ELSEVIER Brain Research 734 (1996) 98-102

BRAIN RESEARCH

Research report

The effect of methamphetamine on histamine level and histidine decarboxylase activity in the rat brain

Chihiro Ito a,b, Kenji Onodera c, Eiko Sakurai b, Mitsumoto Sato a, Takehiko Watanabe b,, Department of Psychiato', Tohoku University School of Medicine, Sendai 980-77, Japan

h Department of Pharmacology L Tohoku University School of Medicine, 2-1 Seir3,o-machi, Aoba-ku, Sendai 980-77, Japan c Department qfPharmacology, Tohoku Unicersity School of Dentist©', Sendai 980-77, Japan

Accepted 7 May 1996

Abstract

To examine biochemical changes in the brain histamine (HA) neuron system after acute and chronic administrations of metham- phetamine (MAP), HA levels and histidine decarboxylase (HDC) activities in the rat cortex, striatum, diencephalon, midbrain, pons-medulla and cerebellum were measured. In the cortex and striatum, acute administration of MAP (1 and 3 mg/kg) increased HA levels 1 h later. Acute administration of MAP (10 mg/kg) and chronic administration of MAP (3 mg/kg) for 21 days also increased HA levels and HDC activities in the cortex and striatum 1 h after the last injection. In the diencephalon, acute administration of MAP (3 and 10 mg/kg) and chronic administration of MAP (3 mg/kg) decreased HA level 1 h after the last injection, but chronic administration of MAP (3 mg/kg) increased HDC activity 1 h after the last injection. There were no significant changes in HA levels and HDC activities in other regions after acute and chronic administrations of MAP. These findings suggest that MAP may activate the brain HA neuron system, although MAP acts more strongly on the cortex and striatum than on the diencephalon.

Keywords: Methamphetamine; Histamine; Histidine decarboxylase; Cortex; Striatum; Diencephalon; Rat

1. Introduct ion

A biogenic amine, histamine (HA), has recently been suggested to be a neurotransmitter or neuromodulator in the mammalian brain. Cell bodies of HA neurons are localized in the tuberomammillary nucleus in the posterior hypothalamic region, while their varicose fibers are found in almost all regions of the brain [9,11,14,19]. The involve- ment of the HA neuron system in diverse brain functions and behaviors has been reviewed [9,11,14,19]. But an effect of methamphetamine (MAP) on the HA neuron system is still unclear, although its effects on other bio- genic amine systems have been extensively studied [15,16]. Treatments with agents that activate the HA neuron system such as intracerebroventricular injection of HA and intra- peritoneal (i.p.) injection of L-histidine, a precursor of HA, metoprine, an inhibitor of HA N-methyltransferase or thioperamide, a histamine H 3 receptor antagonist, inhibited MAP-induced locomotor and stereotyped behavior in mice [1,3,5,8], whereas those that inhibit the HA neuron system

* Corresponding author. Fax: + 81 (22) 717-8060.

such as pyrilamine, a histamine H 1 receptor antagonist (i.p.), or zolantidine, a histamine H 2 receptor antagonist (i.p.), potentiated MAP-induced locomotor and reinforcing effect in mice [7,18]. However, there were few reports on neurochemical changes in the HA neuron system by ad- ministration of MAP except that there was no change of HA level in the whole brain of mice [4,13]. But there are no reports on the neurochemical effect of chronic MAP treatment on the HA neuron system.

In this study, we examined whether acute and chronic administrations of MAP to rats influenced HA levels and HDC activities as signs of HA turnovers in the cortex, striatum, diencephalon, midbrain, pons-medulla and cere- bellum.

2. Materials and methods

2.1. A n i m a l s a n d drug t rea tments

Wistar rats weighing 220-240 g at the beginning of experiments were group-housed (2 rats per cage) with free access to food and water in a room maintained at 22 _+ 2°C and 65 _+ 5% humidity under a 12 h l ight-12 h dark cycle

0006-8993/96/$15.00 Copyright © 1996 Elsevier Science B.V. All rights reserved. Pll S0006-8993(96)00618-X

C. lto et a l . / Brain Research 734 (1996) 98-102 99

(light on at 6.00 h). In acute administration, rats were injected with saline (1 ml /kg , i.p.) or MAP (1, 3 and 10 m g / k g , i.p.). In chronic administration, they were injected once daily with saline (1 ml /kg , i.p.) [S-group] or MAP (3 m g / k g , i.p.) [M-group] for 21 consecutive days. These doses of MAP are relevant to inducing the locomotor and stereotyped behavior, and are not toxic to neurons [15,16]. MAP (Dainippon Pharmaceutical, Japan) was dissolved in 0.9% ( w / v ) NaC1 solution.

2.2. Measurements of HA lerels

Rats were sacrificed by decapitation 1 h after the last injection. The brains were rapidly removed and dissected on ice into 6 regional parts of the cortex, striatum, dien- cephalon, midbrain, pons-medulla and cerebellum by the method of Glowinski and Iversen [2]. After the homoge- nization of the parts in 10 volumes of 3% perchloric acid containing 5 mM Na2-EDTA by a Polytron homogenizer (Kinematica, Lucern, Switzerland) at a maximum setting for 10 s in an ice bath, the homogenates were centrifuged

at 10000 × g for 30 min at 4°C. The supernatants were stored at - 8 0 ° C until HA analyses.

2.3. Measurements of HDC actirities

Six brain parts obtained as described above were ho- mogenized in 10 volumes of HDC solution (100 mM potassium phosphate buffer, pH 6.8, 0.2 mM dithiothreitol, 0.01 mM pyridoxal 5'-phosphate, 1% polyethyleneglycol and 100 Ixg/ml phenylmethanesulfonylfluoride) in a Poly- tron homogenizer (Kinematica, Lucern, Switzerland) at a maximum setting for 10 s in an ice bath. The homogenates were centrifuged at 10000 × g for 30 min and the super- natants were dialyzed against HDC solution overnight. The HDC reaction was started at 37°C by 0.5 mM L-histidine (final concentration) in a total volume of 1.0 ml. Three hours later, the reaction was stopped by adding 0.03 ml of 60% perchloric acid. The mixtures were briefly cen- trifuged, and the supernatants were stored at - 8 0 ° C until HA analyses. Proteins were determined by the method of Lowry et al. [6] with bovine serum albumin as standard.

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Fig. 1. The effect o f acute treatment with methamphetamine (MAP) on histamine levels in the rat brain: (a) cortex, (b) striatum, (c) diencephalon, (d) midbrain, (e l pons-medulla and (f) cerebellum. Rats was sacrificed by decapitation 1 h after administration of M A P (0 [saline 1 m l / k g ] , 1, 3 and 10 m g / k g , i.p.). Results are mean values and their standard errors as vertical bars (n = 6). Statistical analysis was performed by means of A N O V A fo l lowed by Duncan's test (* P < 0.05, * * P < 0.01 vs. the group injected saline).

100 C. lto et al. / Brain Research 734 (1996) 98 102

2.4. HA analyses 3. Results

HA was measured by a sensitive HPLC-fluorometric method as described by Yamatodani et al. [20]. Briefly, HA was separated on a cation exchanger, TSK gel SP2SW (Tosoh, Tokyo, Japan; particle size 5 Ixm) eluted with 0.25 M KHzPO 4 at a flow rate of 0.6 ml /min using a constant flow pump (Model CCPM, Tosoh, Tokyo, Japan). HA eluate was derivatized using an on-line automated Shore's o-phthalaldehyde method [17], and the fluorescence inten- sity was measured at 450 nm with excitation at 360 nm in a spectrofluorometer equipped with a flow cell (Model C-R3A, Shimadzu, Kyoto, Japan) and a chromatographic data processor (Model C-R3A, Shimadzu, Kyoto, Japan).

2.5. Statistics

Statistical analyses of data were carried out using one- way ANOVA followed by Duncan's test for acute admin- istration and Student's t-test for chronic administration. In all cases, P values less than 0.05 were considered statisti- cally significant.

3.1. Effects o fMAP on HA levels in various regions of the rat brain

In the cortex and striatum, acute administration of MAP (1, 3 and 10 mg/kg) or chronic administration of MAP (3 mg/kg) significantly increased HA level 1 h after the last injection (Fig. la,b; Fig. 2a,b). But, in the diencephalon, acute administration of MAP (3 and 10 mg/kg) or chronic administration of MAP (3 mg/kg) significantly decreased HA level 1 h the last injection (Fig. lc; Fig. 2c). There were no significant changes in HA levels of other regions after acute and chronic administrations of MAP (Fig. ld-f ; Fig. 2d-f).

3.2. Effects of MAP on HDC activities in various regions of the rat brain

Acute administration of MAP (10 mg/kg) significantly increased HDC activity in the cortex and striatum 1 h later (Table 1). Moreover, chronic administration of MAP (3

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Fig. 2. The effect of chronic treatment with methamphetamine (MAP) on histamine levels in the rat brain; (a) cortex, (b) striatum, (c) diencephalon, (d) midbrain, (e) pons-medulla and (f) cerebellum. Rats were injected once daily with saline (1 ml /kg , i.p.) [S-group] or MAP (3 mg /kg , i.p.) [M-group] for 21 consecutive days. They were sacrificed 1 h after the last injection. Each value represents the mean + S.E.M. of n = 6 rats. Statistical analysis was performed by means of Student's t-test (* ~ P < 0.01).

C. Ito et al./Brain Research 734 (1996) 98-102 101

Table 1 The effect of acute treatment with methamphetamine (MAP) on histidine decarboxylase activity in the rat brain

Treatment Cortex Striatum Diencephalon M i d b r a i u P o n s - m e d u l l a Cerebellum

Saline 102.1 ± 9.2 98.4 ± 7.8 333.7 ± 41.2 155.0 ± 15.5 71.4 ± 14.9 6.9 + 2.7 MAP (1 mg/kg) 83.4 + 13.7 96.0 ± 14.2 396.5 ± 32.9 179.6 ± 19.8 48.1 ± 8.0 10.9 ± 1.2 MAP (3 mg/kg) 106.6 ± 15.8 96.7 ± 4.1 366.6 ± 45.5 190.2 ± 20.9 59.6 ± 5.8 7.3 ± 1.3 MAP (10 mg/kg) 156.7 ± 28.4 * 130.1 ± 14.1 * 373.5 ± 66.7 158.6 ± 11.6 74.1 ± 19.3 10.4 ± 2.2

Rats were sacrificed 1 h after administration of saline (1 ml/kg, i.p.) or MAP (1, 3 and 10 mg/kg, i.p.). Each value represents the mean ± S.E.M. (fmol/min/mg protein) of n = 6 rats. Statistical analysis was performed by means of one-way ANOVA followed by Duncan's test ( * P < 0.05).

Table 2 The effect of chronic treatment with methamphetamine (MAP) on histidine decarboxylase activity in the rat brain

Treatment Cortex Striatum Diencephalon Midbra ln P o n s - m e d u l l a Cerebellum

S-group 123.8 ± 17.6 108.2 ± 13.9 309.4 ± 17.2 168.0 ± 11.3 82.3 ± 6.1 9.2 ± 2.1 M-group 161.5 ± 5.1 * 171.1 ± 25.6 * 447.9 ± 50.4 * 158.6 ± 10.6 78.1 ± 19.9 9.1 ± 1.2

Rats were injected once daily daily with saline (1 ml/kg, i.p.) [S-group] or MAP (3 mg/kg, i.p.) [M-group] for 21 consecutive days. They were sacrificed 1 h after the last injection. Each value represents the mean ± S.E.M. (fmol/min/mg protein) of n = 6 rats. Statistical analysis was performed by means of Student's t-test ( ~ P < 0.05).

m g / k g ) increased HDC activity in not only the cortex and striatum but also diencephalon 1 h after the last injection (Table 2). There were no significant changes in HDC activities of other regions after acute and chronic adminis- trations of MAP (Tables 1 and 2).

4. Discussion

It is well known that MAP acts on dopamine (DA), norepinephrine, serotonin and acetylcholine neuron sys- tems [15,16]. In the present study, it is also clear that MAP acts on the HA neuron system. Acute and chronic adminis- trations of MAP increased the striatal and cortical HA levels, but decreased the diencephalonic HA level. Acute administration of MAP increased HDC activities in the cortex and striatum, and moreover, chronic administration of MAP increased HDC activities not only in the cortex and striatum but also in the diencephalon. These findings suggests that MAP may activate the HA neuron system, and that chronic treatment with MAP may activate it more strongly. It is likely that a low dose of MAP first increases the HA turnovers in the cortex and striatum, and that moderate and high doses of MAP increase them further- more. As the result, in administrations of moderate and high doses of MAP, the HA produced in the diencephalon may be transported to the cortex and striatum by axonal transport to compensate for their increased HA turnovers, which may result in the decrease of the HA level in the diencephalon, because there are cell bodies of HA neurons in the diencephalon. Moreover, by administration of a high dose of MAP, the cortical and striatal HDC activities may also increase to compensate for their increased HA turnovers. Since chronic treatment with MAP probably acts on the cortex and striatum more strongly, we assume that the HDC in the diencephalon is induced, and that HDC activities not only in the cortex and striatum but also

in the diencephalon increase. Itoh et al. [4] could not find any change of HA metabolism in the whole brain of mice by acute administration of MAP. The discrepancy of their study from the present one may be due to differences not only in animal species but also in the use of whole brain in place of regional brains. Prast et al. [10] showed that DA and apomorphine increased HA release measured by push-pul l technique in the posterior hypothalamus. There- fore, the activation of the HA neuron system by MAP may result from the activation of the DA neuron system.

The effect of MAP on the HA neuron system may be associated with various functions such as sleep-wakeful- ness, ingestive behavior and motor activity, because the HA neuron system has an important role on all these functions [9,11,14,19]. Moreover, the activation of the HA neuron system by chronic administration of MAP may be related to the extradopaminergic brain dysfunction of MAP psychosis and schizophrenia, because it is well known that behavioral sensitization after repeated administration of MAP is an animal model of MAP psychosis and schizophrenia [15,16]. In fact, Prell et al. [12] recently showed that HA metabolites were also elevated with paral- lel to the increase of DA metabolites in the cerebrospinal fluid of patients with chronic schizophrenia.

In conclusion, our study suggests that MAP acts on the HA neuron system in the cortex, striatum and dien- cephalon, which is the first neurochemical demonstration about the effect of MAP on the HA neuron system.

Acknowledgements

This study was partly supported by Grants from the Ministry of Health, the Ministry of Education, Science, Sports and Culture, and Welfare and the Pharmacopsychia- try Research Foundation.

102 C. lto et al. / Brain Research 734 (1996) 98-102

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