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. Author manuscript; available in PMC: 2017 Sep 1.
Published in final edited form as: Behav Pharmacol. 2016 Sep;27(6):542–548. doi: 10.1097/FBP.0000000000000244

Agmatine attenuates the discriminative stimulus and hyperthermic effects of methamphetamine in male rats

David A Thorn a, Jiuzhou Li b, Yanyan Qiu a, Jun-Xu Li a
PMCID: PMC4965281  NIHMSID: NIHMS781497  PMID: 27232669

Abstract

Methamphetamine abuse remains an alarming public heath challenge with no approved pharmacotherapies available. Agmatine is a naturally-occurring cationic polyamine that has previously been shown to attenuate the rewarding and psychomotor-sensitizing effects of methamphetamine. This study examined the effects of agmatine on the discriminative stimulus and hyperthermic effects of methamphetamine. Adult male rats were trained to discriminate 0.32 mg/kg methamphetamine from saline. Methamphetamine dose-dependently increased drug-associated lever responding. The nonselective dopamine receptor antagonist haloperidol (0.1 mg/kg) significantly attenuated the discriminative stimulus effects of methamphetamine (5.9-fold rightward shift). Agmatine (10 –100 mg/kg) did not substitute for methamphetamine but significantly attenuated the stimulus effects of methamphetamine, leading to a maximum of 3.5-fold rightward shift. Acute 10 mg/kg methamphetamine increased the rectal temperature by a maximum of 1.96 ± 0.17 °C. Agmatine (10 – 32 mg/kg) pretreatment significantly attenuated the hyperthermic effect of methamphetamine. Agmatine (10 mg/kg) also significantly reversed methamphetamine-induced temperature increase. Together, these results support further exploration of the value that agmatine may have for treating methamphetamine abuse and overdose.

Keywords: Methamphetamine, agmatine, drug discrimination, hyperthermia, rat

INTRODUCTION

Methamphetamine and related stimulant abuse remains a significant public health challenge, with an estimated 52 million users globally (UNODC, 2010). Despite the well-recognized socioeconomic and health implications associated with methamphetamine abuse and addiction, there is currently no Food and Drug Administration-approved medications available for the treatment of methamphetamine abuse. Preclinical and clinical efforts for the development of potential medications focus on various approaches to modulate the neurochemical and behavioral consequences related to methamphetamine exposure such as agonist replacement therapy (Bergman, 2008; Stoops et al., 2013; Pike et al., 2014) and pharmacological antagonism (Desai et al., 2010; Achat-Mendes et al., 2012; Newman et al., 2012). New efforts to study novel pharmacotherapies of methamphetamine abuse and addiction are still needed.

Agmatine has been known as a natural product for over 100 years. It is a cationic polyamine formed by decarboxylation of l-arginine by arginine decarboxylase and is widely available over the internet and in vitamin shops as a tonic and bodybuilding product and dietary supplement. The pharmacology of agmatine is complicated, involving imidazoline receptors, nitric oxide synthesis, glutamate receptors and polyamine metabolism (Piletz et al., 2013). A recent comprehensive review written by 16 independent research groups summarized the potential therapeutic utilities of agmatine in various clinical disorders including diabetes, neuropathic pain, mood disorders and, notably, opioid addiction (Piletz et al., 2013), and called for more preclinical and translational research attention to agmatine. However, little is known of the effects of agmatine in the abuse- and addiction-related effects of other drugs of abuse.Only two studies haveexamined the effects of agmatine on behavioral actions of methamphetamine (Thorn et al., 2012a; Kitanaka et al., 2014). Agmatine has been shown to attenuate the development and expression of methamphetamine-induced conditioned place preference in rats (Thorn et al., 2012a) and methamphetamine-induced locomotor sensitization and stereotyped behavior in mice (Kitanaka et al., 2014). Although these results suggest the possibility that agmatine may be able to counteract some abuse-related effects of methamphetamine, more research is needed. This study follows our previous report (Thorn et al., 2012a) and examined the effects of agmatine on two significant pharmacological effects of methamphetamine in rats: the discriminative stimulus and hyperthermic effects. Methamphetamine produces strong discriminative stimulus effect across various species including humans (Tidey et al., 1998; Sevak et al., 2009), which is highly related to the subjective effects of methamphetamine and contributes to its abuse liability. High doses of methamphetamine lead to a series of physiological aberrancies including hyperthermia, which is closely related to its neurotoxicity (Matsumoto et al., 2014). For methamphetamine-induced hyperthermia, both prevention and reversal studies were conducted because the former evaluated the possibility of agmatine as a prophylactic drug and the latter was intended to assess the possibility of agmatine as a drug to rescue methamphetamine overdose.

Methods

Subjects

A total of 62 adult male Sprague-Dawley rats (Harlan, Indianapolis, IN) participated in the studies (body temperature studies: 54 rats [n=5–7 per group]; drug discrimination: 8 rats). Rats used in body temperature studies were housed individually on a 12/12-h light/dark cycle with free access to water and food except during experimental sessions, which were conducted during the light period. Body weights of the rats that participated in the drug discrimination study was maintained at 85% of their free-feeding body weight by adjusting the amount of standard rodent chow that was provided in the home cage after daily sessions. Animals were maintained and experiments were conducted in accordance with the Institutional Animal Care and Use Committee, University at Buffalo, the State University of New York, and with the Guide for the Care and Use of Laboratory Animals (11th edition, Institute of Laboratory Animal Resources on Life Sciences, National Research Council, National Academy of Sciences, Washington DC).

Drug discrimination

Drug discrimination studies were conducted in commercially available two-lever operant chambers located within sound-attenuating, ventilated enclosures (Coulbourn Instruments Inc., Allentown, PA, USA) as previously described (Qiu et al., 2014; Qiu et al., 2015). Data were collected through an interface using Graphic State 3.03 software (Coulbourn Instruments Inc.). The experimental protocol has been described in detail elsewhere (Qiu et al., 2015). Briefly, daily sessions consisted of a 10-min timeout period followed by a 10-min response period. During the timeout period, the chamber was dark and lever presses had no programmed consequence; during the response period, the stimulus lights above both levers were illuminated and 10 consecutive responses [fixed ratio (FR) 10] on the correct lever resulted in the delivery of a food pellet (45 mg; BioServ Inc., Frenchtown, New Jersey, USA). A response on the incorrect lever reset the FR requirement on the correct lever. The response period ended after 10 min or the delivery of 20 food pellets, whichever occurred first.

For training sessions, saline or 0.32 mg/kg methamphetamine was injected (i.p.) at the start of the timeout period, 10 min before the response period. When rats received saline, only responding on the saline lever resulted in food delivery. When rats received methamphetamine, only responding on the drug lever resulted in food delivery. Sessions were conducted 7 days/week with the order of training sessions generally following a double alternation schedule (e.g. saline, saline, drug, drug).

Rats met the following test criteria before the start of this study : at least 90% of the total responses occurring on the correct lever, based on the injection given before the session, and fewer than 10 responses (1 FR) occurring on the incorrect lever before delivery of the first food pellet for 2 consecutive training sessions (Li et al., 2013). Test sessions were identical to training sessions, except that 10 consecutive responses on either lever resulted in the delivery of food. When agmatine and methamphetamine were studied as a combination, agmatine was administered 15 min prior to methamphetamine. The order of tests with agmatine and methamphetamine varied nonsystematically among animals.

Body temperature

Body temperature was measured as previously described (Thorn et al., 2012b; Qiu et al., 2014) in a quiet procedure room maintained under environmental conditions (temperature, humidity and lighting) that were identical to those in the animal colony room. Rats were handled for at least 3 days prior to testing drugs in order to habituate rats to the procedure, and they were habituated to the procedure room for at least 30 min prior to each test. Body temperature was measured by gently inserting a rectal probe (5.0 cm) and recording temperature from the digital thermometer (BAT7001H, Physitemp Instruments Inc., Clifton, NJ, USA). Each rat was used to study only one drug dose or combination test. Each rat experienced two test sessions: saline treatment session as a control, which was followed by a drug treatment session. For each test session, body temperature was measured immediately before an injection and every 15 min after the injection was given until the effect of the test drug was no longer evident or until 2 h had elapsed since the injection. Two drug combinations were performed. In one study to evaluate the preventive effect of agmatine, agmatine was administered 15 min prior to methamphetamine administration. In a second study to evaluate the rescue effect of agmatine, agmatine was administered 15 min after methamphetamine administration. The dose of methamphetamine was 10 mg/kg because this dose produced reliable hyperthermia in rats (Molkov et al., 2014).

Drugs

The compounds studied were agmatine sulfate, haloperidol and (+)-methamphetamine hydrochloride (Sigma-Aldrich, St. Louis, MO). Agmatine and methamphetamine were dissolved in 0.9% physiological saline and administered i.p. Haloperidol was dissolved in 0.9% physiological saline with a drop of acetic acid and administered 10 min before the session. The dose of haloperidol (0.1 mg/kg) was used in previous studies to show significant attenuation of methamphetamine discrimination (Gatch et al., 2008). Doses are expressed as mg of the form indicated above per kg of body weight. Injection volumes were 1 ml/kg.

Data analyses

For drug discrimination studies, two dependent variables were collected: (i) the percentage of responses on the methamphetamine-associated lever, calculated by dividing the number of responses on the methamphetamine-associated lever by the total number of responses on both levers and multiplying by 100; and (ii) response rate, calculated by dividing the total number of responses made on both levers by the duration of the response period in seconds. When a rat responded at a rate that was less than 20% of the vehicle control rate (the rate that was recorded after saline was administered), the percentage of responses on the methamphetamine-associated lever for that dose or dose combination was not included for further analysis, although the response rate data were included. The mean percentage of responses on the methamphetamine-associated lever ± 1 S.E.M. and the mean rate of responding ± 1 S.E.M. during test sessions were plotted as a function of dose. For the methamphetamine discrimination data, the ED50 values (95 % confidence intervals [CI]) of methamphetamine in the presence of vehicle or different doses of agmatine were estimated using linear regression. If the 95% CI of the ED50 values did not overlap between the vehicle and agmatine treatment conditions, then it would suggest the discriminative stimulus of methamphetamine was significantly altered (attenuated) by agmatine. Dose ratios were calculated by dividing the ED50 values of methamphetamine when it was treated with agmatine by the values without agmatine treatment. For the response rate, one-way or two-way repeated-measures ANOVA (methamphetamine dose × agmatine treatment) followed by Bonferroni’s post hoc test was used to analyze the data. P < 0.05 is considered statistically significant.

Changes in body temperature (ºC, mean ± S.E.M) were calculated by subtracting the first measurement of body temperature during each test session from all the subsequent measurements, which were then plotted as a function of time. Drug interactions were analyzed using two-way repeated measures analysis of variance (ANOVA) (time × treatment) followed by Bonferroni’s post hoc test. P < 0.05 is considered statistically significant.

Results

Saline produced less than 5% methamphetamine-associated lever responding (upper panel, Fig. 1, filled circle above ‘V’), whereas methamphetamine dose-dependently increased responding on the drug-associated lever up to a maximum of 99.0% at the training dose of 0.32 mg/kg (upper panel, Fig. 1, filled circles) (ED50 [95% CI] = 0.108 [0.074, 0.134] mg/kg, Table 1). The nonselective dopamine receptor antagonist haloperidol at a dose of 0.1 mg/kg significantly shifted the methamphetamine discrimination dose-effect curve rightward, increasing the ED50 values to 0.641 (0.263, 0.874) mg/kg (upper left panel, Fig. 1, open triangles). This represents a 5.9-fold rightward shift. At the doses studied, neither methamphetamine alone nor methamphetamine combined with 0.1 mg/kg haloperidol significantly altered the response rate (one way ANOVA for methamphetamine alone: F (2.09, 14.62) = 0.44, NS; one way ANOVA for the combination: F (2.044, 14.26) = 1.86, NS).

Figure 1.

Figure 1

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Effects of haloperidol (left) and agmatine on the discriminative stimulus effects of methamphetamine in rats discriminating 0.32 mg/kg methamphetamine (n=8). Vertical axes: upper panel, average percentage of responses on the methamphetamine (MA)-associated lever ± S.E.M.; lower panel, average response rate ± S.E.M. in responses per second. Horizonotal axes: dose in mg/kg body weight. ‘V’ indicates vehicle. *P<0.05 as compared with vehicle treatment control.

Table 1.

ED50 (95% CL) values of the discriminative stimulus effects of methamphetamine in the presence of haloperidol and agmatine in rats discriminating 0.32 mg/kg methamphetamine.

Treatment ED50 95% CL Dose Ratio
Methamphetamine 0.108 (0.074, 0.134)
+ 0.1 haloperidol 0.641 (0.263, 0.874) * 5.9
+ 10 agmatine 0.130 (0.066, 0.177) 1.2
+ 32 agmatine 0.295 (0.193, 0.378) * 2.7
+ 100 agmatine 0.380 (0.196, 0.513) * 3.5
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*

Indicates 95% confidence limits of the ED50 values did not overlap with that of vehicle-treated condition.

Within the dose range of 10 – 100 mg/kg, agmatine occasioned < 5% methamphetamine-associated lever responding. Interestingly, 10 mg/kg (but not higher doses) agmatine significantly increased the rate of responding (right panel, data points above “V”) (F (1.39, 9.74) = 4.57, p < 0.05; post hoc, p < 0.05 at the dose of 10 mg/kg agmatine). Agmatine dose-dependently shifted the methamphetamine discrimination dose-effect curve rightward, increasing the ED50 values to 0.130 (0.066, 0.177) mg/kg at a dose of 10 mg/kg, 0.295 (0.193, 0.378) mg/kg at a dose of 32 mg/kg, and 0.380 (0.196, 0.513) mg/kg at a dose of 100 mg/kg agmatine, respectively (upper right panel, Fig. 1). This represents 1.2-, 2.7- and 3.5-fold rightward shifts, respectively. The 95% CI of the ED50 values of methamphetamine in combination with 32 mg/kg or 100 mg/kg agmatine did not overlap with that of controls, suggesting statistically significant rightward shifts. The combination of 10 mg/kg agmatine and 0.032 mg/kg methamphetamine also increased the response rate to a level that was significantly higher than that of 0.032 mg/kg methamphetamine alone (p < 0.01) (lower right panel, Fig. 1). No other significant differences were observed on the response rates.

Agmatine dose-dependently reduced the rectal temperature in rats (left panel, Fig. 2). At 10 and 32 mg/kg, agmatine did not significantly alter the rectal temperature as compared to vehicle-treated condition (two way ANOVA for treatment: F [1, 10] = 1.17, NS for 10 mg/kg; F [1, 10] = 4.41, P =0.06 for 32 mg/kg). At 100 mg/kg, two way ANOVA analysis revealed a significant main effect of treatment (F [1, 10] = 16.43, P < 0.01) and treatment × time interaction (F [8, 80] = 11.00, P < 0.001). Post hoc analysis found that between 15 – 75 min after agmatine administration, the rectal temperature was significantly decreased. Acute treatment with 10 mg/kg methamphetamine markedly increased the rectal temperature to a maximum of 1.96 ± 0.17 °C (mean ± S.E.M) and the effect dissipated 2 h later. Pretreatment with 10 mg/kg and 32 mg/kg agmatine markedly attenuated 10 mg/kg methamphetamine-induced hyperthermia (middle panel, Fig. 2). Two way ANOVA analysis revealed a significant main effect of treatment (F [2, 120] = 88.12, P < 0.001) and treatment × time interaction (F [14, 120] = 3.69, P < 0.001). Post hoc analysis found that at the dose of 10 mg/kg agmatine, the hyperthermia was significantly attenuated at all the time points measured. Similarly, the methamphetamine-induced hyperthermia was significantly attenuated by 32 mg/kg agmatine between 15 – 75 min post-treatment. In order to examine whether agmatine could reverse (rescue) methamphetamine-induced hyperthermia, a dose of 10 mg/kg was administered 15 min after 10 mg/kg methamphetamine treatment. It was found that agmatine quickly and significantly reversed the hyperthermic effect (right panel, Fig. 2). Two way ANOVA revealed a significant main effects of treatment (F [1, 80] = 125.1, P < 0.001) and treatment × time interaction (F [7, 80] = 4.03, P < 0.001). Post hoc analysis found that at the dose of 10 mg/kg agmatine, the hyperthermia was significantly reversed between 30 – 120 min post-treatment.

Figure 2.

Figure 2

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Left: effects of agmatine on rectal temperature in rats. Middle and right: effects of agmatine on preventing (middle) and reversing (right) methamphetamine-induced hyperthermia in rats. Vertical axes: body temperature changes ± SEM (°C). Horizonotal axes: time after drug administration (min). *P<0.05 as compared with vehicle-treated (left) or methamphetamine-treated conditions (middle and right). Unit of drug doses: mg/kg.

Discussion

The primary findings of the current study were that agmatine significantly attenuated the discriminative stimulus effects of methamphetamine in rats discriminating 0.32 mg/kg methamphetamine, leading to a parallel rightward shift of the methamphetamine dose-effect curves. In the assay of a large dose of 10 mg/kg methamphetamine-induced hyperthermia, a relatively small dose of agmatine both prevented and reversed the hyperthermic effect, an effect that was significant across the entire duration of methamphetamine action. The discriminative stimulus effects of methamphetamine are thought to contribute to its high abuse liability. In addition, it has previously been shown that agmatine attenuates methamphetamine-induced conditioned place preference (Thorn et al., 2012a) and behavioral sensitization (Kitanaka et al., 2014). Together, these accumulated findings strongly suggest the potential utility of agmatine as a medication against methamphetamine abuse. Of particular importance, methamphetamine-induced hyperthermia is critically related to methamphetamine-induced toxicity and a major contributing factor to methamphetamine overdose-related death (Matsumoto et al., 2014). The fast rescuing effect of agmatine as seen in this study to ameliorate hyperthermia (Fig. 2) suggests the potential value of agmatine as an emergency medication to rescue methamphetamine overdose. Given that these results are preliminary, caution needs to be taken not to over-interpret this finding as meaning that agmatine is an effective antidote of methamphetamine overdose. However, it certainly calls for more detailed studies including investigstion of the effects of agmatine on high methamphetamine dose-induced neurotoxicity to further explore this possibility.

The discriminative stimulus effects of methamphetamine are primarily mediated through dopamine receptors. Selective dopamine D1- and D2-like receptor antagonists can block the discriminative stimulus effects (Tidey et al., 1998). Consistent with the literature (Gatch et al., 2008), we found that the nonselective dopamine receptor antagonist haloperidol also significantly attenuated the discriminative stimulus effects of methamphetamine in a reversible and surmountable manner (Fig. 1). Ligands that act on non-dopaminergic systems have also been shown to modulate the discriminative stimulus effects of methamphetamine. For example, nicotinic receptors are shown to play an important role in mediating the discriminative stimulus effects of methamphetamine (Gatch et al., 2008; Desai et al., 2010). Drugs acting on the serotonergic system also modulate methamphetamine discrimination (Munzar et al., 1999). Here, agmatine dose-dependently and significantly shifted the methamphetamine discrimination dose-effect curve rightward. Agmatine potentially interacts with multiple targets, including NMDA glutamate receptors (Molderings et al., 2012), on which agmatine acts as an antagonist. However, it is unlikely that the attenuation observed here was due to the action of agmatine on NMDA receptors as NMDA receptor antagonist enhance rather than attenuate the discriminative stimulus effects of methamphetamine (Wooters et al., 2011). Numerous studies how that agmatine has antinociceptive activities and enhances the antinociceptive effects of opioids, and these effects seem to be mediated through α2 adrenoceptors (Yesilyurt et al., 2001; Molderings et al., 2012). But the observed effect of agmatine in this study is also unlikely to be mediated through α2 adrenoceptors as the α2 adrenoceptor antagonist yohimbine, at a dose that is sufficient to block α2 adrenoceptors (Thorn et al., 2012b), did not block the effect of agmatine in a methamphetamine discrimination study (data not shown). Agmatine also binds to imidazoline I1/I2 receptors, α2 binding sites, and serotonin 5-HT3 receptors with low affinity (Molderings et al., 2012). It is yet to be seen which receptor(s) mediates the effects of agmatine for its attenuation of behavioral actions of methamphetamine. It should be noted that although the training dose of methamphetamine in the present study (0.32 mg/kg) is used in the literature (Desai and Bergman, 2010), higher training doses (e.g., 1 mg/kg) are also used. It is yet to be seen whether the same magnitude of attenuation by agmatine also occurs under the conditions where higher methamphetamine training doses are used.

Methamphetamine abuse and overdose can lead to fatal consequences. In the United States, methamphetamine use is responsible for an estimated 94,000 emergency department admissions annually, and hyperthermia appears to be a universal symptom (NIDA, 2011). Methamphetamine overdose-induced hyperpyrexia can be detrimental and there are few treatment options (Schep et al., 2010). It is conceivable that the availability of a safe, effective and fast-acting medication could be life-saving for the cases of methamphetamine overdose in emergency rooms. Several studies have shown that σ receptor antagonists are effective to attenuate methamphetamine-induced hyperthermia and neurotoxicity in rodents (Seminerio et al., 2011; Seminerio et al., 2012; Kaushal et al., 2013). In this study, a relatively small dose of agmatine (10 mg/kg) markedly prevented methamphetamine-induced hyperthermia. More importantly, when agmatine was administered after methamphetamine, it completely blunted further rectal temperature increase, effectively reversing methamphetamine-induced hyperthermia (right panel, Fig. 2). Although larger doses than 32 mg/kg of agmatine produced a modest hypothermia, the observed anti-hyperthermic effect of agmatine cannot be explained by the functional blockade effect as 10 mg/kg agmatine alone did not alter the rectal temperature but markedly reversed the hyperthermia induced by methamphetamine.

Agmatine is a naturally-occurring compound and it is present in mammal tissues. For example, plasma agmatine in both rats (0.45 ng/ml) and humans (47 ng/ml) is well above detectable levels as a result of endogenous release (Raasch et al., 1995; Feng et al., 1997). Agmatine is also widely available over-the-counter and in internet shops as a dietary supplement. One clinical trial reported that an intake of 3.56 g/day of agmatine for 21 days is well tolerated and has minimal adverse effects (Keynan et al., 2010). Remarkably, two authors from the same study recently reported their own daily use of a high dose of agmatine (2.67 g/day) for up to 5 years and no health-related adverse effects were found, suggesting the high safety of agmatine as a dietary supplement or as a potential medication (Gilad et al., 2014). The safety profile of agmatine combined with the current finding that agmatine is effective to reduce methamphetamine-induced hyperthermia suggests the possibility that agmatine might be useful to reverse methamphetamine overdose-related toxicity. These results are preliminary and more detailed studies are required to confirm this interesting finding.

In summary, this study extends our previous findings by showing that agmatine attenuated the discriminative stimulus effects of methamphetamine and methamphetamine-induced hyperthermia. These results raised the possibility that agmatine may have value to reduce methamphetamine abuse and reverse overdose. Given the wide availability and apparently good safety profiles, the transition from preclinical studies to clinical assessment seems relatively easy. More studies are warranted to assess the effectiveness of agmatine against other abuse- and addiction-related behavioral effects of methamphetamine and to examine the neurobiological mechanisms by whcih agmatine prevents methamphetamine-induced neurotoxicity.

Acknowledgments

This work was supported by the National Institute on Drug Abuse of the National Institutes of Health (award nos R01DA034806 and R21DA033426). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Conflicts of Interest

There are no conflicts of interest.

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