Psychopharmacology (2008) 197:107–114 DOI 10.1007/s00213-007-1013-7
ORIGINAL INVESTIGATION
Participation of hippocampal ionotropic glutamate receptors in histamine H1 antagonist-induced memory deficit in rats Takayoshi Masuoka & Shunsuke Saito & Chiaki Kamei
Received: 24 May 2007 / Accepted: 30 October 2007 / Published online: 7 December 2007 # Springer-Verlag 2007
Abstract Rationale Pyrilamine, a selective histamine H1 antagonist, impaired spatial memory, and decreased hippocampal theta activity during a radial maze task. Objective We investigated the ameliorative effects of glutamatergic drugs on pyrilamine-induced spatial memory deficit and the decrease in hippocampal theta activity in rats. Materials and methods Drug effects were measured using an eight-arm radial maze with four arms baited. Hippocampal theta rhythm during the radial maze task was also recorded with a polygraph system using a telemetric technique. Results Intraperitoneal injection of pyrilamine (35 mg/kg) resulted in impaired reference and working memory in the radial maze task and a decrease in the amplitude and power of hippocampal theta waves. The working memory deficit and the decrease in hippocampal theta power were antagonized by intrahippocampal injection of D-cycloserine (1 μg/side), spermidine (10 μg/side), spermine (10 μg/ side), aniracetam (1 μg/side), and 1-(1,3-benzodioxol-5ylcarbonyl) piperidine (1-BCP) (1 μg/side), but not concanavalin A. Conclusion These results clearly indicate that H1 antagonistinduced working memory deficit, and the decrease in hippocampal theta activity was closely associated with hippocampal glutamatergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptors. T. Masuoka : S. Saito : C. Kamei (*) Department of Medicinal Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8530, Japan e-mail:
[email protected]
Keywords H1 receptor . NMDA receptor . AMPA receptor . Kainate receptor . Radial maze task . Hippocampal theta activity . Reference memory . Working memory
Introduction De Almeida and Izquierdo (1986) first reported that histamine facilitates memory performance via H1 and H2 receptors using step-down inhibitory avoidance in rats. Recently, it was revealed that histamine in hippocampal CA1 area enhanced the retrieval process of memory performance via H1 receptor, while activation of H2 receptor, but not H1 receptor, in the CA1 area facilitates memory consolidation in the learning process (Da Silva et al. 2006). We have reported that the working memory deficit induced by pyrilamine, an H1 antagonist, was prevented by an intrahippocampal injection of HTMT, an H1 agonist, in the radial maze task (Masuoka and Kamei 2007). Furthermore, intrahippocampal injection of pyrilamine caused working memory deficit in the three-panel runway task and radial maze task (Nakazato et al. 2000; Masuoka and Kamei 2007); therefore, it was thought at the time that H1 receptors in the hippocampus were closely associated with working memory in rats. On the other hand, it is well recognized that the hippocampal theta rhythm recorded from the CA1 plays a critical role in memory function (Elazar and Adey 1967; Olvera-Córtes et al. 2004). In previous reports, we also demonstrated that hippocampal theta activity is closely correlated with memory/learning function using eight-arm radial maze performance. We have reported that hippocampal theta power in radial maze performance gradually decreased with spatial memory formation (Masuoka et al. 2006a). In addition, when scopolamine was administrated to spatial
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memory-acquired rats, scopolamine caused spatial memory deficit and increased hippocampal theta power (Masuoka et al. 2006b). These findings indicate that hippocampal theta activity was activated when spatial information could not be recalled. On the other hand, in pyrilamine-induced spatial memory deficit, pyrilamine decreased hippocampal theta power in spatial memoryacquired rats, which was antagonized by an H1 agonist (Masuoka and Kamei 2007); therefore, it seems likely that the further decrease of theta activity observed after memory acquisition is also involved in memory deficit. These findings indicate that an appropriate amount of theta activity was essential to perform the radial maze task correctly, and hyperactivation or inactivation of hippocampal theta activity may inhibit the recall of spatial memory. H1 receptors are well known to modulate the glutamatergic system in the rat hippocampus. For instance, Rodriguez et al. (1997) reported that histamine acts on both H1 and H2 receptors presynaptically to increase the release of glutamate from rat hippocampal synaptosomes. On the other hand, it is generally recognized that glutamate activates various glutamate receptors, N-methyl-D-aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors, kainate receptors, and metabotropic glutamate receptors. Behavioral studies indicated that hippocampal H1 receptors were closely associated with NMDA receptors. For instance, Nakazato et al. (2000) reported that intrahippocampal injection of an NMDA receptor glycine binding-site partial agonist, D-cycloserine, reversed the working memory deficit induced by intrahippocampal injection of pyrilamine. In addition, Huang et al. (2003) demonstrated that spatial memory deficit induced by intrahippocampal injection of MK-801, an NMDA receptor antagonist, was prevented by intrahippocampal injection of histamine. This ameliorative effect of histamine was antagonized by intrahippocampal injection of pyrilamine using the radial maze task; however, little work has been done on the participation of other ionotropic glutamate receptors in H1 antagonistinduced memory deficit. In the present study, therefore, we studied the effects of ionotropic glutamate receptor modulators on pyrilamineinduced memory deficit and the decrease in hippocampal theta activity in rats.
Materials and methods Animals Male Wistar rats, 7 weeks old (body weight, 200–220 g), were purchased from Japan SLC, Shizuoka, Japan.
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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 0700 to 1900 hours). Their body weight was maintained at 80–85% of the free-feeding weight. Water was given ad libitum. All procedures involving animals were carried out in accordance with the Guidelines for Animal Experiments at Okayama University Advanced Science Research Center. Surgery The rats were anesthetized with pentobarbital sodium (Nembutal®, 35 mg/kg, i.p., Abbott Laboratories, North Chicago, IL, USA) and then fixed to a stereotaxic apparatus (SR-5, Narishige, Tokyo, Japan). Stainless steel wire electrodes (200 μm) and guide cannulas made of stainless steel tubing (outer diameter; 550 μm) 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 (1959). 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. Eight-arm radial maze The apparatus used was described in our previous paper (Chen et al. 1999). The procedure was as follows (Taga et al. 2001; Nishiga and Kamei 2003): to familiarize rats with the radial maze, they received one daily habituation session for 3 days before training. On the first day, food pellets (45 mg, each, Bio-Serv, A Holton Industries, Frenchtown, N.J., 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 a 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 one trial per 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 one error per trial for five successive trials. The number of entries into unbaited arms was scored as the total error. The first entry into never-baited arms was scored as a reference memory error, while re-entry into arms where
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the pellet had already been taken was scored as a working memory error. Electroencephalographic measurement and analysis Electroencephalograms were recorded with a polygraph system (RM-6000, Nihon Kohoden, Tokyo, Japan) using a telemetric technique during the eight-arm radial maze task. Twenty seconds before each task, a telemetry transmitter (ZB-701J) was connected to the miniature receptacle on the head. Electroencephalographic signals were transmitted to the telemetry receiver (ZR-701J) and recorded with a thermal recorder (WT-645G). Analog signals were converted into digital values using a multichannel A-D converter and recorded using the data acquisition program VitalRecorder (Kissei Comtec, Nagoya, Japan). Fast Fourier transformer (FFT) spectral powers were calculated using the data analysis program BIMUTAS®II (Kissei Comtec). In this system, data sampling was carried out at a rate of 1,024 Hz. The power spectrum densities of the hippocampal theta rhythm were integrated and averaged for the whole task. In the present study, the hippocampal theta rhythm was defined as a 5–12 Hz band. The power spectrum at 5–12 Hz in the vehicle-administrated group was defined as 100% in each rat.
Fig. 1 Effects of NMDA receptor agonists on pyrilamine-induced memory deficit in rats. Pyrilamine was injected 30 min before the test trial, and D-cycloserine, spermidine, or spermine was injected 5 min before the test trial. Columns and vertical bars represent the mean± SEM (n=14). *, **Significantly different from the control group at P
