1Drug TargeT InsIghTs 2016:10 Brain Histamine N-Methyltransferase As a Possible Target of Treatment for Methamphetamine Overdose Junichi Kitanaka1, nobue Kitanaka1, F. scott hall2, george r. uhl3 and Motohiko Takemura1 1Department of Pharmacology, Hyogo College of Medicine, Hyogo, Japan. 2Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA. 3New Mexico VA Healthcare System/BRINM, Albuquerque, NM, USA. A BSTR ACT: Stereotypical behaviors induced by methamphetamine (METH) overdose are one of the overt symptoms of METH abuse, which can be easily assessed in animal models. Currently, there is no successful treatment for METH overdose. There is increasing evidence that elevated levels of brain histamine can attenuate METH-induced behavioral abnormalities, which might therefore constitute a novel therapeutic treatment for METH abuse and METH overdose. In mammals, histamine N-methyltransferase (HMT) is the sole enzyme responsible for degrading histamine in the brain. Metoprine, one of the most potent HMT inhibitors, can cross the blood–brain barrier and increase brain histamine levels by inhibiting HMT. Consequently, this compound can be a candidate for a prototype of drugs for the treatment of METH overdose. K E Y WOR DS: methamphetamine, overdose, Stereotyped behavior, histamine N-methyltransferase, brain histaminergic system, metoprine CITATION: Kitanaka et al. Brain histamine N-Methyltransferase as a Possible Target of Treatment for Methamphetamine Overdose. Drug Target Insights 2016:10 1–7 doi:10.4137/DTI.s38342. TYPE: review RECEIVED: December 23, 2015. RESUBMITTED: January 25, 2016. ACCEPTED FOR PUBLICATION: January 27, 2016. ACADEMIC EDITOR: anuj Chauhan, editor in Chief PEER REVIEW: Four peer reviewers contributed to the peer review report. reviewers’ reports totaled 341 words, excluding any confidential comments to the academic editor. FUNDING: This research was supported, in part, by a grant-in-aid for researchers, hyogo College of Medicine (2015 to nK) and JsPs KaKenhI grant number 15K08603 (to JK). The authors confirm that the funder had no influence over the study design, content of the article, or selection of this journal. COMPETING INTERESTS: Metoprine was donated by glaxosmithKline. authors disclose no other potential conflicts of interest. COPYRIGHT: © the authors, publisher and licensee Libertas academica Limited. This is an open-access article distributed under the terms of the Creative Commons CC-BY-nC 3.0 License. CORRESPONDENCE: kitanaka-hyg@umin.net Paper subject to independent expert single-blind peer review. all editorial decisions made by independent academic editor. upon submission manuscript was subject to anti-plagiarism scanning. Prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties. This journal is a member of the Committee on Publication ethics (COPe). Provenance: the authors were invited to submit this paper. Published by Libertas academica. Learn more about this journal. Journal name: Drug Target Insights Journal type: Review Year: 2016 Volume: 10 Running head verso: Kitanaka et al Running head recto: Treatment for methamphetamine overdose Introduction Methamphetamine (METH; N-methyl-1-phenylpropan-2- amine) is a powerful psychomotor stimulant similar in struc- ture to amphetamine (AMPH; 1-phenylpropan-2-amine). Although METH is used in the treatment of attention-deficit hyperactivity disorder, narcolepsy, and severe obesity,1 the clinical utility of METH is limited by its abuse potential. METH is typically abused via intranasal, intravenous, or inhalation routes of administration, rather than orally, world- wide, including Japan and the United States.2,3 METH addic- tion, including adverse effects associated with acute METH use and long-term effects associated with METH addiction, is a serious public health problem.4–8 Currently, there are no effective treatments for METH addiction, abuse or acute overdose.7,9,10 The molecular basis of action of METH is considered to be very similar to that of AMPH because of their structural similarities. METH interacts with proteins that affect mono- amine function, including the dopamine transporter (DAT), monoamine oxidases (MAOs), and the vesicular mono- amine transporter-2 (VMAT2), inhibiting their functions in a manner similar to AMPH,11,12 although with somewhat different potencies on dopamine transport.13,14 METH inhi- bition of DAT, MAO, and VMAT2 results in the elevation of presynaptic cytosolic DA levels and the impulse-independent release of dopamine into the synaptic clefts of the dopaminergic neurons via reverse transport mediated by DAT. The abnor- mally released dopamine then binds to pre- and postsynaptic dopamine D1 and D2 receptors, resulting in behavioral and psychological alterations.15 Behavioral alterations in animals are augmented with repeated treatment in a dose-dependent manner (eg, sensitization).16 Dopamine receptor antagonists drastically attenuate METH-induced behavioral and psychological alterations, including both acute and sensitized effects. In human beings, METH sensitization is associated with progressive development of METH-induced psychosis,17 which is improved by treatment with haloperidol,18 a classical antipsychotic that has antagonistic actions at dopamine D2 receptors, but with pronounced extrapyramidal side effects.19,20 In the search for an effective pharmacotherapy for METH- induced symptoms without these adverse effects, other neu- ronal systems have been investigated.21–24 Our research has focused on a possible involvement of brain histaminergic systems in METH actions, especially high-dose METH effects such as METH-induced stereotypy in mice. Here, we will review the brain histaminergic systems, and evidence that may suggest that alterations in histaminergic function may be a possible therapeutic approach to the treatment of METH overdose associated with high METH doses, or the sensitized state associated with long-term METH use. http://www.la-press.com/drug-target-insights-journal-j23 http://www.la-press.com http://dx.doi.org/10.4137/DTI.S38342 http://creativecommons.org/licenses/by-nc/3.0/ http://creativecommons.org/licenses/by-nc/3.0/ mailto:kitanaka-hyg@umin.net http://www.la-press.com http://www.la-press.com/drug-target-insights-journal-j23 Kitanaka et al 2 Drug TargeT InsIghTs 2016:10 METH Overdose: Experimental Procedures and Behavioral Effects In rodents, systemic administration of METH induces loco- motor hyperactivity that is replaced by repetitive and com- pulsive behaviors called stereotypies at higher doses.16,25,26 For instance, a single administration of METH at doses of 0.5–2  mg/kg induces hyperlocomotion,16,27–30 while rodents exhibit stereotypy when treated with higher doses of METH (5–20  mg/kg).31–37 Rodents exhibiting stereotypy after acute high doses of METH are considered to be a model for METH overdose. To evaluate METH-induced stereotypy reproducibly, Tatsuta et al developed an experimental procedure using mice as follows35: test subjects are placed in a transparent acrylic box (30  ×  30  ×  35  cm) with ~25  g of fresh wood chips spread on the floor of the chamber and observed for stereotypy for one hour after drug challenge by observers unaware of the treat- ments. METH-induced stereotypy lasts for ~170 minutes after a 10  mg/kg i.p. injection in mice.35 The frequencies of each behavioral component of stereotypical behavior (see description of categories below) observed for two-hour postinjection are the same as the frequencies observed for one hour (two-hour obser- vations38 vs. one-hour observations39). Therefore, the period of one hour was chosen in all of our subsequent experiments. Behavior is assessed at 30-second intervals, and the predominant behavior observed during each interval is recorded. Since indi- vidual stereotypical behaviors are unchanged for long periods (.30 seconds) after drug treatment, it is possible to record the observations by hand. The behaviors scored are inactive (awake and inactive, or sleeping), ambulation, rearing (standing on the hind legs, with forelegs unsupported or supported on the walls), persistent locomotion, head bobbing (up-and-down movements of the head), continuous sniffing, circling, and continuous nail and/or wood chip biting or licking. Ambulation, rearing, and persistent locomotion are considered to be exploratory behav- iors, and the last four categories are considered stereotypies. Ste- reotypical cage climbing40 is not observed in our experimental procedure because of the use of an acrylic test chamber without a stainless steel grid top. Persistent locomotion is not classified as stereotypy because the mice scored as having persistent locomotion show horizontal locomotor activity less than or equal to that displayed by mice showing hyperlocomotion induced by 1 mg/kg METH (which is not generally defined as a stereotypy) mea- sured by automated Animex Auto.41 The cumulative number of intervals within each five-minute period in which stereotypies are observed is evaluated as a time course (maximal value = 10). Animal handling and care were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (8th edition, Institute of Laboratory Animal Resources-National Research Council, National Academy Press, 2011), and all experiments were reviewed and approved by the Institutional Animal Research Committee of Hyogo College of Medicine. Using the experimental procedure described above, we found that a single administration of METH (5  mg/kg) induces stereotypical sniffing, while stereotypical biting is predominantly observed at 10  mg/kg METH.33,35 Another group reported that a single administration of METH (20  mg/kg) induces repetitive self-injurious behavior.31,37 In line with these observations, METH-induced stereotypical biting appears to be a more severe symptom than stereotypical sniffing as an animal model of METH overdose. Possible pharmacological properties of compounds that will be effec- tive for METH overdose should (1) inhibit METH-induced stereotypical biting or (2) shift stereotypical biting to sniffing (eg, a leftward shift in the METH dose–response relation- ship, producing less severe stereotypies). Using this approach, we investigated a possible involvement of brain histaminergic neurons in METH-induced stereotypical behavior, as a way to approach potential novel treatments for METH overdose. Brain Histaminergic Systems: Potential Roles in Drug Addiction, Drug Abuse, and Drug Overdose Histamine is a biogenic amine produced by the body and plays major roles in allergic reactions and secretion of gastric acid.42–44 It is also released by neurons that originate from the tuberomammillary nucleus of the posterior hypothalamus and project to various brain areas,45,46 suggesting that histamine has crucial roles in the central nervous system.47 Brain histamine is considered to be involved in the regulation of arousal, hormone release, feeding/drinking, and pain perception.48–54 As shown in Figure 1, histamine is synthesized by decarboxylation of the amino acid l-histidine in a reaction catalyzed by histidine decarboxylase (HDC), stored in mast cells, basophils, entero- chromaffin-like cells, and histaminergic neurons, and released on stimulation. Released histamine in turn activates histamin- ergic receptors, causing physiological reactions. In brain, for termination of histaminergic neurotransmission after activa- tion of histamine receptors, histamine is transferred from the extracellular space into cytoplasm by organic cation transporter 3 and/or the equilibrative nucleoside transporter (ENT4), and catabolized by the cytosolic enzyme histamine N-methyltrans- ferase (HMT) to form N-methylhistamine, which is inactive in the histaminergic system.55,56 HMT is the sole enzyme that degrades histamine in brain,57,58 whereas diamine oxidase (DAO; histaminase) catabolizes histamine in peripheral tis- sues.49,59 It is noted that both HMT mRNA and HMT-like immunoreactivity are expressed in mouse stomach57,58 and that the urinary excretions of histamine and N t-methylhistamine are affected by food intake in human beings;60 there is a possi- bility that HMT might, at least in part, function in peripherally. There is evidence that some drugs of abuse (METH, etha- nol, and caffeine), acting through quite different initial molecu- lar targets, release histamine and increase endogenous histamine levels in brain.61–65 What is the role of released histamine by these drugs in drug abuse and addiction? There are two main possi- bilities: (1) that histamine contributes to the addictive or adverse effects associated with these drugs or (2) that histamine release acts in opposition to those effects and is part of a homeostatic counterreaction. Supporting this latter idea, Chandorkar and http://www.la-press.com http://www.la-press.com/drug-target-insights-journal-j23 Treatment for methamphetamine overdose 3Drug TargeT InsIghTs 2016:10 coworkers demonstrated that intraperitoneal administration of high doses of l-histidine, a substrate for histamine synthesis (Fig. 1), reduces METH- and apomorphine-induced stereo- typical behaviors in mice, suggesting that increased levels of histamine in brain suppress abnormal behaviors associated with administration of high doses of these drugs.36,66 Observation reported by Ito et al support Chandorkar’s perspective, finding that pretreatment with l-histidine inhibits METH-induced stereotypy and behavioral sensitization in rats, while stereotypy and behavioral sensitization are exacerbated when rats were pre- treated with a-fluoromethylhistidine, an irreversible inhibitor of HDC (Fig. 1) that reduces brain histamine levels.67 In line with these observations, it is likely that increasing levels of brain histamine may attenuate METH-induced behavioral effects. This is supported by the evidence that the l-histidine effects were blocked by treatment with brain-penetrating histamine H1/H2 receptor antagonists. 67 HMT: A Key Enzyme Regulating High-dose Effects of METH As described above, compounds such as l-histidine and a-fluoromethylhistidine are useful for the increase or decrease in neuronal histamine release, resulting in increasing or decreasing brain histamine levels, respectively.66–71 However, these compounds potentially alter the levels of histamines throughout the body. By contrast, inhibition of HMT activ- ity predominantly modulates central histaminergic activity, while peripheral histaminergic activity is affected, to a lesser extent, by inhibiting an HMT activity. At present, there are no compounds that increase HMT activity. Several HMT inhibitors are available for research purposes.72–74 The dimaprit analog SKF 91488 (S-[4-(N,N-dimethylamino)butyl]isothio- urea) is one of the most potent HMT inhibitors currently known.74 However, to inhibit HMT activity in the brain, SKF 91488 needs to be administered by an intracerebroventricular route.65,75 Intraperitoneal administration of SKF 91488 does not appear to affect HMT activity in the brain, suggesting that the compound does not cross the brood–brain barrier.74 There are no reports of the effects of SKF 91488 on rodent behavior except that by Malmberg-Aiello et al,75 which describes that intracerebroventricular administration of SKF 91488 produces antinociceptive effects in hot plate, abdominal constriction, and paw pressure tests (Table 1). These observations suggest that SKF 91488 increases brain histamine levels by inhibiting an HMT activity resulting in antinociceptive effects by acti- vating central histaminergic neurotransmission52 and that HMT inhibitors may be used to reveal important roles of cen- tral histaminergic system. However, an alternative compound would be desirable for both research and clinical applications. In contrast to the limitations of SKF 9148874 for studies of central histamine function, metoprine (2,4-diamino-5- (3′,4′-dichlorophenyl)-6-methylpyrimidine; formerly called BW 197U), a diaminopyrimidine derivative and potent HMT inhibitor,73 readily crosses the blood–brain barrier.76 Thus, this compound can be administered systemically in order to inhibit the HMT activity in the brain. Intraperitoneal administration of metoprine produces various behavioral effects, including decreases in food intake77 and increases in water consump- tion.78 These observations support a hypothesis that central histaminergic system may involve in the regulation of feeding/ drinking.54 Studies with metoprine also suggest that brain histaminergic systems may be involved in mood and memory processes.79,80 Regarding regulation of drug abuse-related phe- notypes by central histaminergic systems, Itoh et al81 reported that pretreatment with metoprine inhibited METH-induced hyperlocomotion in mice, suggesting that central histamin- ergic systems inhibit METH-induced behavioral effects. We have investigated whether metoprine could inhibit METH- induced stereotypy, a high-dose behavioral effect intended to model METH overdose. Pretreatment with metoprine dose Figure 1. histamine synthesis and catabolism in mammals. Abbreviations: aDh, alcohol dehydrogenase; DaO, diamine oxidase; hDC, histidine decarboxylase; hMT, histamine N-methyltransferase; MaO, monoamine oxidase; sah, S-adenosylhomosysteine; saM, S-adenosylmethionine. http://www.la-press.com http://www.la-press.com/drug-target-insights-journal-j23 Kitanaka et al 4 Drug TargeT InsIghTs 2016:10 dependently decreased METH-induced stereotypical biting, while increasing sniffing, suggesting that metoprine may ame- liorate high-dose METH-induced symptoms by producing a leftward shift in METH behavioral effects (Table 1).65 The inhibitory effect of metoprine on METH-induced stereotypi- cal biting is likely to be mediated by histamine H1 (but not H2/H3) receptors located in the brain, since the metoprine effect was blocked by coadministration of metoprine with brain- penetrating histamine H1 receptor antagonists. 65 It is likely that metoprine-activated histaminergic neurotransmission via central histamine H1 receptors accounted for the attenuation of METH-induced stereotypical biting. This is supported by the evidence that (1) metoprine increased histamine levels, but decreased N t-methylhistamine levels, in the hypothala- mus and (2) pretreatment with l-histidine, which increased the levels of brain histamine, also reduced the frequency of METH-induced stereotypical biting.82 Iwabuchi et al83 reported that METH-induced locomotor hyperactivity and the development of behavioral sensitization were facilitated more in the histamine H1/H2 gene double knockout mice than in the wild-type mice, indicating that brain histaminer- gic system is negatively associated with METH action via his- tamine H1/H2 receptors (see also reports by Munzar et al, 84,85 which described a possible involvement of histamine H3 receptors in METH-seeking behavior). In addition, pretreat- ment with histamine H3 receptor (autoreceptor) agonists such as (R)-a-methylhistamine, imetit, and immepip decreased hypothalamic histamine levels and increased the frequency of METH-induced stereotypical biting.86 Moreover, it was noted that there was a very strong negative correlation (r = -0.918, P  ,  0.001) between the frequency of METH-induced ste- reotypical biting and hypothalamic histamine levels, suggest- ing that activation of brain histaminergic system may suppress high-dose behavioral effects of METH, and might conse- quently reduce high-dose effects associated with the progres- sion to drug dependence and acute overdose.87 HMT Inhibitors: Candidate Compounds of Treatment for METH Overdose No agents that modulate histaminergic system other than the HMT inhibitors and l-histidine have been reported to ame- liorate symptoms of acute injections of high-dose METH, although ABT-239, an antagonist selective for histamine H3 receptors, attenuates moderate doses of METH-induced locomotor hyperactivity.88 In our preliminary experiments, metoprine itself did not induce an anxiety-like behavior and memory impairments in the marble-burying test and Y-maze test, respectively (S. Okumura and T. Sakamoto, unpublished observations). Therefore, metoprine is likely to have limited side effects, although it has been associated with increases in locomotor behaviors,65,89,90 anxiogenic79 (but there is a nega- tive finding),65 antiamnesic,80 and antinociceptive effects75 in rodents (Table 1). Regarding metoprine-induced locomotor hyperactivity, a dose–response effect of metoprine on gen- eral locomotion was biphasic with the greatest hyperactivity noted at a dose of 10  mg/kg of metoprine.65 The biphasic reaction to metoprine dose appears to be mediated by brain histamine-mediated effects, since histamine itself injected into the brain induces biphasic locomotor alterations as well.91,92 Several types of seizures are also inhibited by meto- prine (Table 1).70,71,93,94 Whether similar mechanisms underlie these effects and effects on METH-induced behavior is uncertain. In any case, the anticonvulsant topiramate did not affect METH-induced stereotypical biting, suggesting that the antagonism of METH-induced effects by metoprine is not something that is produced by all anticonvulsive drugs.38 Another piece of evidence consistent with histaminergic modulation of systems associated with high-dose METH effects comes from studies of HDC gene knockout mice, which demonstrate tic-like stereotypical movements, which can be ameliorated by histamine repletion.95 This might Table 1. effects of hMT inhibitors on rodent behaviors. HMT INHIBITOR EFFECT REFERENCE Feeding/drinking Metoprine Decrease in food intake 77 Metoprine Increase in water consumption 78 Mood Metoprine anxiogenic-like 79 Memory process Metoprine antiamnesic 80 Pain sKF 91488 antinociceptive 75 BW 301u antinociceptive 75 Locomotor activity Metoprine Increase in locomotor activity 89 Metoprine Increase in number of rearing 89 Metoprine Increase in locomotor activity 65 Metoprine Increase in locomotor activity 90 Seizures Metoprine Inhibition of audiogenic seizure 93 Metoprine Decrease in duration of convulsions 70 Metoprine Inhibition of amygdaloid kindled seizure 94 Metoprine Delay in the onset of seizure episodes 71 METH-induced behavior Metoprine Decrease in MeTh-induced hyperlocomotion 81 Metoprine Decrease in MeTh-induced stereotypical biting 65 sKF 91488 Decrease in MeTh-induced stereotypical biting 65 Notes: Metoprine = 2,4-diamino-5-(3′,4′-dichlorophenyl)-6-methylpyrimidine, sKF 91488 = S-[4-(N, N-dimethylamino)butyl]isothiourea, BW 301u = 2,4- diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine. Abbreviations: hMT, histamine N-methyltransferase; MeTh, methamphetamine. http://www.la-press.com http://www.la-press.com/drug-target-insights-journal-j23 Treatment for methamphetamine overdose 5Drug TargeT InsIghTs 2016:10 suggest that modulation of histaminergic function might be useful in other types of striatal dysfunctions associated with abnormal movements, or repetitive behaviors. With regard to the high-dose METH effects associated with sensitization or other adverse effects, it would appear that metoprine may be beneficial based on the model discussed here. Possible treatments of metoprine with histamine H3 receptor antagonists or with modafinil for METH overdose should be evaluated in the future studies because histamine H3 receptor antagonists and modafinil increase tissue lev- els of histamine in the hypothalamus.96,97 It remains to be seen how metoprine will affect other METH-induced behaviors, specifically, including others more specific to addiction or METH overdose. In any case, the present data support the proposal that HMT inhibitors such as meto- prine are possible candidate compounds for the treatment of METH-related conditions, including METH-induced psychosis and overdose. Acknowledgments The authors are grateful to Dr. Tomohiro Tatsuta of Ibogawa Hospital, Hyogo, Japan, for his remarkable contribution to the development of a method to evaluate stereotypy observed under METH overdose. Metoprine was generously donated by GlaxoSmithKline (Stevenage, UK). Author Contributions Conceived and designed the experiments: JK, NK, FSH, and MT. Analyzed the data: NK, JK, FSH, and MT. Wrote the first draft of the manuscript: NK, JK, FSH, GRU, and MT. Contributed to the writing of the manuscript: JK, NK, FSH, GRU, and MT. Agreed with manuscript results and conclu- sions: JK, NK, FSH, GRU, and MT. Jointly developed the structure and arguments for the paper: FSH and GRU. Made critical revisions and approved the final version: JK, NK, FSH, GRU, and MT. 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