishiga, C. Kamei, Ameliorative effects of histamine on 7chlorokynurenic acid-induced spatial memory deficits in rats, Psychopharmacology 166 (2003) 360–365. [15] D.S. Olton, Hippocampal function and memory for temporal context, in: R.L. Issacson, K.H. Pribram (Eds.), The Hippocampus, vol. 4, Plenum, New York, 1986, pp. 281–298. [16] E. Olvera-C´ortes, M.A. Guevara, I. Gonzalez-Burgos, Increase of the hippocampal theta activity in the Morris water maze reflects learning rather than motor activity, Brain Res. Bull. 62 (2004) 379–384. [17] G. Paxinos, C. Watson, The Rat Brain in Stereotaxic Coordinates, 4th ed., Academic Press, San Diego, 1997. [18] J.K. Robinson, J.B. Mao, Differential effects on delayed non-matchingto-position in rats of microinjections of muscarinic receptor antagonist scopolamine or NMDA receptor antagonist MK-801 into the dorsal or ventral extent of the hippocampus, Brain Res. 765 (1997) 51–60. [19] M. Segal, Histamine produces a Ca2+ -sensitive depolarization of hippocampal pyramidal cells in vitro, Neurosci. Lett. 19 (1980) 67–71. [20] M. Segal, Histamine modulates reactivity of hippocampal CA3 neurons to afferent stimulation in vitro, Brain Res. 213 (1981) 443–448. [21] U. Sławinska, S. Kasicki, The frequency of rat’s hippocampal theta rhythm is related to the speed of locomotion, Brain Res. 796 (1998) 327–331. [22] C. Taga, Y. Sugimoto, M. Nishiga, Y. Fujii, C. Kamei, Effects of vasopressin on histamine H1 receptor antagonist-induced spatial memory deficits in rats, Eur. J. Pharmacol. 423 (2001) 167–170.