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Chronic methamphetamine administration reduces histamine-stimulated phosphoinositide hydrolysis in mouse frontal cortex
BBRC Biochemical and Biophysical Research Communications 300 (2003) 932–937 www.elsevier.com/locate/ybbrc
Chronic methamphetamine administration reduces histamine-stimulated phosphoinositide hydrolysis in mouse frontal cortex Junichi Kitanaka,* Nobue Kitanaka, and Motohiko Takemura Department of Pharmacology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan Received 11 December 2002
Abstract In the present study, it was hypothesized that in vivo pretreatment with repeated methamphetamine would alter the agoniststimulated phosphoinositide hydrolysis in mouse frontal cortical slices. Male ICR mice that received the methamphetamine injection (1.0 mg/kg, intraperitoneally) once a day for five consecutive days showed behavioral sensitization to the same dose of methamphetamine 5 days after the last injection of the initial chronic treatment regimen (test day 10). On test day 10, the reduction of histamine (0.1–1.0 mM)-stimulated phosphoinositide hydrolysis in the mouse frontal cortex was observed. The reduction was specific to histamine, but not to norepinephrine (10 lM–0.1 mM) or L -glutamate (0.1–0.5 mM). The reduction occurred without any change in the expression level of histamine H1 receptor mRNA. The reduction recovered 25 days after the last injection of the initial chronic treatment regimen (test day 30). The direct application to the slices of a pharmacologically effective concentration of methamphetamine in vitro ð10 lMÞ did not alter the histamine signal transduction. The present results suggest that the reduction is probably one of neuroadaptations in the frontal cortex contributing to behavioral sensitization. Ó 2002 Elsevier Science (USA). All rights reserved. Keywords: Methamphetamine; Behavioral sensitization; Chronic treatment; Histamine; Phosphoinositide hydrolysis; Frontal cortex; Mice
Chronic administration of psychostimulants, such as amphetamines, cocaine, and methylphenidate, in rodents induces behavioral sensitization (or reverse tolerance) and long-lasting behavioral manifestations [1–3]. Since this phenomenon is assumed to be one of the initial biological states towards drug-seeking behavior, a major feature of drug addiction, it is important to reveal the molecular basis of the behavioral sensitization for a better understanding of how drug abuse addicts humans [2,4]. Once the behavioral sensitization is established, an augmentation of the locomotor-stimulating effect of psychostimulants persists for weeks or even months after a final challenge of the drug [1]. In addition to the enhanced release of dopamine in the striatum [5,6], functional adaptations of certain proteins in the brain contribute to the behavioral sensitization (for a review, see [4,7,8]). For example, alterations of the expression of * Corresponding author. Fax: +81-798-45-6332. E-mail address: [email protected] (J. Kitanaka).
some proteins including the heterotrimeric GTP-binding protein b1 subunit gene (GNB1) essential for the intracellular signal transduction mechanisms are followed by behavioral sensitization [9]. In view of these observations, there is a possibility that an enduring consequence of the changes in the neurotransmitter signal would result in the establishment of behavioral sensitization. Therefore, it is of interest to examine the alterations of the activity of the intracellular signal transduction mechanisms, such as phosphoinositide hydrolysis by phospholipase C and cyclic AMP formation by adenylate cyclase, in the frontal cortex under adaptative states for repeated drug administration because of evidence of the direct neural interaction between the basal ganglia and forebrain [3]. Characterization of receptor-mediated signal transduction was performed in rat and mouse cerebral cortices. Of the receptor agonists tested, norepinephrine, carbachol, and histamine produced large responses in terms of phosphoinositide hydrolysis via an
0006-291X/02/$ - see front matter Ó 2002 Elsevier Science (USA). All rights reserved. doi:10.1016/S0006-291X(02)02948-0
J. Kitanaka et al. / Biochemical and Biophysical Research Communications 300 (2003) 932–937
a1 -adrenergic, muscarinic acetylcholine, and histamine H1 receptor-mediated manner, respectively [10,11]. In line with these observations, the present study was designed to examine whether the repeated administration of methamphetamine influences phosphoinositide hydrolysis stimulated by the receptor agonists in mouse frontal cortical slices. Here, we describe the findings from experiments in which mice were sensitized with the chronic methamphetamine treatment regimen. Phosphoinositide hydrolysis was stimulated by histamine but not by norepinephrine which was reduced reversibly in frontal cortical slices.
Materials and methods Animals. Male ICR mice (5 weeks old on purchase; Japan SLC, Shizuoka, Japan) were housed in groups of 3–6 in a temperatureð22 1 °CÞ and humidity-controlled environment under a 12-h light/ dark cycle (lights on at 07:00 h) with free access to food and water except during the locomotor activity measurements. The animals were maintained in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals (NIH publication No. 85-23, revised 1985). The experimental protocols were approved by the Institutional Animal Research Committee and all possible efforts to reduce discomfort to the animals were made. Mice were allowed at least 7 days of habituation in this facility before any treatment began. Drugs and radioligands. Methamphetamine hydrochloride was obtained from Dainippon Pharmaceutical (Osaka, Japan). myo-[23 H]Inositol with PT6-271 stabilizer (specific activity ¼ 666 GBq/mmol) was obtained from Amersham Pharmacia Biotech (Buckinghamshire, UK). [a-32 P]dCTP (specific activity ¼ 111 TBq/mmol) was obtained from NEN Life Science Products (Boston, MA). Histamine dihydrochloride was from Wako Pure Chemicals (Osaka, Japan). ())-Arterenol bitartrate [())-norepinephrine] was from Sigma–Aldrich (St. Louis, MO). An RNA size marker was obtained from Toyobo (Osaka, Japan). Drug treatment. Mice were weighed (30–34 g on day 1) and randomly divided into two treatment groups: according to the protocol shown in Table 1, they were injected intraperitoneally (i.p.) with 0.1 ml/ 10 g volume of sterile saline or 1.0 mg/kg methamphetamine hydrochloride dissolved in saline once per day for six consecutive days (test days 0–5) and on the 9th and 11th or 31st days (test days 8 and 10 or 30, respectively). Measurement of locomotor activity. All mice were placed into a standard transparent rectangular rodent cage ð42 26 17 cmÞ in an apparatus with an infrared sensor that detects thermal radiation from animals (Supermex; Muromachi Kikai, Tokyo, Japan) in a quiet room for 30 min prior to injection. The 30-min habituation period was sufficient to allow the locomotor activity to stabilize based on preliminary experiments (data not shown). Then, mice received a drug injection (Table 1) and were immediately returned to the same test cage and were subjected to measurement of locomotor activity for 30 min. After
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measurements, mice were returned to their home cages, although some of them were subjected to the measurement of phosphoinositide hydrolysis (see below). All experiments were performed between 10:00 and 17:00. No mouse reduced body weight but either maintained or gained body weight during the methamphetamine injection period (data not shown). Measurement of phosphoinositide hydrolysis. Mice were decapitated and the brains were immediately removed. The frontal cortices were dissected and transverse slices (300 lm thickness) were cut using a McIlwain tissue chopper. The slices were prelabeled with myo-[23 H]inositol (740 kBq/ml) for 1 h in Krebs–Ringer bicarbonate buffer containing 10 mM lithium ion [110 mM NaCl, 5.5 mM KCl, 10 mM LiCl, 1.2 mM MgCl2 , 1.2 mM KH2 PO4 , 2.5 mM CaCl2 , 11 mM D -glucose, and 20 mM NaHCO3 , pH 7.4, equilibrated with O2 =CO2 (95:5)] and phosphoinositide hydrolysis was measured as described previously [12,13]. The incubation period of the slices with agonists (histamine, norepinephrine, or L -glutamate) was 1 h. When the effect of pretreatment with methamphetamine on agonist-induced phosphoinositide hydrolysis in vitro was investigated, slices labeled with myo-[2-3 H]inositol were pretreated with 10 lM methamphetamine for 30 min and then coincubated with methamphetamine and histamine for 1 h. The values were expressed as the percent total incorporated counts using the formula: ½3 Hinositol phosphates released (% total amount of ½3 Hinositol incorporated into the slices) ¼ ðdpm in inositol phosphates 100)/ (dpm in inositol phosphates + dpm in organic fraction) [12]. Expression of mRNA for histamine H1 receptor. Total RNA recovery from tissues was performed as described previously [14]. Total RNAs ð10 lg=laneÞ were fractionated using 2.2 M formaldehyde/1.5% agarose gel electrophoresis and transferred onto a nylon membrane (GeneScreen Plus, NEN Research Products, Boston, MA) with 20 SSC buffer at room temperature. Northern blotting was performed with a 428-bp DNA fragment of the mouse histamine H1 receptor cDNA [corresponding to the region between nucleotide 1126 and 1553 of the deposited sequence data (GenBank Accession No. D50095)] and a 1013-bp DNA fragment of the mouse glyceraldehyde 3-phosphate dehydrogenase [G3PDH, corresponding to the region between nucleotide 39 and 1051 of the deposited sequence data (GenBank Accession No. M32599)] labeled with [a-32 P]dCTP by the random priming method. The hybridization membranes were exposed to an X-ray film with an intensifying screen at )80 °C for 25 days for histamine H1 receptor or for 7 h for G3PDH, respectively. The developed autoradiograms were analyzed using an Apple Macintosh computer-based image analysis system with the ATTO Densitograph software program (version 4.0, ATTO, Tokyo, Japan). Quantitation of histamine H1 receptor mRNA expression was shown as the percentage density of the automatically defined hybridization area compared with that on day 1. Variation in total RNA recoveries between samples was normalized by assessments of hybridization to G3PDH mRNA using the same blots. The expression level of G3PDH mRNA was chosen as a control because of its ubiquitous expression throughout the mouse brain [15]. Statistical analyses. Statistical analyses were performed using a repeated measure analysis of variance (ANOVA) followed by a FisherÕs protected least-significant difference (PLSD) post hoc comparison or paired t test as indicated. Differences were considered significant if the probability of error was less than 0.05. All values are reported as means SEM of n experiments.
Table 1 Experimental protocol Test day
0
1
2
3
4
5
8
10 or 30
Group A Group B
SAL SAL
SAL METH
SAL METH
SAL METH
SAL METH
SAL METH
SAL SAL
METH METH
Drug solutions were prepared daily and administrated by i.p. injection in a volume of 0.1 ml/10 g of body weight. SAL, saline; METH, methamphetamine (1.0 mg/kg).
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Results Locomotor activities Treatment of 1.0 mg/kg methamphetamine induced significant locomotor activities in mice [Fig. 1, Group A vs. Group B; P < 0:0001, F ð6; 182Þ ¼ 22:430]. In Group A mice, an increased locomotor activity was observed after a single injection of methamphetamine (1.0 mg/kg, i.p.) on days 10 and 30 [P ¼ 0:0164, F ð6; 91Þ ¼ 2:789]. The same locomotor activity as that of mice in Group A on day 10 was observed in Group B mice on test day 1. Except on test day 1 vs. 8 and test day 3 vs. 30, a significant hyperlocomotion was observed after the administration of methamphetamine in Group B mice [P < 0:0001, F ð6; 91Þ ¼ 59:848]. On test day 8, mice in Group B that received saline showed a conditioned locomotion, but the increased locomotor activity returned to the basal level within 30 min (data not shown). Effect of chronic methamphetamine administration on agonist-induced phosphoinositide hydrolysis in mouse frontal cortex The results presented in Fig. 2 demonstrate that phosphoinositide hydrolysis activity was induced by the submaximal (0.1 mM) and maximal (1.0 mM) concentrations of histamine [10]. Significant differences were observed in the interaction between the groups and test days with the dose of both 0.1 and 1.0 mM histamine [P ¼ 0:0077, F ð3; 64Þ ¼ 4:458 and P ¼ 0:0010, F ð3; 64Þ ¼ 6:390, respectively], while there were no significant differences without histamine stimulation [P ¼ 0:2886,
Fig. 1. Locomotor activity in mice after i.p. injection of 0.1 ml/10 g saline or 1.0 mg/kg methamphetamine. Locomotor activity was monitored for 30 min immediately after each injection. The means are shown with bars for SEM ðn ¼ 14Þ.
Fig. 2. Histamine-stimulated phosphoinositide hydrolysis in mouse frontal cortical slices after methamphetamine treatment in vivo. The ½3 Hinositollabeled slices were exposed to histamine at the indicated concentrations for 1 h. The ½3 Hinositol phosphates (inositol monophosphate + inositol bisphosphate + inositol trisphosphate) were eluted with the buffer (0.1 M formic acid/1 M ammonium formate) from a column containing AG1-X8 anion exchange resin and its radioactivity was measured by a liquid scintillation counter. The means are shown with bars for SEM ðn ¼ 9Þ. P < 0:001, compared with test day 10 of Group A (t test). yy P < 0:01, compared with test day 10 of Group B (one-way ANOVA followed by FisherÕs PLSD).
F ð3; 64Þ ¼ 1:290]. In Group B, there were significant changes in both 0.1 and 1.0 mM histamine [P ¼ 0:0012, F ð3; 32Þ ¼ 7:285 and P ¼ 0:0006, F ð3; 32Þ ¼ 8:332, respectively]. FisherÕs PLSD revealed that phosphoinositide hydrolysis activity was reduced significantly in mouse frontal cortical slices on test day 10 compared with test days 1 and 3 after chronic methamphetamine treatment regimen (Group B), although the reduction was significantly recovered to the normal level in Group B mice on test day 30. On the other hand, there was no significant change in phosphoinositide hydrolysis induced by the submaximal and maximal concentrations of histamine in the frontal cortices of mice in Group A [P ¼ 0:1644, F ð3; 32Þ ¼ 1:854 and P ¼ 0:3290, F ð3; 32Þ ¼ 1:206, respectively]. There was a significant difference between Groups A and B on test day10 with both submaximal and maximal concentrations of histamine by the paired t test [P ¼ 0:0007, t ¼ 5:319, and DF ¼ 8 and P ¼ 0:0006, t ¼ 5:400, and DF ¼ 8, respectively]. To contrast with it, as shown in Fig. 3, there was no significant change in phosphoinositide hydrolysis induced by submaximal ð10 lMÞ and maximal (0.1 mM) concentrations of norepinephrine [10] in frontal cortices of mice in Group A or B at day 10 of the chronic methamphetamine treatment regimen [P ¼ 0:3394, F ð2; 48Þ ¼ 1:118]. Phosphoinositide
J. Kitanaka et al. / Biochemical and Biophysical Research Communications 300 (2003) 932–937
Fig. 3. Norepinephrine-stimulated phosphoinositide hydrolysis in mouse frontal cortical slices after methamphetamine treatment in vivo. The ½3 Hinositol-labeled slices were exposed to norepinephrine at the indicated concentrations for 1 h. The means are shown with bars for SEM ðn ¼ 9Þ.
hydrolysis induced by L -glutamate (0.1–0.5 mM) showed no significant changes in Group A or B (data not shown). Effect of the pretreatment of the slices with methamphetamine in vitro on histamine-stimulated phosphoinositide hydrolysis When the frontal cortical slices prepared from na€ıve mice were pretreated with 10 lM methamphetamine for
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Fig. 5. Histamine H1 receptor (H1R) mRNA expression level. Quantitation was shown as the percentage density of the automatically defined hybridization area compared with that of test day 1. Variation in total RNA recoveries between samples was normalized by assessments of hybridization to G3PDH mRNA. The means are shown with bars for SEM ðn ¼ 4Þ.
30 min in vitro and then subjected to stimulation with methamphetamine ð10 lMÞ and histamine (1.0 mM) for the next 1 h, no significant change in phosphoinositide hydrolysis was observed compared with controls (Fig. 4) [P ¼ 0:6691, F ð1; 76Þ ¼ 0:186]. Expression level of mRNA for histamine H1 receptor in the frontal cortex in mice after chronic methamphetamine treatment The single bands of mouse histamine H1 receptor mRNA and G3PDH mRNA were detected with a size of 3.0 and 1.6 kb, respectively, estimated by comparison with an RNA size marker (data not shown). No significant change in the expression level of histamine H1 receptor mRNA was observed in the frontal cortex during repeated administration of methamphetamine within the test days examined [F ð2; 9Þ ¼ 0:591, P ¼ 0:5831] (Fig. 5). Discussion
Fig. 4. Phosphoinositide hydrolysis in mouse frontal cortical slices after methamphetamine treatment in vitro. The ½3 Hinositol-labeled slices were pretreated with 10 lM methamphetamine for 30 min and then exposed to 10 lM methamphetamine and 1 mM histamine for 1 h. The means are shown with bars for SEM ðn ¼ 20Þ.
Alterations in the neural gene expressions and subsequent protein expressions following chronic treatment with psychostimulants are important subcellular events towards behavioral sensitization [9,16–18]. In addition to these observations, treatment with cycloheximide, a protein synthesis inhibitor, suppresses behavioral sensitization to methamphetamine in mice [19], suggesting that the de novo synthesis and/or the turnover of the proteins are essential for behavioral sensitization. At the neural adaptation levels, dopamine signal trans-
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duction and its modulation of glutamatergic synaptic neurotransmission in the nucleus accumbens were altered as a consequence of the chronic psychostimulant administration sufficient to elicit the behavioral sensitization [20,21]. These neural adaptations are proposed to contribute importantly to the expression of behavioral sensitization. More recently, Trantham et al. [22] reported the lack of membrane bistability normally present in prefrontal cortical neurons in rats after repeated cocaine administration, suggesting the enduring alteration of the neuronal activity in the brain region outside the basal ganglia following the repeated psychostimulant administration. However, the reasons why the behavioral sensitization to psychostimulants persists for a long period have not been fully elucidated in terms of the neuroadaptations. In the present study, it was hypothesized that in vivo pretreatment with repeated methamphetamine would alter the agoniststimulated phosphoinositide hydrolysis in mouse frontal cortical slices because of the existing evidence indicating the neural circuits between the basal ganglia and forebrain [3]. To examine whether the present procedure (Table 1) produced a long-lasting behavioral sensitization, mice received a single injection of methamphetamine 5–25 days after the last challenge of the initial chronic treatment regimen. As shown in Fig. 1, mice pretreated with repeated methamphetamine (Group B) showed a much greater locomotor response to methamphetamine than did saline-pretreated mice (Group A), indicating that the initial 5-day exposure to methamphetamine caused the behavioral sensitization that lasted for more than 3 weeks. On test day 8, mice in Group B showed a greater locomotor response to saline than did mice in Group A, suggesting that our experimental procedure produced a conditioned locomotion similar to that pointed out by Crombag et al. [23]. In the present study, we did not focus on the mice which showed conditioned locomotion because the conditioned locomotion was still smaller than the locomotor response to methamphetamine shown by Group B mice on test day 3 which did not show any reduction of histamine signal transduction (see below). Under our treatment regimen, we next examined whether chronic methamphetamine would alter the agonist-stimulated phosphoinositide hydrolysis. The most striking finding was the reduction of histamine-stimulated phosphoinositide hydrolysis in mouse frontal cortex following the repeated methamphetamine treatment (Fig. 2). The reduction was histamine-specific: neither norepinephrine- (Fig. 3) nor L -glutamate- (data not shown) stimulated phosphoinositide hydrolysis changed after the repeated administration of methamphetamine. The significant effect of repeated methamphetamine was observed 5 days after the final injection of the chronic treatment period (test day 10 in Fig. 2), suggesting that this is a long-lasting consequence of methamphetamine
administration. Although there is a significant difference between the degree of reduction of histamine-stimulated phosphoinositide hydrolysis on test days 10 and 30 (Fig. 2), behavioral sensitization was detected on both those days (Fig. 1). As shown in Fig. 1, the magnitudes of behavioral sensitization on test days 3 (activity count ¼ 3581 134) and 30 ð3773 463Þ are similar, and this is correlated with the degree of histamine (0.1 mM)-stimulated phosphoinositide hydrolysis on those two test days (% hydrolysis ¼ 1:23 0:31 and 1:24 0:17, respectively), suggesting a correlation between the degree of phosphoinositide hydrolysis reduction and behavioral sensitization. The reduction occurred without any change in the expression level of histamine H1 receptor mRNA (Fig. 5) or GNB1 mRNA (N. Kitanaka et al., unpublished data), suggesting that no longlasting alteration in these gene expressions participated in the reduction of histamine signal transduction. The present findings (Fig. 5) also suggested that there was no neurotoxicity of the related neurons involved in histamine signal transduction. Consistent with this was the finding that the reduction of histamine-induced phosphoinositide hydrolysis on test day 10 recovered after a 25-day drug-free period (test day 30 in Fig. 2). Although there is a possibility that the chemical interaction between histamine and methamphetamine distributing into the brain may be responsible for the significant reduction of histamine-stimulated phosphoinositide hydrolysis through histamine H1 receptors, it might be excluded because the direct application of the slices to a pharmacologically effective concentration of methamphetamine in vitro (10 lM; [24,25]) did not alter the histamine signal transduction (Fig. 4). Another possible molecular mechanism underlying the reduction of histamine-induced signal transduction might involve alterations in the functional interaction of the related proteins such as a coupling of histamine H1 receptors and G proteins. Further studies are needed to test this possibility. Since a distribution of efferent projections of histaminergic nerve fibers originating from the tuberomammillary nucleus was found throughout the rat cerebral cortex [26], brain histamine is assumed to be a neuromodulator [27]. It is also supported by evidence of the existence of mRNA for histamine N-methyltransferase, a primary enzyme responsible for histamine metabolism, in the mouse brain including the cerebral cortex [15]. With respect to the pharmacological effect of histamine on locomotor activity, there is evidence suggesting that repeated treatment with methamphetamine (3 mg/ kg, i.p.) with L -histidine (750 mg/kg, i.p.), a precursor of histamine, which elevates the brain histamine concentration, inhibited the methamphetamine-induced stereotyped behavior in rats [28]. They also reported that blockade of histamine signal transduction by treatment of the rats with a-fluoromethylhistidine, a histidine decarboxylase inhibitor, or with histamine H1 =H2 receptor
J. Kitanaka et al. / Biochemical and Biophysical Research Communications 300 (2003) 932–937
antagonists enhanced methamphetamine-induced stereotyped behavior, suggesting that histamine signal transduction in the brain modulates negatively an augmentation of locomotor and stereotyped responses to psychostimulants. The present data as well as the previous findings [28] strongly suggest the physiological role of brain histamine in the establishment of behavioral sensitization. The involvement of phosphoinositide hydrolysis pathway in drug addiction is still poorly understood. Thus, the present study is an important addition to the existing body of evidence that implicates other molecular cascade in drug addiction. Although the molecular mechanisms underlying the reduction of histamine-stimulated phosphoinositide hydrolysis in the mouse frontal cortex as a consequence of methamphetamine treatment in vivo are not clear, it is suggested that the phenomenon is probably one of a number of neuroadaptations in the frontal cortex contributing to behavioral sensitization.
Acknowledgments This research was supported in part by Grant-in-Aid for scientific research (No. 14771345) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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Chronic methamphetamine administration reduces histamine-stimulated phosphoinositide hydrolysis in mouse frontal cortex Junichi Kitanaka,* Nobue Kitanaka, and Motohiko Takemura Department of Pharmacology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan Received 11 December 2002
Abstract In the present study, it was hypothesized that in vivo pretreatment with repeated methamphetamine would alter the agoniststimulated phosphoinositide hydrolysis in mouse frontal cortical slices. Male ICR mice that received the methamphetamine injection (1.0 mg/kg, intraperitoneally) once a day for five consecutive days showed behavioral sensitization to the same dose of methamphetamine 5 days after the last injection of the initial chronic treatment regimen (test day 10). On test day 10, the reduction of histamine (0.1–1.0 mM)-stimulated phosphoinositide hydrolysis in the mouse frontal cortex was observed. The reduction was specific to histamine, but not to norepinephrine (10 lM–0.1 mM) or L -glutamate (0.1–0.5 mM). The reduction occurred without any change in the expression level of histamine H1 receptor mRNA. The reduction recovered 25 days after the last injection of the initial chronic treatment regimen (test day 30). The direct application to the slices of a pharmacologically effective concentration of methamphetamine in vitro ð10 lMÞ did not alter the histamine signal transduction. The present results suggest that the reduction is probably one of neuroadaptations in the frontal cortex contributing to behavioral sensitization. Ó 2002 Elsevier Science (USA). All rights reserved. Keywords: Methamphetamine; Behavioral sensitization; Chronic treatment; Histamine; Phosphoinositide hydrolysis; Frontal cortex; Mice
Chronic administration of psychostimulants, such as amphetamines, cocaine, and methylphenidate, in rodents induces behavioral sensitization (or reverse tolerance) and long-lasting behavioral manifestations [1–3]. Since this phenomenon is assumed to be one of the initial biological states towards drug-seeking behavior, a major feature of drug addiction, it is important to reveal the molecular basis of the behavioral sensitization for a better understanding of how drug abuse addicts humans [2,4]. Once the behavioral sensitization is established, an augmentation of the locomotor-stimulating effect of psychostimulants persists for weeks or even months after a final challenge of the drug [1]. In addition to the enhanced release of dopamine in the striatum [5,6], functional adaptations of certain proteins in the brain contribute to the behavioral sensitization (for a review, see [4,7,8]). For example, alterations of the expression of * Corresponding author. Fax: +81-798-45-6332. E-mail address: [email protected] (J. Kitanaka).
some proteins including the heterotrimeric GTP-binding protein b1 subunit gene (GNB1) essential for the intracellular signal transduction mechanisms are followed by behavioral sensitization [9]. In view of these observations, there is a possibility that an enduring consequence of the changes in the neurotransmitter signal would result in the establishment of behavioral sensitization. Therefore, it is of interest to examine the alterations of the activity of the intracellular signal transduction mechanisms, such as phosphoinositide hydrolysis by phospholipase C and cyclic AMP formation by adenylate cyclase, in the frontal cortex under adaptative states for repeated drug administration because of evidence of the direct neural interaction between the basal ganglia and forebrain [3]. Characterization of receptor-mediated signal transduction was performed in rat and mouse cerebral cortices. Of the receptor agonists tested, norepinephrine, carbachol, and histamine produced large responses in terms of phosphoinositide hydrolysis via an
0006-291X/02/$ - see front matter Ó 2002 Elsevier Science (USA). All rights reserved. doi:10.1016/S0006-291X(02)02948-0
J. Kitanaka et al. / Biochemical and Biophysical Research Communications 300 (2003) 932–937
a1 -adrenergic, muscarinic acetylcholine, and histamine H1 receptor-mediated manner, respectively [10,11]. In line with these observations, the present study was designed to examine whether the repeated administration of methamphetamine influences phosphoinositide hydrolysis stimulated by the receptor agonists in mouse frontal cortical slices. Here, we describe the findings from experiments in which mice were sensitized with the chronic methamphetamine treatment regimen. Phosphoinositide hydrolysis was stimulated by histamine but not by norepinephrine which was reduced reversibly in frontal cortical slices.
Materials and methods Animals. Male ICR mice (5 weeks old on purchase; Japan SLC, Shizuoka, Japan) were housed in groups of 3–6 in a temperatureð22 1 °CÞ and humidity-controlled environment under a 12-h light/ dark cycle (lights on at 07:00 h) with free access to food and water except during the locomotor activity measurements. The animals were maintained in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals (NIH publication No. 85-23, revised 1985). The experimental protocols were approved by the Institutional Animal Research Committee and all possible efforts to reduce discomfort to the animals were made. Mice were allowed at least 7 days of habituation in this facility before any treatment began. Drugs and radioligands. Methamphetamine hydrochloride was obtained from Dainippon Pharmaceutical (Osaka, Japan). myo-[23 H]Inositol with PT6-271 stabilizer (specific activity ¼ 666 GBq/mmol) was obtained from Amersham Pharmacia Biotech (Buckinghamshire, UK). [a-32 P]dCTP (specific activity ¼ 111 TBq/mmol) was obtained from NEN Life Science Products (Boston, MA). Histamine dihydrochloride was from Wako Pure Chemicals (Osaka, Japan). ())-Arterenol bitartrate [())-norepinephrine] was from Sigma–Aldrich (St. Louis, MO). An RNA size marker was obtained from Toyobo (Osaka, Japan). Drug treatment. Mice were weighed (30–34 g on day 1) and randomly divided into two treatment groups: according to the protocol shown in Table 1, they were injected intraperitoneally (i.p.) with 0.1 ml/ 10 g volume of sterile saline or 1.0 mg/kg methamphetamine hydrochloride dissolved in saline once per day for six consecutive days (test days 0–5) and on the 9th and 11th or 31st days (test days 8 and 10 or 30, respectively). Measurement of locomotor activity. All mice were placed into a standard transparent rectangular rodent cage ð42 26 17 cmÞ in an apparatus with an infrared sensor that detects thermal radiation from animals (Supermex; Muromachi Kikai, Tokyo, Japan) in a quiet room for 30 min prior to injection. The 30-min habituation period was sufficient to allow the locomotor activity to stabilize based on preliminary experiments (data not shown). Then, mice received a drug injection (Table 1) and were immediately returned to the same test cage and were subjected to measurement of locomotor activity for 30 min. After
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measurements, mice were returned to their home cages, although some of them were subjected to the measurement of phosphoinositide hydrolysis (see below). All experiments were performed between 10:00 and 17:00. No mouse reduced body weight but either maintained or gained body weight during the methamphetamine injection period (data not shown). Measurement of phosphoinositide hydrolysis. Mice were decapitated and the brains were immediately removed. The frontal cortices were dissected and transverse slices (300 lm thickness) were cut using a McIlwain tissue chopper. The slices were prelabeled with myo-[23 H]inositol (740 kBq/ml) for 1 h in Krebs–Ringer bicarbonate buffer containing 10 mM lithium ion [110 mM NaCl, 5.5 mM KCl, 10 mM LiCl, 1.2 mM MgCl2 , 1.2 mM KH2 PO4 , 2.5 mM CaCl2 , 11 mM D -glucose, and 20 mM NaHCO3 , pH 7.4, equilibrated with O2 =CO2 (95:5)] and phosphoinositide hydrolysis was measured as described previously [12,13]. The incubation period of the slices with agonists (histamine, norepinephrine, or L -glutamate) was 1 h. When the effect of pretreatment with methamphetamine on agonist-induced phosphoinositide hydrolysis in vitro was investigated, slices labeled with myo-[2-3 H]inositol were pretreated with 10 lM methamphetamine for 30 min and then coincubated with methamphetamine and histamine for 1 h. The values were expressed as the percent total incorporated counts using the formula: ½3 Hinositol phosphates released (% total amount of ½3 Hinositol incorporated into the slices) ¼ ðdpm in inositol phosphates 100)/ (dpm in inositol phosphates + dpm in organic fraction) [12]. Expression of mRNA for histamine H1 receptor. Total RNA recovery from tissues was performed as described previously [14]. Total RNAs ð10 lg=laneÞ were fractionated using 2.2 M formaldehyde/1.5% agarose gel electrophoresis and transferred onto a nylon membrane (GeneScreen Plus, NEN Research Products, Boston, MA) with 20 SSC buffer at room temperature. Northern blotting was performed with a 428-bp DNA fragment of the mouse histamine H1 receptor cDNA [corresponding to the region between nucleotide 1126 and 1553 of the deposited sequence data (GenBank Accession No. D50095)] and a 1013-bp DNA fragment of the mouse glyceraldehyde 3-phosphate dehydrogenase [G3PDH, corresponding to the region between nucleotide 39 and 1051 of the deposited sequence data (GenBank Accession No. M32599)] labeled with [a-32 P]dCTP by the random priming method. The hybridization membranes were exposed to an X-ray film with an intensifying screen at )80 °C for 25 days for histamine H1 receptor or for 7 h for G3PDH, respectively. The developed autoradiograms were analyzed using an Apple Macintosh computer-based image analysis system with the ATTO Densitograph software program (version 4.0, ATTO, Tokyo, Japan). Quantitation of histamine H1 receptor mRNA expression was shown as the percentage density of the automatically defined hybridization area compared with that on day 1. Variation in total RNA recoveries between samples was normalized by assessments of hybridization to G3PDH mRNA using the same blots. The expression level of G3PDH mRNA was chosen as a control because of its ubiquitous expression throughout the mouse brain [15]. Statistical analyses. Statistical analyses were performed using a repeated measure analysis of variance (ANOVA) followed by a FisherÕs protected least-significant difference (PLSD) post hoc comparison or paired t test as indicated. Differences were considered significant if the probability of error was less than 0.05. All values are reported as means SEM of n experiments.
Table 1 Experimental protocol Test day
0
1
2
3
4
5
8
10 or 30
Group A Group B
SAL SAL
SAL METH
SAL METH
SAL METH
SAL METH
SAL METH
SAL SAL
METH METH
Drug solutions were prepared daily and administrated by i.p. injection in a volume of 0.1 ml/10 g of body weight. SAL, saline; METH, methamphetamine (1.0 mg/kg).
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Results Locomotor activities Treatment of 1.0 mg/kg methamphetamine induced significant locomotor activities in mice [Fig. 1, Group A vs. Group B; P < 0:0001, F ð6; 182Þ ¼ 22:430]. In Group A mice, an increased locomotor activity was observed after a single injection of methamphetamine (1.0 mg/kg, i.p.) on days 10 and 30 [P ¼ 0:0164, F ð6; 91Þ ¼ 2:789]. The same locomotor activity as that of mice in Group A on day 10 was observed in Group B mice on test day 1. Except on test day 1 vs. 8 and test day 3 vs. 30, a significant hyperlocomotion was observed after the administration of methamphetamine in Group B mice [P < 0:0001, F ð6; 91Þ ¼ 59:848]. On test day 8, mice in Group B that received saline showed a conditioned locomotion, but the increased locomotor activity returned to the basal level within 30 min (data not shown). Effect of chronic methamphetamine administration on agonist-induced phosphoinositide hydrolysis in mouse frontal cortex The results presented in Fig. 2 demonstrate that phosphoinositide hydrolysis activity was induced by the submaximal (0.1 mM) and maximal (1.0 mM) concentrations of histamine [10]. Significant differences were observed in the interaction between the groups and test days with the dose of both 0.1 and 1.0 mM histamine [P ¼ 0:0077, F ð3; 64Þ ¼ 4:458 and P ¼ 0:0010, F ð3; 64Þ ¼ 6:390, respectively], while there were no significant differences without histamine stimulation [P ¼ 0:2886,
Fig. 1. Locomotor activity in mice after i.p. injection of 0.1 ml/10 g saline or 1.0 mg/kg methamphetamine. Locomotor activity was monitored for 30 min immediately after each injection. The means are shown with bars for SEM ðn ¼ 14Þ.
Fig. 2. Histamine-stimulated phosphoinositide hydrolysis in mouse frontal cortical slices after methamphetamine treatment in vivo. The ½3 Hinositollabeled slices were exposed to histamine at the indicated concentrations for 1 h. The ½3 Hinositol phosphates (inositol monophosphate + inositol bisphosphate + inositol trisphosphate) were eluted with the buffer (0.1 M formic acid/1 M ammonium formate) from a column containing AG1-X8 anion exchange resin and its radioactivity was measured by a liquid scintillation counter. The means are shown with bars for SEM ðn ¼ 9Þ. P < 0:001, compared with test day 10 of Group A (t test). yy P < 0:01, compared with test day 10 of Group B (one-way ANOVA followed by FisherÕs PLSD).
F ð3; 64Þ ¼ 1:290]. In Group B, there were significant changes in both 0.1 and 1.0 mM histamine [P ¼ 0:0012, F ð3; 32Þ ¼ 7:285 and P ¼ 0:0006, F ð3; 32Þ ¼ 8:332, respectively]. FisherÕs PLSD revealed that phosphoinositide hydrolysis activity was reduced significantly in mouse frontal cortical slices on test day 10 compared with test days 1 and 3 after chronic methamphetamine treatment regimen (Group B), although the reduction was significantly recovered to the normal level in Group B mice on test day 30. On the other hand, there was no significant change in phosphoinositide hydrolysis induced by the submaximal and maximal concentrations of histamine in the frontal cortices of mice in Group A [P ¼ 0:1644, F ð3; 32Þ ¼ 1:854 and P ¼ 0:3290, F ð3; 32Þ ¼ 1:206, respectively]. There was a significant difference between Groups A and B on test day10 with both submaximal and maximal concentrations of histamine by the paired t test [P ¼ 0:0007, t ¼ 5:319, and DF ¼ 8 and P ¼ 0:0006, t ¼ 5:400, and DF ¼ 8, respectively]. To contrast with it, as shown in Fig. 3, there was no significant change in phosphoinositide hydrolysis induced by submaximal ð10 lMÞ and maximal (0.1 mM) concentrations of norepinephrine [10] in frontal cortices of mice in Group A or B at day 10 of the chronic methamphetamine treatment regimen [P ¼ 0:3394, F ð2; 48Þ ¼ 1:118]. Phosphoinositide
J. Kitanaka et al. / Biochemical and Biophysical Research Communications 300 (2003) 932–937
Fig. 3. Norepinephrine-stimulated phosphoinositide hydrolysis in mouse frontal cortical slices after methamphetamine treatment in vivo. The ½3 Hinositol-labeled slices were exposed to norepinephrine at the indicated concentrations for 1 h. The means are shown with bars for SEM ðn ¼ 9Þ.
hydrolysis induced by L -glutamate (0.1–0.5 mM) showed no significant changes in Group A or B (data not shown). Effect of the pretreatment of the slices with methamphetamine in vitro on histamine-stimulated phosphoinositide hydrolysis When the frontal cortical slices prepared from na€ıve mice were pretreated with 10 lM methamphetamine for
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Fig. 5. Histamine H1 receptor (H1R) mRNA expression level. Quantitation was shown as the percentage density of the automatically defined hybridization area compared with that of test day 1. Variation in total RNA recoveries between samples was normalized by assessments of hybridization to G3PDH mRNA. The means are shown with bars for SEM ðn ¼ 4Þ.
30 min in vitro and then subjected to stimulation with methamphetamine ð10 lMÞ and histamine (1.0 mM) for the next 1 h, no significant change in phosphoinositide hydrolysis was observed compared with controls (Fig. 4) [P ¼ 0:6691, F ð1; 76Þ ¼ 0:186]. Expression level of mRNA for histamine H1 receptor in the frontal cortex in mice after chronic methamphetamine treatment The single bands of mouse histamine H1 receptor mRNA and G3PDH mRNA were detected with a size of 3.0 and 1.6 kb, respectively, estimated by comparison with an RNA size marker (data not shown). No significant change in the expression level of histamine H1 receptor mRNA was observed in the frontal cortex during repeated administration of methamphetamine within the test days examined [F ð2; 9Þ ¼ 0:591, P ¼ 0:5831] (Fig. 5). Discussion
Fig. 4. Phosphoinositide hydrolysis in mouse frontal cortical slices after methamphetamine treatment in vitro. The ½3 Hinositol-labeled slices were pretreated with 10 lM methamphetamine for 30 min and then exposed to 10 lM methamphetamine and 1 mM histamine for 1 h. The means are shown with bars for SEM ðn ¼ 20Þ.
Alterations in the neural gene expressions and subsequent protein expressions following chronic treatment with psychostimulants are important subcellular events towards behavioral sensitization [9,16–18]. In addition to these observations, treatment with cycloheximide, a protein synthesis inhibitor, suppresses behavioral sensitization to methamphetamine in mice [19], suggesting that the de novo synthesis and/or the turnover of the proteins are essential for behavioral sensitization. At the neural adaptation levels, dopamine signal trans-
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duction and its modulation of glutamatergic synaptic neurotransmission in the nucleus accumbens were altered as a consequence of the chronic psychostimulant administration sufficient to elicit the behavioral sensitization [20,21]. These neural adaptations are proposed to contribute importantly to the expression of behavioral sensitization. More recently, Trantham et al. [22] reported the lack of membrane bistability normally present in prefrontal cortical neurons in rats after repeated cocaine administration, suggesting the enduring alteration of the neuronal activity in the brain region outside the basal ganglia following the repeated psychostimulant administration. However, the reasons why the behavioral sensitization to psychostimulants persists for a long period have not been fully elucidated in terms of the neuroadaptations. In the present study, it was hypothesized that in vivo pretreatment with repeated methamphetamine would alter the agoniststimulated phosphoinositide hydrolysis in mouse frontal cortical slices because of the existing evidence indicating the neural circuits between the basal ganglia and forebrain [3]. To examine whether the present procedure (Table 1) produced a long-lasting behavioral sensitization, mice received a single injection of methamphetamine 5–25 days after the last challenge of the initial chronic treatment regimen. As shown in Fig. 1, mice pretreated with repeated methamphetamine (Group B) showed a much greater locomotor response to methamphetamine than did saline-pretreated mice (Group A), indicating that the initial 5-day exposure to methamphetamine caused the behavioral sensitization that lasted for more than 3 weeks. On test day 8, mice in Group B showed a greater locomotor response to saline than did mice in Group A, suggesting that our experimental procedure produced a conditioned locomotion similar to that pointed out by Crombag et al. [23]. In the present study, we did not focus on the mice which showed conditioned locomotion because the conditioned locomotion was still smaller than the locomotor response to methamphetamine shown by Group B mice on test day 3 which did not show any reduction of histamine signal transduction (see below). Under our treatment regimen, we next examined whether chronic methamphetamine would alter the agonist-stimulated phosphoinositide hydrolysis. The most striking finding was the reduction of histamine-stimulated phosphoinositide hydrolysis in mouse frontal cortex following the repeated methamphetamine treatment (Fig. 2). The reduction was histamine-specific: neither norepinephrine- (Fig. 3) nor L -glutamate- (data not shown) stimulated phosphoinositide hydrolysis changed after the repeated administration of methamphetamine. The significant effect of repeated methamphetamine was observed 5 days after the final injection of the chronic treatment period (test day 10 in Fig. 2), suggesting that this is a long-lasting consequence of methamphetamine
administration. Although there is a significant difference between the degree of reduction of histamine-stimulated phosphoinositide hydrolysis on test days 10 and 30 (Fig. 2), behavioral sensitization was detected on both those days (Fig. 1). As shown in Fig. 1, the magnitudes of behavioral sensitization on test days 3 (activity count ¼ 3581 134) and 30 ð3773 463Þ are similar, and this is correlated with the degree of histamine (0.1 mM)-stimulated phosphoinositide hydrolysis on those two test days (% hydrolysis ¼ 1:23 0:31 and 1:24 0:17, respectively), suggesting a correlation between the degree of phosphoinositide hydrolysis reduction and behavioral sensitization. The reduction occurred without any change in the expression level of histamine H1 receptor mRNA (Fig. 5) or GNB1 mRNA (N. Kitanaka et al., unpublished data), suggesting that no longlasting alteration in these gene expressions participated in the reduction of histamine signal transduction. The present findings (Fig. 5) also suggested that there was no neurotoxicity of the related neurons involved in histamine signal transduction. Consistent with this was the finding that the reduction of histamine-induced phosphoinositide hydrolysis on test day 10 recovered after a 25-day drug-free period (test day 30 in Fig. 2). Although there is a possibility that the chemical interaction between histamine and methamphetamine distributing into the brain may be responsible for the significant reduction of histamine-stimulated phosphoinositide hydrolysis through histamine H1 receptors, it might be excluded because the direct application of the slices to a pharmacologically effective concentration of methamphetamine in vitro (10 lM; [24,25]) did not alter the histamine signal transduction (Fig. 4). Another possible molecular mechanism underlying the reduction of histamine-induced signal transduction might involve alterations in the functional interaction of the related proteins such as a coupling of histamine H1 receptors and G proteins. Further studies are needed to test this possibility. Since a distribution of efferent projections of histaminergic nerve fibers originating from the tuberomammillary nucleus was found throughout the rat cerebral cortex [26], brain histamine is assumed to be a neuromodulator [27]. It is also supported by evidence of the existence of mRNA for histamine N-methyltransferase, a primary enzyme responsible for histamine metabolism, in the mouse brain including the cerebral cortex [15]. With respect to the pharmacological effect of histamine on locomotor activity, there is evidence suggesting that repeated treatment with methamphetamine (3 mg/ kg, i.p.) with L -histidine (750 mg/kg, i.p.), a precursor of histamine, which elevates the brain histamine concentration, inhibited the methamphetamine-induced stereotyped behavior in rats [28]. They also reported that blockade of histamine signal transduction by treatment of the rats with a-fluoromethylhistidine, a histidine decarboxylase inhibitor, or with histamine H1 =H2 receptor
J. Kitanaka et al. / Biochemical and Biophysical Research Communications 300 (2003) 932–937
antagonists enhanced methamphetamine-induced stereotyped behavior, suggesting that histamine signal transduction in the brain modulates negatively an augmentation of locomotor and stereotyped responses to psychostimulants. The present data as well as the previous findings [28] strongly suggest the physiological role of brain histamine in the establishment of behavioral sensitization. The involvement of phosphoinositide hydrolysis pathway in drug addiction is still poorly understood. Thus, the present study is an important addition to the existing body of evidence that implicates other molecular cascade in drug addiction. Although the molecular mechanisms underlying the reduction of histamine-stimulated phosphoinositide hydrolysis in the mouse frontal cortex as a consequence of methamphetamine treatment in vivo are not clear, it is suggested that the phenomenon is probably one of a number of neuroadaptations in the frontal cortex contributing to behavioral sensitization.
Acknowledgments This research was supported in part by Grant-in-Aid for scientific research (No. 14771345) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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