Neuropharmacology Poster Session
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Introduction
We reported previously that histamine resulted in facilitation of the impaired memory retrieval induced by aging or hippocampal lesions in rats using step-through avoidance tests (1, 3, 5). Moreover, it has been demonstrated that histamine ameliorates scopolamine-induced learning deficits in the elevated plus-maze test in mice (7, 8) and the water maze test in rats (10). On the other hand, alpha-fluoromethylhistidine (alpha-FMH), a potent inhibitor of histidine decarboxylase, was also demonstrated to show an impairment in active avoidance tasks when administered by either intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) injection (4). Alpha-FMH was reported to almost completely decrease endogenous brain histamine content from the nerve terminals without affecting other neurotransmitters (2, 6, 9). In these studies, however, the memory parameter used was transfer latency, which is affected by behavioral toxicity such as decreases in locomotor activity or muscle relaxant activity. The aim of our investigation was to clarify whether endogenous histamine is involved in spatial memory using the 8-arm radial maze task in rats.
Materials and Methods
Radial-Arm Maze Performance To familiarize the rats with the radial maze, prior to training they received one daily habituation trial for two days. After adaptation, all rats were trained with one trial per day. In each trial, a single food pellet was placed in the food cup in each of the 8 arms. A rat was placed on the center platform and allowed to make arm choice to obtain food pellets freely until all 8 pellets had been eaten or 10 min had elapsed. Rats were trained continually until reaching a criterion of at least 7 different arms in the first 8 choices and all 8 within the first 9 choices before the test. The animals were tested with either drug or vehicle after successfully completing the maze on 3 consecutive days. The test trial was performed for 3 min or until the rat collected all pellets. The number of total errors (TE) was used to represent accurate choice. Drugs were dissolved in a vehicle consisting of saline and injected i.c.v. with a fixed volume of 5 µl over a period of 60 sec at a constant speed with a continual infusion pump (KN-201, Natsume, Tokyo, Japan). Determination of Brain Histamine Contents After behavioral tests, the rats were sacrificed by decapitation, the brain was quickly removed and placed on an ice cold stainless steel plate. The brain regions were subsequently dissected and histamine contents were determined by HPLC (CCP & 8010 series, Tosoh, Tokyo, Japan).
Results
Alpha-FMH caused an increase in the number of TE. At doses of 20 and 50 µg, it had no significant effect. However, at a dose of 100 µg, this drug significantly increased the number of TE from 1 to 4 h after injection (P < 0.05) (Fig.1). At the meanwhile, as shown in Table 1, alpha-FMH decreased histamine contents in all brain regions measured. At a dose of 50 µg, it significantly decreased histamine contents in the hypothalamus (P < 0.05). A significant effect was observed in the cortex, hippocampus and hypothalamus at a dose of 100 µg (P < 0.01). In addition, the correlation coefficients of the number of TE and decrease in the cortex and hippocampus were r=0.927 and r=0.940, respectively. Moreover, the running time per choice was not influenced by injection of alpha-FMH even at a dose of 100 µg (data not shown).
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Fig.1:Effect of alpha-fluoromethylhistidine on 8-arm radial maze performance in rats. Alpha-fluoromethylhistidine was injected intracerebroventricularly.
Table 1 Changes in brain histamine contents after alpha-fluoromethyhistidine injection
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Histamine contents (ng/g tissue)
Brain regions
Saline 20 µg 50 µg 100 µg
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Cortex 32.6 ± 1.8 27.8 ± 2.8 24.0 ± 1.4 1 9.8 ± 1.7**
Hippocampus 25.6 ± 1.3 22.9 ± 1.3 19.1 ± 3.6 14.0 ± 1.3**
Hypothalamus 303.1 ± 20.1 251.8 ± 35.8 196.5 ± 28.1* 162.3 ± 15.8**
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Alpha-fluoromethylhistidine was injected 2 h before the test trial.
Each value represents the mean ± S.E.M. of 7 rats
*;**: Significantly different from saline-treated group
with P < 0.05 and P < 0.01, respectively.
The i.c.v. injection of histamine antagonized dose-dependently the spatial memory deficits induced by alpha-FMH (Fig.2). Although it caused no significant effect at a dose of 20 ng, a significant effect was observed at doses of 50 (p < 0.05) and 100 ng (p < 0.05). On the other hand, metoprine had no significant effects on memory deficit induced by alpha-FMH even at a dose of 20 mg/kg. In contrast, thioperamide antagonized alpha-FMH-induced spatial memory deficits at a dose of 10 µg (p < 0.05) (Fig.2).
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Fig.2: Effects of histamine, metoprine and thioperamide on spatial memory deficits induced by alpha-FMH.
As shown in Table 2, alpha-FMH (20 µg), at a dose which showed no appreciable effect when given alone, showed significant effects when administered in combinatation with pyrilamine (20 mg/kg) (p < 0.05) or R-(alpha)-methylhistamine (5 µg) (p < 0.05). On the other hand, a combination of alpha-FMH (100 µg) and pyrilamine or R-(alpha)-methylhistamine (5 µg) created no apparent effects, as compared with either given separately.. In addition, Neither alpha-FMH (20 µg) nor alpha-FMH (100 µg) showed no appreciable change, when combined with zolantidine (20 mg/kg).
Table 2. Effects of pyrilamine, zolantidine and R-(alpha)-methylhistamine on an increase of total errors induced by alpha-FMH.
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Alpha-fluoromethylhistidine
Drugs
0 20 µg 100 µg
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Saline 0.2 ± 0.1 0.4 ± 0.2 3.0 ± 0.6
Pyrilamine (20 mg/kg) 0.9 ± 0.5 1.9 ± 0.6* 3.4 ± 0.7
Zolantidine (20 mg/kg) 0.3 ± 0.1 0.5 ± 0.3 2.7 ± 0.8
(R)-alpha-methyl-
histamine (5 µg.) 1.4 ± 0.7 2.1 ± 0.7* 3.7 ± 1.1
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Each value represents the mean ± S.E.M. of 19-21 rats.
*: Significantly different from alpha-fluoromethylhistidine-treated group
with P < 0.05.
Discussion and Conclusion
In conclusions, endogenous histamine in the cortex and hippocampus plays an important role in spatial cognition of rats in the 8-arm radial maze task.
References
- Chen, Z.; Sugimoto, Y.; Kamei, C. Effects of histamine and its related compounds on impairment of passive avoidance response following hippocampal lesions in rats. J. Brain Sci. 23: 225-240; 1997.
- Duggan, D. E.; Hooke, K. F.; Maycock, A. L. Inhibition of histamine synthesis in vitro and in vivo by S-alpha-fluoromethylhistidine. Biochem. Pharmacol. 33: 4003-4009; 1984.
- Kamei, C.; Chen, Z.; Nakamura, S.; Sugimoto, Y.; Effects of intracerebro- ventricular injection of histamine on memory deficits induced by hippocampal lesions in rats. Meth. Find. Exp. Clin. Pharmacol. 19: 253-259; 1997.
- Kamei, C.; Okumura, Y.; Tasaka, K. Influence of histamine depletion on learning and memory recollection. Psychopharmacology 111: 376-382; 1993.
- Kamei, C.; Tasaka, K. Effect of histamine on memory retrieval in old rats. Biol. Pharm. Bull. 16: 128-132; 1993.
- Maeyama, K.; Watanabe, T.; Yamatodani, A.; Taguchi, Y.; Kambe, H.; Wada, H. Effect of alpha-fluoromethylhistidine on the histamine content of the brain of W/Wv mice devoid of mast cells: turnover of brain histamine. J. Neurochem. 41: 128-134; 1983.
- Miyazaki, S.; Imaizumi, M.; Onodera, K. Ameliorating effects of histidine on scopolamine-induced learning deficits using an elevated plus-maze test in mice. Life Sci. 19: 1563-1570; 1995.
- Miyazaki, S.; Imaizumi, M.; Onodera, K. Effects of thioperamide on the cholinergic system and the step-through passive avoidance test in mice. Meth. Find. Exp. Clin. Pharmacol. 17: 653-658; 1995.
- Prast, H.; Argyriou, A.; Philippu, A. Histaminergic neurons facilitate social memory in rats. Brain Res. 734: 316-318; 1996.
- Smith, P.S.; Hunter, A.J. Bennett, G.W. Effects of (R)-alpha-methylhistamine and scopolamine on spatial learning in the rats assessed using a water maze. Psychopharmacology 114: 651-656; 1994.
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