Nobue Kitanaka1, Junichi Kitanaka1*, F Scott Hall2, Satoshi Okumura1#, Tomoyuki Sakamoto1#, George R Uhl3 and Motohiko Takemura1
1Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
2Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA
3Office of Research & Development, New Mexico VA Healthcare System/BRINM, Albuquerque, NM, USA
#These authors contributed equally to this study as medical students participating in an orientation course for medical sciences (2014) held in the Department of Pharmacology, Hyogo College of Medicine
Received: 02 May, 2017; Accepted: 11 May, 2017; Published: 12 May, 2017
Junichi Kitanaka, Department of Pharmacology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan, Tel: 81798456333; Fax: 81798456332; E-mail:
Kitanaka N, Kitanaka J, Hall FS, Okumura S, Sakamoto T, et al. (2017) How the histamine N-methyltransferase inhibitor metoprine alleviates methamphetamine reward. J Addict Med Ther Sci 3(2): 016-023. DOI: 10.17352/2455-3484.000021
© 2017 Kitanaka N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Methamphetamine; Drug addiction; Reward; Histaminergic system; Metoprine; Histamine N-methyltransferase
Several agents that activate brain histaminergic neurotransmission have been reported to improve methamphetamine (METH)-induced behavioral aberrations. In this review, we present research demonstrating that pretreatment with metoprine, a selective inhibitor of histamine N-methyltransferase (HMT), attenuates the reinforcing effects of METH in mice. Pretreatment with metoprine decreased METH-induced reinforcement as evaluated in the conditioned place preference (CPP) test. Metoprine pretreatment alone produced an increase in the CPP score with the same score level as that observed in mice treated with METH plus metoprine. No changes in alternation behaviors or numbers of marbles buried were observed in metoprine-treated mice measured in the Y-maze test and in the marble burying test, respectively. The locomotor activity was augmented after metoprine administration. These observations suggest that metoprine alleviates METH-induced rewarding property and hyperlocomotion. Metoprine is likely to augment spontaneous locomotor activities without mood alterations or short-term memory impairment. Brain histaminergic system is a new hope for treatment of METH dependence.
Methamphetamine (METH) is a highly addictive psychomotor stimulant drug that is abused worldwide . METH abuse results in numerous adverse effects after acute administration, as well as an array of adverse outcomes associated with binge use, long-term use, and withdrawal [2-4]. Acutely METH releases dopamine from synaptic terminals through multiple actions that include inducing reverse transport of dopamine via the dopamine transporter (DAT), impairing the function of the vesicular monoamine transporter-2 (VMAT2), leading to increased cytoplasmic dopamine concentrations, and inhibition of monoamine oxidase [5-8]. Moreover, these changes contribute to the production of oxidative metabolites, metabolic impairments, oxidative damage to dopamine terminals, and depletion of tissue dopamine levels [9-11]. METH and related drugs consequently produce broad effects on the central nervous system both acutely and chronically [12-14].
Due to its highly addictive properties, and the adverse consequences associated with acute and chronic use of METH, effective treatments for METH dependence are needed. Unfortunately, various attempts at pharmacotherapy trials have yielded unpromising and inconsistent results with medications developed to date [15-17]. Several novel alternative approaches have been a matter of intense investigation more recently, including dopamine D3 receptor antagonists and partial agonists , and manipulations of brain histamine systems . The later possibility is addressed in this report.
Based on a variety of findings, an increasing amount of scientific attention has been focused recently on the histaminergic system with respect to its potential roles in the causes and treatment of psychotic disorders, drug addiction/abuse, and other psychiatric conditions. Content of the histamine metabolite tele-methylhistamine is increased in the cerebrospinal fluid of schizophrenic patients as compared with healthy control subjects . Dysfunction of the histamine-forming enzyme histidine decarboxylase (HDC) has been suggested to contribute to Tourette’s syndrome in humans, with similar phenomena observed in mouse models . Moreover, based upon the positioning of histamine H3 receptors in neural circuits influencing dopaminergic and striatal function, histamine H3 receptor antagonists have been investigated as potential anti-psychotic drugs [22-24]. In addition, brain histaminergic neurons have been suggested to influence amphetamine reinforcement, which was reduced by lesion of histaminergic neurons . In this review, we will examine other recent evident suggesting that histamine may have a role in drug reinforcement and addiction. The work that will be discussed will deal mainly with the relationship between alterations in brain histamine content and METH-induced behavior in animal models.
Brain histaminergic system
In the body histamine is synthesized by the decarboxylation of the amino acid L-histidine in a reaction catalyzed by HDC (EC18.104.22.168) and is stored mainly in mast cells, basophils, and neurons. Although a great deal of the histamine content of the brain comes from mast cells, histaminergic neurons in the brain are found solely in the tuberomamillary nucleus located in the posterior hypothalamus, but send projections throughout much of the central nervous system [26-28]. Regarding the function of histamine as a neurotransmitter, there are several important aspects of histamine neurotransmission that are important for understanding the role of histamine in brain function. (1) Aspects of histamine release are different from other monoamines. Depolarization releases neuronal histamine in the same fashion as other monoamines (i.e. dopamine, norepinephrine, and serotonin) [29-31], but the levels of extracellular histamine released are at most twice basal levels [30,31]. In contrast to histamine, other monoamines reach extracellular levels after neuronal depolarization-dependent releases that are several hundred-fold basal levels. (2) Aspects of histamine transport are different from other monoamines. There is no evidence for “histamine specific transporter” responsible for histamine clearance , as is the case for the other monoamine transporters, although histamine levels in the synaptic cleft return to a basal levels after stimulation [33,34]. The organic cation transporter 3 (SLC22A3), previously called the extraneuronal monoamine transporter, is believed to maintain tissue histamine levels [35-37]. Concentrations of monoamines are regulated by SLC6 type high-affinity monoamine transporters , including DAT (SLC6A3) [39-41], the serotonin transporter (SERT; SLC6A4) [42-44], and the norepinephrine transporter (NET; SLC6A2) [45,46]. Despite current limitations in our knowledge of brain histamine dynamics, histamine is believed to be released from presynaptic vesicles by stimulation, and bind to histamine receptors located on postsynaptic (subtypes H1-H4) and presynaptic (mainly H3) membranes [47-50]. Histamine receptors are thought to have crucial roles in many physiological functions, including the sleep-wake cycle, food intake, neuroendocrine regulation, cognition, and drug reinforcement [51-54]. Histaminergic neurotransmission is terminated by metabolic inactivation of histamine by a histamine degrading enzyme histamine N-methyltransferase (HMT; EC22.214.171.124) . Both HMT mRNAs and HMT protein-like immunoreactivity are located predominantly in the central nervous system [56-58]. HMT is considered to be the primary mechanism of histamine metabolism in brain, while histamine is metabolized by diamine oxidase (histaminase; EC126.96.36.199) in peripheral tissues [47,59]. Metoprine (2,4-diamino-5-(3’,4’-dichlorophenyl)-6-methylpyrimidine) is an HMT inhibitor , which was originally developed as an anticancer drug . Metoprine easily crosses the blood-brain barrier when administered systemically  and increases tissue histamine content [63-68]. The involvement of central histaminergic systems in the behavioral and psychological effects of METH dependence can thus be investigated in using metoprine.
METH-induced behavior and metoprine
Acute METH administration releases histamine in the hypothalamus , and increases tissue histamine content . The physiological relevance of METH-induced histamine release is unknown, but two possibilities might account for the significance of histamine release. Firstly, histamine released by METH might be associated with METH-induced behavior. This would be the most obvious view of the relationship between METH and histamine function. However, some evidence suggests otherwise. For instance, in histamine-deficient mice METH-induced hyperlocomotion and behavioral sensitization are augmented as compared with wild-type mice . Alternatively, it might be suggested that histamine release is a part of a compensatory mechanism that restrains METH behavioral responses, limiting METH effects and the development of some chronic adaptations to METH such as sensitization. A failure of homeostasis in the brain resulting from reduced METH-induced histamine release may contribute to development of aberrant behaviors associated with chronic METH administration. If this is the case, it might be possible that these behaviors might be improved by increasing brain histamine levels pharmacologically.
There is some evidence, that high-dose METH-induced behaviors are reduced by agents which increase brain histamine content. L-histidine, a precursor for histamine synthesis, crosses the blood-brain barrier with a low Km value  and is converted to histamine by HDC in the brain, increasing tissue histamine content [67,73]. Pretreatment with high doses of L-histidine attenuates METH-induced hyperlocomotion , behavioral sensitization [74,75], and stereotyped behavior [73,76,77]. The HMT inhibitors metoprine and the dimaprit analogue SKF 91488 (S-[4-(N, N-dimethylamino)butyl]isothiourea) increase tissue histamine content by inhibiting HMT [63-68,78], and these agents attenuate METH-induced stereotypy . In line with these observations, it is likely that the increase in the tissue histamine contents might improve aberrant behavior observed at high METH doses, as exemplified by stereotypy and sensitization. This hypothesis is supported by evidence that METH-induced behaviors are exacerbated when histaminergic neurotransmission is suppressed by pharmacological  or genetic  manipulations.
Although this evidence supports a role for histamine in counteracting some of the behaviors observed after administration of high METH doses, it has not been determined whether effects observed at low METH doses, such as the rewarding and reinforcing effects, are similarly affected. To address this question, we examined the effect of metoprine pretreatment on METH-induced CPP in mice. In CPP testing, mice are initially presented with a testing apparatus that has two or three distinctive compartments (distinctive in terms of visual and tactile cues). Mice are allowed to explore the compartments and the preference to each department is determined over 1-3 sessions. Ideally the preference for the compartments is approximately equal, although pairing with the less-preferred side is also effective (see review by Tzschentke  for a discussion of this issue). Subsequently, mice are confined to one of the compartments and receive an injection of a test drug (such as METH) in one compartment and saline in another compartment. After a series of such pairings over several days, preference is assessed again. An increase in preference reflects the positively reinforcing effects of the drugs, indicative of drug reward, while a decrease in preference reflects avoidance, indicative of aversive drug effects. Using this procedure mice readily develop a conditioned place preference for METH after 3 pairings with 0.5 mg/kg METH i.p. . During the test locomotor stimulant effects of METH can also be measured.
Metoprine alone can produce locomotor stimulation, depending on dose [63,66], and thus might also be speculated to have some reinforcing effects when administered alone. In order to look at the potential interactive effects of modulating histamine with metoprine on METH reinforcement, mice were first examined in a modified conditioning procedure. Mice received only a single injection of METH (0.5 mg/kg, i.p.) during a single conditioning session (and one saline injection in the opposite compartment in a second session). Mice were then given a CPP test the following day, followed by a second test 5 days later. Control mice received saline injections during both training sessions. As shown in (Figure 1A), even a single METH injection produced significant CPP. This preference was reduced, but still significant, 5 days later. A second group of mice were pretreated with metoprine (10 mg/kg, 1.p.) or saline, 1 h before METH conditioning (again control subjects received saline injections). The main finding of this study is that a pretreatment with metoprine reduced METH-induced CPP (Figure 1B). The result suggests that behavioral effects produced by relatively low doses of METH are reduced by activation of brain histaminergic systems. However, at the same time metoprine induced CPP when administered to control mice, suggesting that it may have reinforcing effects of its own. Nonetheless, the data is consistent with a potential inhibitory effect of brain histaminergic activation, as shown by metoprine pretreatment on METH-induced CPP. In any case further investigation is warranted.