HA release measured by in vivo brain microdialysis in the rat hypothalamus. Correspondence address: Chihiro Ito, MD, Dep
P s y c h i a t y and Clinical Neurosciences (1997), 51, 79-81
Regular Article
The effect of methamphetamine on histamine release in the rat hypothalamus CHIHIRO ITO, ML),' KENJI ONODERA, P H L ) , ~ATSUSI YAMATODANI, TAKEHIKO WATANABE, MU,* AND MITSUMOTO SATO, MD'
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Departmenfi of 'Psychiatry and 'Pharmacology I, Tohoku University School ofhfedicine, 3Deparfment ofPharmacology, Tohoku University School ofDentistry, Sendai and 4Department ofhfedical Physics, School of Allied Health Sciences, Osaka University Faculty ofhfedicine, Suita, Japan
Abstract
In the present study, the effect of methamphetamine (MAP) on histamine (HA) release measured by in v i m brain microdialysis in the rat hypothalamus was investigated. Administration of MAP (3 mg/kg) significantly increase HA release from 40 to 160 min after the injection. This finding suggests that a moderate dose of MAP activates the hypothalamic HA neuron system, which may be related to effects of MAP on intrinsic biological rhythms.
Key words
histamine release, hypothalamus, in vim brain microdialysis, methamphetamine.
INTRODUCTION
METHODS
A biogenic amine, histamine (HA), has recently been suggested to be a neurotransmitter or neuromodulator in the mammalian central nervous system. 1-4 Cell bodies of HA neurons are localized in the tuberomammillary nucleus in the posterior hypothalamic region, while their varicose fibers are widely distributed in almost all the regions of the brain.'-4 The involvements of the HA neuron system in various brain functions and behaviors have been reviewed. In particular, the hypothalamic HA neuron system has important roles in feeding, drinking and the sleep-wakefulness cycle.'-4 Methamphetamine (MAP; Dainippon Pharmaceutical Co., Japan) has been recognized as an efficacious appetite suppressant that may be associated with releasing actions of catecholamines mediated through catecholamine transporters in the h y p o t h a l a m ~ s . ~But * ~ there have been no biochemical reports about the change of the hypothalamic HA neuron system after administration of MAP, although there have been a few reports about the change of HA level in the whole brain of mice.' In the present study, we examined the effect of MAP on HA release measured by in vivo brain microdialysis in the rat hypothalamus.
Microdialysis methods
Correspondence address: Chihiro Ito, MD, Department of Psychiatry, Tohoku University School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai 980-77, Japan. Received 12 June 1996; revised 24 September 1996; accepted 29 October 1996.
Male Wistar rats weighing 220-240 g at the start of treatment were group-housed (one rat per cage) with free access to water in a room maintained at 2 2 + 2 " C and 6 5 2 5 % humidity under a 12 h light-12 h dark cycle (light on at 0600 h). The rats were anesthetized with sodium pentobarbital (50 mg/kg, i.p.) and placed in a stereotaxic frame (Korf Instrument, Tujunga, CA). The skull was exposed and a hole was drilled for the implantation of a guide cannula (CMA/11, Carnegie Medicin, Stockholm, Sweden) into the anterior hypothalamic area (coordinates: rostra1 - 1.6 mm, lateral + 0.5 mm, ventral - 9.2 mm, from the bregma and dura surface) according to the atlas of Pellegrino and Cushman.8 The guide cannula was implanted and secured with dental cement. Three days after the operation, a microdialysis probe (CMA/Il, membrane length 2 mm; Carnegie Medicin, Stockholm, Sweden) was inserted along the guide cannula, and a microdialysis experiment was begun in a free-moving state. The microdialysis probe was continuously perfused at 4 pL/min for 120 min with artificial cerebrospinal fluid, consisting of 140 mmol/L NaCl, 3 mmol/L KCl, 2.5 mmol/L CaCl,, and 1 mmol/L MgCl,, pH 7.4, to achieve the rapid stabilization of HA releases.' Then the flow rate was reduced to 2 pL/min and fractions were collected for every 20 min. After the first three fractions had been collected, saline (1 mL/kg) or MAP (1 and 3 mg/kg) were injected intraperitoneally. Metham-
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phetamine was dissolved in 0.9% (w/v) NaCl solution. The dialysate was mixed with 1/30 volume of 60% perchloric acid, and stored at - 8 0 ° C until HA assay. After the experiments, the brains were removed and fixed in 4% paraformaldehyde in 0.1 mol/L sodium phosphate buffer pH 7.4, immersed in 30% sucrose, and cut into 50 pm coronal sections in cryostat to confirm the location of the probe. Measurements of histamine levels
HA was measured by a sensitive HPLC-fluorometric method described by Yamatodani et a1.I' Briefly, HA was separated on a cation exchanger, TSK gel SP2SW (Tosoh, Tokyo, Japan; particle size 5 pm) eluted with 0.25 mol/L KH,PO, at a flow rate of 0.6 mL/min using a constant flow pump (Model CCPM, Tosoh, Tokyo, Japan). The HA eluate was arrived at using an on-line automated Shore's o-phthalaldehyde method," and the fluorescence intensity was measured at 450 mm with excitation at 360 mm in a spectrofluorometer equipped with a flow cell (Model C-R3A; Shimadzu, Kyoto, Japan) and a chromatographic data processor (Model C-RSA, Shimadzu, Kyoto, Japan).
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Figure 1. T h e effect of MAP on H A release in the anterior hypothalamic area. T h e average values of the first three fractions are taken as 100%. T h e times of saline (1 mg/kg, i.p.) or MAP (1 and 3 nIg/kg, i.p.) injections are indicated by an arrow. (0)Saline experiments, (m) MAP (1 nig/kg) experiments, (A) MAP (3 mg/kg) experiments. Kesults are mean values and their standard errors as vertical bars ( P I = 4). Statistical analysis was performed by means of ANOVA (*P< 0.05 1)s the group injected saline).
Statistical analyses
In the microdialysis, a mean of the first three fractions was defined as the mean basal release, and the following fractions were expressed as a percentage of the mean basal release. The statistical analyses of data were carried out using a one way analysis of variance (ANOVA) followed by Duncan's test. In all cases, P values less than 0.05 were considered statistically significant.
RESULTS MAP (3 mg/kg) significantly increased the anterior hypothalamic HA releases 40, 60, 80, 100, 120, 140 and 160 mm later. The peak HA release at 100 min was 365 f 145% ( m e a n t SEM, n = 4) of the basal line, which was 238.0 ir 25.6 fmol/40 pL (mean t SEM, n = 4). However, MAP (1 mg/kg) did not change the HA release (Fig. 1). DISCUSSION In the present study, MAP significantly increased HA release in the anterior hypothalamus measured by in vivo brain microdialysis. Itoh et al. could not find any change of HA metabolism in the whole brain of mice by the 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 rather than brain regions. The doses of MAP in the present study are not toxic to neurons and release catecholamine mediated through catecholamine transporter^.^ More than 5 mg/kg of MAP are diffusely taken into the cell through the cell membrane.5 Moreover, Mochizuki et al. reported that HA release in the anterior hypothalamus results from neuronal origin, because the HA
release increased with electrical stimulation against the ipsilateral tuberomammillary nucleus or the infusion of 100 mmol/L K through the dialysis membrane, and the increase of HA release was completely suppressed by the removal of extracellular Ca2 or the infusion of 10 M tetrodotoxin. l 2 This finding suggests that MAP activates the hypothalamic H'A neuron system. W e recently also found that MAP increased HA levels and activities of HA synthetase in the striatum and cortex.I3 Methamphetamine acts through monoamine uptake transporters, but the u p t f b system of HA was not influenced by MAP or cocaine. Moreover, although HA synthesis and release are mainly regulated by H, receptors as autoreceptors, we recently found that the bindings of H, receptors were not affected in the brains of rats treated acutely and chronically with MAP." The HA neuron system has many interrelations with other neurotransmitters that are released by MAP.I6 In particular, Prast ef al. recently reported that dopamine and apomorphine increased the hypothalamic HA release in the push-pull cannula method. l7 Therefore, the MAP-induced increase of HA release in the hypothalamus may result from the increase of dopamine release of dopamine release by MAP. The reason why HA metabolism in the hypothalamus was activated by administration of MAP above a moderate dose in the present study may not only be because MAP acts on the striatum and cortex more strongly than diencephalon but also because HA release may result from the increase of dopamine release by MAP. The hypothalamic HA release from the hypothalamus shows a clear circadian rhythm, being high in the dark +
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Methamphetamine and histamine
period and low in the light period in rat.18 The injection of HA intracerebroventricularly (i.c.v.) depressed the feeding behavior of rat,l9vZ0while the infusion (i.c.v.) of a n inhibitor of HA synthesis, a-fluoromethylhistidine, or the microinjection of HI antagonists into the hypothalamus induced transient increase in feeding.21.22Therefore, MAP-induced HA release in the hypothalamus may be partially related to effects of MAP on circadian rhythm including sleepwakefulness and appetite. In conclusion, our present study suggests that MAP activates the hypothalamic HA neuron system.
ACKNOWLEDGMENTS This study was partly supported by Grants in Aid from the Ministry of Education, Science, Sports and Culture and the Ministry of Health and Welfare of Japan.
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