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. Author manuscript; available in PMC: 2022 Aug 1.
Published in final edited form as: Drug Alcohol Depend. 2021 May 26;225:108785. doi: 10.1016/j.drugalcdep.2021.108785

Effects of the GluN2B-selective antagonist Ro 63–1908 on acquisition and expression of methamphetamine conditioned place preference in male and female rats

Justin R Yates 1, Hunter L Campbell 1, Lauren L Hawley 1, Matthew J Horchar 1, Joy L Kappesser 2, Makayla R Wright 1
PMCID: PMC8282733  NIHMSID: NIHMS1708632  PMID: 34052688

Abstract

Background:

Methamphetamine abuse has increased significantly in recent years. Currently, there are no FDA-approved pharmacotherapies for the treatment of methamphetamine use disorder. The goal of the current study was to determine if the N-methyl-D-aspartate (NMDA) GluN2B-selective antagonist Ro 63–1908 can block the conditioned rewarding effects of methamphetamine as assessed in conditioned place preference (CPP).

Methods:

Two main experiments were conducted. In the first experiment, male (n = 24) and female (n = 24) rats received either vehicle or Ro 63–1908 (1.0–10.0 mg/kg) 30 min prior to the posttest to determine if blocking the GluN2B subunit attenuates expression of methamphetamine CPP. In the second experiment, male (n = 18) and female (n = 18) rats received either vehicle or Ro 63–1908 (1.0 or 3.0 mg/kg) 30 min prior to each conditioning session to determine if blocking the GluN2B subunit attenuates acquisition of methamphetamine CPP.

Results:

Ro 63–1908 (3.0 mg/kg) blocked acquisition of methamphetamine CPP in male rats, but only attenuated CPP in female rats. Ro 63–1908 did not alter expression of CPP in either sex. Increasing the dose of Ro 63–1908 (10.0 mg/kg) failed to block acquisition of CPP in an additional group of female rats (n = 6). A control experiment showed that Ro 63–1908 (3.0 mg/kg) did not produce CPP or conditioned place aversion in male rats (n = 6) or in female rats (n = 6).

Conclusions:

The results of this study show that Ro 63–1908 is able to decrease the conditioned rewarding effects of methamphetamine.

Keywords: conditioned place preference, methamphetamine, glutamate, NMDA receptor, GluN2B, rat

1. Introduction

Methamphetamine is a psychostimulant drug that has been prescribed to treat attention-deficit/hyperactivity disorder (ADHD) (as Desoxyn) that is reinforcing in several species (e.g., Balster and Schuster, 1973; Harrod et al., 2001; Hart et al., 2001; Munzar et al., 1999) and has high abuse potential (see Courtney and Ray, 2014). Because there are no FDA-approved pharmacotherapies for treating methamphetamine use disorder, finding a treatment option has been of considerable interest in recent years. Several pharmacological treatments have been used to reduce methamphetamine use, including agonist replacement therapy (i.e., amphetamine and methylphenidate) (Galloway et al., 2011; Miles et al., 2013; Rezaei et al., 2015; Rush et al., 2011; but see Pike et al., 2014 for mixed results), antidepressant medications such as bupropion (Ahmadi et al., 2019; Anderson et al., 2015; Elkashef et al., 2008; Heinzerling et al., 2014; Newton et al., 2006; Shoptaw et al., 2008, but see Stoops et al., 2015) and mirtazapine (Colfax et al., 2011), and the mu opioid receptor antagonist naltrexone (Anggadiredja et al., 2004; but see Coffin et al., 2018; Stoops et al., 2015). Even though several drug classes have been shown to reduce methamphetamine use or decrease cravings in individual studies, results of a recent meta-analysis revealed that most drugs reviewed did not provide statistically significant reductions in methamphetamine use (Chen et al., 2019). The results of this meta-analysis highlight the need to test novel molecular targets for the treatment of methamphetamine use disorder.

Although methamphetamine’s primary mechanisms of action are to reverse the vesicular monoamine transporter (VMAT2) (Peter et al., 1994) and monoamine transporters, such as the dopamine transporter (DAT) (Eschleman et al., 1994), as well as to inhibit monoamine oxidase (MAO) (Suzuki et al., 1980), there is evidence that methamphetamine directly interacts with the glutamatergic system. Glutamate is the major excitatory neurotransmitter in the mammalian brain and binds to several types of metabotropic receptors (mGluRs) and ionotropic receptors (iGluRs), including N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (see Ozawa et al., 1998 for a review). In humans, acute administration of methamphetamine increases glutamate/glutamine levels in dorsal anterior cingulate cortex in women, but not in men (White et al., 2018), but decreased levels of glutamate/glutamine are observed in recently abstinent men and women (Ernst and Chang, 2008). Methamphetamine significantly increases evoked excitatory currents within prefrontal cortex (PFC) in male rats and mice (Han et al., 2012; Lominac et al., 2016; Mishra et al., 2017; but see Pena-Bravo et al., 2019) and in female rats (Pena-Bravo et al., 2019). In male rodents, methamphetamine increases extracellular levels of glutamate in striatum (Bustamante et al., 2002; Nash and Yamamoto, 1992) and medial prefrontal cortex (mPFC) (Han et al., 2012), decreases extracellular glutamate levels in dorsal hippocampus (Han et al., 2012), alters NMDA receptor subunit and vesicular glutamate transporter (VGLUT2) expression in striatum (Furlong et al., 2018; Simões et al., 2008), and increases GluN1 and GluN2B subunit expression in PFC (Mishra et al., 2017; Simões et al., 2008) and in hippocampus (Li et al., 2014; Simões et al., 2007). Additionally, repeated methamphetamine administration decreases NMDA receptor binding in PFC and hippocampus (Lee et al., 2011). Overall, this evidence suggests that targeting the glutamatergic system may provide novel treatment options for methamphetamine use disorder.

To this end, the NMDA receptor channel blocker MK-801 decreases methamphetamine conditioned place preference (CPP) (Kim and Jang, 1997). Considering MK-801 is a psychotomimetic that can cause Olney’s lesions (Olney et al., 1989), using this drug as a therapeutic for methamphetamine use disorder is unrealistic. Although all NMDA receptors are composed of two NR1 subunits, these receptors are also composed of two NR2 subunits that can be subdivided into GluN2A-D. The GluN2B subunit has received considerable attention, as ifenprodil, a GluN2B antagonist, is able to attenuate the rewarding effects of opiates (Ma et al., 2006; Ma et al., 2011; Suzuki et al., 1999), prevent reinstatement of nicotine-seeking behavior (Gipson et al., 2013), and block the acquisition of methamphetamine CPP (Kurokawa et al., 2011).

Although Kurokawa et al. (2011) have previously shown that ifenprodil can block the conditioned rewarding effects of methamphetamine, they only tested the effects of ifenprodil on the acquisition of CPP. That is, they administered ifenprodil prior to each methamphetamine injection. In order to determine if a drug is effective in treating a substance use disorder, it is important to test the effects of the potential pharmacotherapy after animals have already acquired the association between an environmental context and the drug of abuse. This is known as the expression of CPP. Ifenprodil is able to block the expression of morphine CPP (e.g., Ma et al., 2006), but research has not determined if GluN2B-selective antagonists can block the expression of methamphetamine CPP. Additionally, Kurokawa et al. (2011) only tested male mice in their study. Given that a large number of preclinical studies have used male subjects exclusively (see second paragraph of Introduction), the goal of the current study was to determine if the highly selective GluN2B-selective antagonist Ro 63–1908 is able to attenuate the expression and/or the acquisition of methamphetamine CPP in males and in females. We selected Ro 63–1908 because it has higher affinity for the GluN2B subunit compared to ifenprodil (Gill et al., 2002; Higgins et al., 2005).

2. Material and methods

2.1. Subjects

A total of 48 male (241.354 ± 1.271 g/64.143 ± 0.451 days old at the beginning of testing) and 48 female (178.417 ± 1.234 g/52.146 ± 1.085 days old at the beginning of testing) Sprague Dawley rats (Envigo, Indianapolis, IN) were used in the present experiments. Rats were housed individually immediately upon delivery to the laboratory. Rats were housed in a temperature- and humidity-controlled colony room that was maintained on a light–dark cycle in which lights were on from 7:00 a.m. to 7:00 p.m. Rats were allowed to acclimate to the colony for at least 6 days before the start of the experiment. Rats had ad libitum access to food and water in their home cage for the entire experiment. Testing occurred during the light phase. All procedures were in accordance with the “Guide for the Care and Use of Laboratory Animals” (National Research Council, 2018) and were approved by the Institutional Animal Care and Use Committee at Northern Kentucky University (IACUC protocol #2019–04).

2.2. Drugs

Methamphetamine hydrochloride (Sigma Aldrich, St. Louis, MO) was mixed in 0.9% NaCl (saline). 1-[2-(4-hydroxyphenoxy)-ethyl]-4-[(4-methylphenyl)methyl]-4-piperidinol hydrochloride (Ro 63–1908; GluN2B IC50 of ~0.003–0.01 μM compared to GluN2A IC50 of ~100 μM and GluN2D IC50 of ~10 μM; Gill et al., 2002) (Tocris Bioscience, Minneapolis, MN) was mixed in 5% Tween 80 in saline and gently stirred and heated to get into solution. Saline served as the control for methamphetamine injections, and vehicle (saline mixed with 5% Tween 80) served as the control for Ro 63–1908 injections. All injections were delivered subcutaneously (s.c.) at a volume of 1.0 ml/kg. The doses were calculated based on salt weight. The dose of methamphetamine and injection time (immediately before each session) were chosen based on previous research (Hensleigh and Pritchard, 2014; Risca et al., 2020; Schindler et al., 2002). Similarly, each dose of Ro 63–1908 and injection time (30 min before each session) were chosen from published research (Higgins et al., 2003; Higgins et al., 2005; Higgins et al., 2016) and from preliminary research conducted in our laboratory. A 30-min pretreatment of time of Ro 63–1908 was used to ensure that it was behaviorally active during conditioning sessions (acquisition experiment) or during the posttest (expression experiment).

2.3. Apparatus

Eight 3-compartment chambers (68 × 21 × 21 cm; ENV-013; MED Associates; St. Albans, VT) located inside sound-attenuating chambers (ENV-020M; MED Associates) were used to measure locomotor activity and CPP. The three compartments were separated by sliding guillotine doors. The middle compartment (12 × 21 × 21 cm) had gray walls with a smooth gray PVC floor. The end compartments (28 × 21 × 21 cm) provided different contexts, with one compartment having black walls with a stainless-steel grid rod floor and the other end compartment having white walls with a stainless-steel mesh floor. Recessed trays were located 2 cm below each compartment. A computer controlled the experimental session using Med-IV/Med-V software. A series of infrared photobeams (6 beams in the black and white compartments and 3 beams in the gray compartment) were used to detect the rats’ presence in a particular compartment and record the amount of time spent in that compartment, as well as to record locomotor activity (non-repeating photobeam breaks) and repeating photobeam breaks during conditioning sessions.

2.4. General Procedure

The CPP paradigm lasted for a total of 10 days for all rats. On the first day of each CPP experiment, the rats were given a pretest. They were able to travel freely in the CPP chamber for 15 min. The time spent in each compartment was recorded. The chamber that the rat spent the least amount of time in during the pretest was the one that was paired with methamphetamine during the conditioning phase (i.e., biased design). Following the pretest, rats experienced 8 days of conditioning, in which rats were confined by the guillotine door to either the black or the white compartment for 30 min. Rats received an injection of methamphetamine (1.0 mg/kg; s.c.) and then were immediately placed in the initially non-preferred chamber every other day. On alternating days, rats received an injection of saline (1.0 ml/kg; s.c.) and then were immediately placed in the initially preferred chamber. During the posttest, the guillotine doors were removed, and rats were allowed to explore all three compartments for 15 min. The time spent in each compartment was recorded. Locomotor activity was measured by counting the number of non-repeating photobeam breaks in each compartment. Repeating photobeam breaks were also recorded.

2.4.1. Expression of Methamphetamine CPP.

Rats received one of four doses of Ro 63–1908 (0, 1.0, 3.0, 10.0 mg/kg; s.c.; n = 6 per dose per sex) 30 min before the posttest. Rats were randomly assigned to receive a particular dose of Ro 63–1908.

2.4.2. Acquisition of Methamphetamine CPP.

Rats received one of three doses of Ro 63–1908 (0, 1.0, 3.0 mg/kg; s.c.; n = 6 each dose each sex) 30 min before receiving each injection of methamphetamine and received an injection of vehicle 30 min before receiving each injection of saline. Rats were then given a posttest as described above in the General Procedure section. Rats did not receive any injections before the posttest. As in the expression experiments, rats were randomly assigned to receive a particular dose of Ro 63–1908.

2.4.3. Acquisition of Ro 63–1908 CPP.

Because we found that Ro 63–1908 (3.0 mg/kg) blocked acquisition of methamphetamine CPP in male rats, we conducted a control experiment to determine if Ro 63–1908 produces CPP or conditioned place aversion (CPA) on its own. Twelve additional rats (n = 6 each sex) were tested in a procedure similar to the one described in the General Procedure section; however, instead of injecting rats with methamphetamine, we injected them with Ro 63–1908 (3.0 mg/kg; s.c.) 30 min before placing them in the initially non-preferred chamber. Every other day, rats received an injection of vehicle (1.0 ml/kg) 30 min before being placed in the initially preferred chamber.

2.5. Statistical Analyses

All analyses were performed in Jamovi (version 1.6.18.0). We primarily used mixed factor ANOVAs to analyze CPP data and locomotor activity/repeating photobeam breaks (see subsections below for specific details). For all analyses, Tukey’s post hoc tests were used when a main effect of Ro 63–1908 dose was observed, and follow-up ANOVAs, pairwise comparisons, and/or independent-samples t tests were conducted when significant interactions were observed. The type of post hoc test used is specified in each subsection of the Results section. Statistical significance was defined as p < .05 for each ANOVA; however, p values were adjusted according to the Tukey method when performing pairwise comparisons to control for Type I error, or they were adjusted using a Bonferroni correction when performing multiple independent-samples t tests. When sphericity was violated, degrees of freedom were corrected using Greenhouse-Geisser estimates. Cohen’s f was used as a measure of effect size for each ANOVA, whereas Cohen’s d was used as a measure of effect size for each t test.

2.5.1. Time Spent in Each Compartment During Pretest.

We wanted to determine if rats spent an equal amount of time in the white and black compartments during the pretest (i.e., determine if we had a biased or unbiased apparatus). For the expression and the acquisition experiments, the mixed factor ANOVA included compartment as a within-subjects factor and sex and Ro 63–1908 dose as between-subjects factors. For the control experiment (Ro 63–1908 CPP), the mixed factor ANOVA included compartment as a within-subjects factor and sex as a between-subjects factor.

2.5.2. Expression of Methamphetamine CPP.

CPP was quantified by comparing the time spent in the methamphetamine-paired compartment during the posttest to the time spent in this compartment during the pretest. A mixed factor ANOVA was used to determine if Ro 63–1908 altered the expression of methamphetamine CPP, with test (pretest vs. posttest) as a within-subjects factor and sex and Ro 63–1908 dose as between-subjects factors.

Because the time spent in the methamphetamine-paired and saline-paired compartments were not equivalent during the posttest (i.e., rats spent more time in the methamphetamine-paired compartment during the posttest), we divided the number of non-repeating photobeam breaks (locomotor activity) in the methamphetamine-paired and the saline-paired compartments by the time spent in each compartment. To determine if Ro 63–1908 altered non-repeating photobeam breaks per second during the posttest of the expression experiment, a two-way ANOVA was conducted, with Ro 63–1908 dose and sex as between-subjects factors. The same analysis was used for repeating photobeam breaks/s.

2.5.3. Acquisition of Methamphetamine CPP.

CPP data were analyzed as described above.

To determine if Ro 63–1908 augmented the locomotor-stimulant effects of methamphetamine during the acquisition experiment, locomotor activity was analyzed with a mixed-factor ANOVA, with methamphetamine treatment (methamphetamine vs. saline) and session as within-subjects factors and sex and Ro 63–1908 dose as between-subjects factors. Because the time spent in the methamphetamine-paired and the saline-paired compartments was identical for each conditioning session (30 min per session), we analyzed the total number of photobeam breaks as opposed to photobeam breaks per second as in the expression experiment. Repeating photobeam breaks were analyzed in the same manner.

2.5.4. Acquisition of Ro 63–1908 CPP.

For the control experiment, a mixed factor ANOVA was used to determine if Ro 63–1908 (3.0 mg/kg) produced CPP or aversion on its own, with test as a within-subjects factor and sex as a between-subjects factor. To determine if Ro 63–1908, when administered alone, altered locomotor activity relative to vehicle, locomotor activity was analyzed with a mixed-factor ANOVA, with Ro 63–1908 treatment (Ro 63–1908 vs. vehicle) and session as within-subjects factors and sex as a between-subjects factor. The same analysis was used to determine if Ro 63–1908 altered repeating photobeam breaks.

3. Results

3.1. Time Spent in Each Compartment During Pretest

Table 1 shows the time spent in each compartment during the pretest for the expression, the acquisition, and the control experiments. For all experiments, there was a main effect of compartment, all F’s ≥ 10.436, all p’s ≤ .001, all f’s ≥ 0.906. For each experiment, Tukey’s post hoc tests showed that the time spent in the gray compartment was lower than the time spent in the white compartment and in the black compartment. In the expression experiment, Tukey’s post hoc tests also showed that the time spent in the white compartment was higher compared to the time spent in the black compartment.

Table 1.

Mean (± SEM) time spent (in s) in each compartment of the CPP chamber during the pretest.

Expression of Methamphetamine CPP
Males (n = 24) Females (n = 24)
Compartment M SEM Compartment M SEM
Gray* 225.268 14.583 Gray* 180.154 11.934
White 338.667 9.187 White# 402.419 17.386
Black 336.317 10.013 Black 315.349 12.857
Acquisition of Methamphetamine CPP
Males (n = 18) Females (n = 18)
Compartment M SEM Compartment M SEM
Gray* 219.852 11.549 Gray* 168.793 11.579
White 344.197 13.888 White 388.329 21.946
Black 335.951 14.542 Black 342.878 15.356
Acquisition of Ro 63–1908 (3.0 mg/kg) CPP
Males (n = 6) Females (n = 6)
Compartment M SEM Compartment M SEM
Gray* 210.498 15.978 Gray* 188.953 20.219
White 337.670 27.155 White 340.218 41.264
Black 351.832 26.027 Black 370.828 45.776
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*

p < .05, compared to the white and the black compartments

#

p < .05, compared to the black compartment of the same sex and compared to the white compartment of the opposite sex.

While no other significant effects/interactions were observed for the acquisition or the control experiments, there was a significant compartment × sex interaction in the expression experiment, F(2, 80) = 6.084, p = .003, f = 0.350. Pairwise comparisons (with Tukey p-adjusted values) revealed that the time spent in the gray compartment was lower than the time spent in either the white compartment or in the black compartment for both sexes (all p’s < .001). Whereas males spent a similar amount of time in the white and in the black compartment (p = 1.000), females spent more time in the white compartment compared to the black compartment (p = .004). Females also spent more time in the white compartment compared to males (p = .014), but not in the gray (p = .175) or in the black compartment (p = .877).

3.2. Expression of Methamphetamine CPP

To test the contribution of the GluN2B subunit to the expression of methamphetamine CPP, Ro 63–1908 was administered 30 min before the posttest. Results of the mixed factor ANOVA revealed a main effect of test only, F(1, 40) = 96.884, p < .001, f = 1.511. Regardless of Ro 63–1908 treatment or sex, rats showed expression of methamphetamine CPP as the time spent in the methamphetamine-paired compartment was higher during the posttest compared to the pretest (Figs. 1a and 1b).

Figure 1.

Figure 1.

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Effects of Ro 63–1908 on the expression of methamphetamine CPP. Mean (± SEM) time spent in the methamphetamine-paired compartment during the pretest and during the posttest for males (a) and for females (b). Mean (± SEM) non-repeating photobeam breaks/s (i.e., locomotor activity) in each compartment for males (c) and for females (d). Mean (± SEM) repeating photobeam breaks/s in each compartment for males (e) and for females (f). *p < .05, compared to pretest (main effect of test). #p < .05, compared to the methamphetamine-paired chamber (main effect of compartment). $p < .05, compared to females. @p < .05, compared to each dose of Ro 63–1908. ^p < .05, compared to vehicle (averaged across each chamber). $p < .05, compared to female rats.

3.3. Effects of Ro 63–1908 on Locomotor Activity During Posttest of Expression Experiment

Table 2 shows the total non-repeating and repeating photobeam breaks following each dose of Ro 63–1908 across males and females. Because the time spent in each compartment differed during the posttest, we divided the total non-repeating/repeating photobeam breaks by the time spent in the methamphetamine-paired and the saline-paired compartments. For locomotor activity (non-repeating photobeam breaks/s) (Figs. 1c and 1d), there were main effects of chamber, F(1, 40) = 32.533, p < .001, f = 0.867, sex, F(1, 40) = 5.517, p = .024, f = 0.328, and Ro 63–1908 dose, F(3, 40) = 16.575, p < .001, f = 1.031. None of the interactions were statistically significant. Overall, non-repeating photobeam breaks/s were higher in the saline-paired compartment compared to the methamphetamine-paired compartment, and males had greater locomotor activity compared to females. Tukey’s post hoc test showed that each dose of Ro 63–1908, averaged across sex, significantly increased locomotor activity compared to vehicle. Locomotor activity, averaged across sex and session, was also higher following the highest dose of Ro 63–1908 (10.0 mg/kg) compared to the lowest dose of Ro 63–1908 (1.0 mg/kg).

Table 2.

Mean (± SEM) non-repeating photobeam breaks (i.e., locomotor activity) and repeating photobeam breaks during the expression experiment across each Ro 63–1908 dose for males and females.

Locomotor Activity (Non-repeating Photobeam Breaks) Repeating Photobeam Breaks
Vehicle
Males (n = 6) Females (n = 6) Males (n = 6) Females (n = 6)
Compartment M SEM Compartment M SEM Compartment M SEM Compartment M SEM
Methamphetamine 460.833 71.781 Methamphetamine 625.667 60.508 Methamphetamine 406.167 133.648 Methamphetamine 323.667 42.022
Saline 235.833 50.640 Saline 478.167 27.724 Saline 60.000 15.822 Saline 208.833 36.667
Ro 63–1908 (1.0 mg/kg)
Males (n = 6) Females (n = 6) Males (n = 6) Females (n = 6)
Compartment M SEM Compartment M SEM Compartment M SEM Compartment M SEM
Methamphetamine 835.500 96.375 Methamphetamine 986.500 65.426 Methamphetamine 221.667 27.039 Methamphetamine 403.667 67.047
Saline 487.167 76.745 Saline 427.667 31.203 Saline 80.500 29.722 Saline 79.333 41.670
Ro 63–1908 (3.0 mg/kg)
Males (n = 6) Females (n = 6) Males (n = 6) Females (n = 6)
Compartment M SEM Compartment M SEM Compartment M SEM Compartment M SEM
Methamphetamine 1018.667 188.974 Methamphetamine 952.000 90.736 Methamphetamine 159.000 58.208 Methamphetamine 221.500 70.272
Saline 677.333 146.028 Saline 765.833 107.985 Saline 125.167 54.662 Saline 86.833 13.085
Ro 63–1908 (10.0 mg/kg)
Males (n = 6) Females (n = 6) Males (n = 6) Females (n = 6)
Compartment M SEM Compartment M SEM Compartment M SEM Compartment M SEM
Methamphetamine 1048.667 126.725 Methamphetamine 952.500 138.187 Methamphetamine 326.333 40.374 Methamphetamine 118.667 27.256
Saline 557.167 127.192 Saline 795.000 52.040 Saline 103.333 39.553 Saline 179.500 56.141
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Note, inferential statistics were not performed on the total non-repeating/repeating photobeam breaks as we analyzed non-repeating photobeam breaks/s and repeating photobeam breaks/s.

For repeating photobeam breaks/s (Figs. 1e and 1f), there was a main effect of dose, F(3, 40) = 2.972, p = .043, f = 0.367, and there were significant chamber × sex, F(1, 40) = 4.192, p = .047, f = 0.276, and chamber × sex × Ro 63–1908 interactions, F(3, 40) = 3.624, p = .021, f = 0.423. None of the other main effects/interactions were statistically significant. Tukey’s post hoc tests showed that Ro 63–1908 (3.0 mg/kg) decreased repeating photobeam breaks compared to vehicle. Although there was a significant chamber × sex interaction, there were no significant pairwise comparisons (all p’s ≥ .079). Because the three-way interaction resulted in 120 pairwise comparisons (many that were not of direct interest), we probed this interaction two different ways. First, we conducted two separate mixed factor ANOVAs for each sex, with chamber as a within-subjects factor and Ro 63–1908 dose as a between-subjects factor. For males, there was a main effect of chamber only, F(1, 20) = 6.665, p = .018, f = 0.508. For females, there was a significant chamber × Ro 63–1908 dose interaction only, F(3, 20) = 3.321, p = .041, f = 0.539. This interaction may have been driven by the elevated repeated photobeam breaks/s in the methamphetamine-paired compartment compared to the saline-paired compartment following vehicle treatment; however, none of the pairwise comparisons were statistically significant (all p’s ≥ .167).

The second way we probed the significant chamber × sex × Ro 63–1908 interaction was by directly comparing male and females at each Ro 63–1908 dose for both methamphetamine-paired and saline-paired compartments. We performed four independent-samples t tests to determine if repeating photobeam breaks in the methamphetamine-paired compartment differed across males and females. We divided our alpha level by four to control for Type I error (adjusted alpha level of .0125). We performed a similar analysis to determine if repeating photobeam breaks in the saline-paired compartment differed across males and females. Males had more repeating photobeam breaks/s in the saline-paired compartment following vehicle treatment compared to females, t(10) = 4.590, p < .001, d = 2.650, but they had fewer photobeam breaks/s in the methamphetamine-paired compartment following Ro 63–1908 (10.0 mg/kg) treatment, t(10) = −3.341, p = .007, d = −1.929.

3.4. Acquisition of Methamphetamine CPP

To test the contribution of the GluN2B subunit to the acquisition of methamphetamine CPP, Ro 63–1908 was administered 30 min before each methamphetamine injection during conditioning sessions. Figure 2 shows the acquisition of methamphetamine CPP in males (Fig. 2a) and in females (Fig. 2b) following Ro 63–1908 pretreatment (0–3.0 mg/kg). Overall, rats developed CPP to methamphetamine, as evidenced by a significant main effect of test, F(1, 30) = 45.769, p < .001, f = 1.183. However, there was a main effect of Ro 63–1908 dose, F(2, 30) = 3.976, p = .029, f = 0.425, as well as a significant test × Ro 63–1908 dose interaction, F(2, 30) = 13.125, p < .001, f = 0.857. Furthermore, there was a significant test × sex × Ro 63–1908 dose interaction, F(2, 30) = 3.457, p = .045, f = 0.386. Tukey’s post hoc tests showed that time spent in the methamphetamine-paired compartment was lower following Ro 63–1908 (3.0 mg/kg) pretreatment relative to vehicle pretreatment and to Ro 63–1908 (1.0 mg/kg) pretreatment.

Figure 2.

Figure 2.

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Effects of Ro 63–1908 on the acquisition of methamphetamine CPP in males (a) and in females (b). *p < .05, compared to pretest. $p < .05, compared to female rats. ^p < .05, compared to vehicle pretreatment.

Because the test × Ro 63–1908 dose interaction was qualified by a significant test × sex × Ro 63–1908 dose interaction, the results of the three-way interaction will be discussed only. To probe this interaction, we first conducted two separate mixed factor ANOVAs for each sex. These ANOVAs included test as a within-subjects factor and Ro 63–1908 dose as a between-subjects factor. For males, there were main effects of test, F(1, 15) = 11.858, p = .004, f = 0.799, and Ro 63–1908 dose, F(2, 15) = 9.525, p = .002, f = 0.973, as well as a significant test × Ro 63–1908 dose interaction, F(2, 15) = 9.634, p = .002, f = 0.980. Pairwise comparisons showed that rats spent more time in the methamphetamine-paired compartment during the posttest compared to the pretest following vehicle pretreatment (p = .002), but not following pretreatment of either dose of Ro 63–1908 (p’s of .222 and .783, respectively). Ro 63–1908 (3.0 mg/kg) pretreated rats spent significantly less time in the methamphetamine-paired compartment during the posttest compared to rats pretreated with vehicle (p < .001) and with Ro 63–1908 (1.0 mg/kg) (p = .008).

For females, there was a main effect of test, F(1, 15) = 40.554, p < .001, f = 1.525, and a significant test × Ro 63–1908 dose interaction, F(2, 15) = 6.482, p = .009, f = 0.781. Like males, females spent more time in the methamphetamine-paired compartment during the posttest compared to the pretest following vehicle pretreatment (p < .001), but not following treatment of either dose of Ro 63–1908 (p’s of .621 and .088, respectively). However, neither dose of Ro 63–1908 decreased the time spent in the methamphetamine-paired compartment during the posttest compared to vehicle (p’s of .388 and .492, respectively).

The second way we probed the significant test × sex × Ro 63–1908 dose interaction was by directly comparing males and females at each Ro 63–1908 dose for both the pretest and the posttest. Because each test contains three comparisons (each Ro 63–1908 dose), we divided our alpha level by three to control for Type I error (adjusted alpha level of .017). Males and females did not differ in the time spent in the methamphetamine-paired compartment at pretest across each dose of Ro 63–1908. Females spent significantly more time in the methamphetamine-paired compartment during the posttest following Ro 63–1908 (3.0 mg/kg) administration relative to males, t(10) = −3.155, p = .010, d = −1.821.

3.5. Effects of Ro 63–1908 on Methamphetamine-Induced Locomotion

Figure 3 shows locomotor activity (non-repeating photobeam breaks) during conditioning sessions of the acquisition experiment for males (Fig. 3a–c) and for females (Fig. 3d–f). Overall, there were main effects of methamphetamine treatment, F(1, 30) = 189.535, p < .001, f = 2.427, session, F(3, 90) = 4.400, p = .006, f = 0.329, and Ro 63–1908 dose, F(2, 30) = 6.978, p = .003, f = 0.602. There were also methamphetamine treatment × session, F(3, 90) = 3.500, p = .019, f = 0.283, methamphetamine treatment × Ro 63–1908 dose, F(2, 30) = 14.106, p < .001, f = 0.891, session × sex, F(3, 90) = 4.022, p = .010, f = 0.311, session × Ro 63–1908 dose, F(6, 90) = 2.330, p = .039, f = 0.287, and methamphetamine treatment × session × sex interactions, F(3, 90) = 7.948, p < .001, f = 0.471. None of the other main effects or interactions were statistically significant. Overall, locomotor activity was higher following methamphetamine administration compared to saline administration. Tukey’s post hoc tests also showed that locomotor activity was higher on sessions 3 and 4 compared to session 1 and that locomotor activity was higher following Ro 63–1908 (1.0 mg/kg) pretreatment compared to vehicle pretreatment and to Ro 63–1908 (3.0 mg/kg) pretreatment.

Figure 3.

Figure 3.

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Mean (± SEM) non-repeating photobeam breaks in male rats (a–c) and in female rats (d–f) across each conditioning session of the acquisition experiment. *p < .05, compared to other methamphetamine session (significant methamphetamine treatment × Ro 63–1908 dose interaction). #p < .05, compared to saline sessions following vehicle pretreatment (main effect of methamphetamine treatment). ^p < .05, compared to the vehicle + methamphetamine and methamphetamine + Ro 63–1908 (3.0 mg/kg) groups. $p < .05, compared to female rats, and %p < .05, compared to sessions 1–3 (methamphetamine treatment × session × sex interaction).

For the methamphetamine treatment × Ro 63–1908 dose interaction, methamphetamine-induced hyperactivity was elevated following Ro 63–1908 (1.0 mg/kg) pretreatment relative to vehicle pretreatment (p < .001) and to Ro 63–1908 (3.0 mg/kg) pretreatment (p < .001). Ro 63–1908 (3.0 mg/kg) did not augment the locomotor-stimulant effects of methamphetamine compared to vehicle (p = .956). Vehicle pretreatment did not affect locomotor activity following saline injections (p’s ≥ .983).

We probed the session × Ro 63–1908 dose interaction by first averaging the time spent in the methamphetamine-paired and the saline-paired compartments before analyzing these data with separate repeated measures ANOVAs for each Ro 63–1908 dose. Following vehicle pretreatment, locomotor activity significantly increased across sessions, F(3, 33) = 10.208, p < .001, f = 0.864. Locomotor activity was lower on session 1 compared to sessions 3 and 4, and activity was lower on session 2 compared to session 4. Locomotor activity did not increase across sessions following pretreatment with either dose of Ro 63–1908.

Because the methamphetamine treatment × session × sex interaction qualifies the methamphetamine treatment × session and the session × sex interactions, we will focus on the three-way interaction. Given the large number of pairwise comparisons arising from this interaction, we probed this interaction using two methods. First, we conducted two repeated measures ANOVAs, one for each sex. These ANOVAs included methamphetamine treatment and session as within-subjects factors. For males, there were main effects of methamphetamine treatment, F(1, 17) = 76.230, p < .001, f = 1.990, and session, F(3, 51) = 4.693, p = .006, f = 0.449, as well as a significant methamphetamine treatment × session interaction, F(3, 51) = 7.225, p < .001, f = 0.583. Tukey’s post hoc tests showed that locomotor activity was higher on session 4 compared to sessions 1 and 2. The interaction can be explained by the finding that locomotor activity was significantly higher on the fourth methamphetamine session compared to the first three sessions (all p’s ≤ .038), whereas locomotor activity did not change across saline sessions (all p’s ≥ .488). For females, there was a main effect of methamphetamine treatment only, F(1, 17) = 37.532, p < .001, f = 1.387.

The second way we probed the significant test × Ro 63–1908 dose × sex interaction was by directly comparing males and females across each methamphetamine session and across each saline session. Because each treatment contains four comparisons (each session), we divided our alpha level by four to control for Type I error (adjusted alpha level of .0125). Across methamphetamine sessions, males had significantly higher locomotor activity on session 4 compared to females, t(34) = 2.794, p = .005, d = 0.931. Across saline sessions, males had significantly lower locomotor activity on session 4 compared to females, t(34) = −3.141, p = .003, d = −1.047.

3.6. Effects of Ro 63–1908 on Methamphetamine-Induced Increases in Repeating Photobeam Breaks

Figure 4 shows repeating photobeam breaks in the acquisition experiment for males (Figs. 4a–4c) and for females (Figs. 4d–4f). There were main effects of methamphetamine treatment, F(1, 30) = 11.099, p < .001, f = 0.562, and sex, F(1, 30) = 4.847, p = .036, f = 0.347, as well as a significant methamphetamine treatment × session interaction, F(2.232, 66.967) = 4.948, p = .008, f = 0.354. Repeating photobeams breaks were higher following methamphetamine treatment compared to saline treatment, and males displayed more repeating photobeam breaks compared to females. Pairwise comparisons showed that repeating photobeam breaks were higher on the fourth methamphetamine conditioning session compared to the first session (p = .010). Additionally, repeating photobeam breaks were higher on the third and fourth methamphetamine conditioning sessions compared to the third and fourth saline conditioning sessions (p’s of .005 and .006, respectively). Repeating photobeam breaks did not differ across saline sessions (all p’s ≥ .333).

Figure 4.

Figure 4.

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Mean (± SEM) repeating photobeam breaks in male rats (a–c) and in female rats (d–f) across each conditioning session of the acquisition experiment. *p < .05, compared to the first methamphetamine session. #p < .05, compared to saline sessions following vehicle pretreatment. $p < .05, compared to female rats (averaged across Ro 63–1908 doses). ^p < .05, compared to the third and fourth saline + vehicle sessions.

3.7. Acquisition of Ro 63–1908 CPP

Because Ro 63–1908 (3.0 mg/kg) blocked the acquisition of methamphetamine CPP, we conducted a control experiment in which both male and female rats were given alternating injections of Ro 63–1908 (3.0 mg/kg) and vehicle 30 minutes before being isolated to one of the end compartments. There were no main effects or a significant interaction between sex and Ro 63–1908 dose (Fig. 5a).

Figure 5.

Figure 5.

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Mean (± SEM) time spent in the Ro 63–1908-paired compartment during the pretest and during the posttest for males and females (a). Mean (± SEM) non-repeating photobeam breaks in male rats (b) and in female rats (c) across each conditioning session. Mean (± SEM) repeating photobeam breaks in male rats (d) and in female rats (e) across each conditioning session. #p < .05, relative to vehicle (main effect of Ro 63–1908 treatment).

3.8. Locomotor Effects of Ro 63–1908 in Control Experiment

When administered alone, Ro 63–1908 (3.0 mg/kg) significantly increased locomotor activity compared to vehicle (main effect of Ro 63–1908 treatment), F(1, 10) = 145.625, p < .001, f = 3.472 (Figs. 5b and 5c). There were no other main effects of interactions. For repeating photobeam breaks, there were no main effects or interactions (Figs. 5d and 5e).

4. Discussion

In the current experiment, we intentionally used a dose of methamphetamine that has been shown to produce CPP in males and in females (Hensleigh and Pritchard, 2014; Risca et al., 2020; Schindler et al., 2002) as we wanted to determine if Ro 63–1908 could attenuate the acquisition and/or expression of methamphetamine CPP to a similar extent across each sex. We found that Ro 63–1908 (3.0 mg/kg) blocks the acquisition of methamphetamine CPP in male rats and attenuates, but not completely blocks, the acquisition of methamphetamine CPP in female rats. Importantly, the ability of Ro 63–1908 to decrease the conditioned rewarding effects of methamphetamine does not result from aversion to Ro 63–1908 as rats tested in a control experiment did not develop a significant preference or an aversion to the environment paired with Ro 63–1908. Furthermore, this dose of Ro 63–1908 did not alter the locomotor-stimulant effects of methamphetamine, although a lower dose (1.0 mg/kg) enhanced methamphetamine-induced hyperactivity. Whereas Ro 63–1908 blocked the acquisition of methamphetamine CPP, it did not affect the expression of CPP.

Previous research has demonstrated the importance of the GluN2B subunit to methamphetamine CPP. Increased GluN2B expression is observed in male mice (Kurokawa et al., 2011; Li et al., 2014) and in male zebrafish (Jiang et al., 2016) following acquisition of methamphetamine CPP, and the GluN2B antagonist ifenprodil blocks the acquisition of methamphetamine CPP in male mice (Kurokawa et al., 2011). The current study extends the literature by showing that the GluN2B subunit is an important mediator of the acquisition of methamphetamine CPP in both male rats and in female rats. Importantly, impairments to general learning do not appear to account for the current results, as ifenprodil blocks the acquisition of morphine CPP without altering food-induced or social interaction CPP (Ma et al., 2006). Additionally, GluN2B-selective antagonists often lack the psychotomimetic effects observed with NMDA receptor antagonists like MK-801 (Jiménez-Sánchez et al., 2014; Lima-Ojeda et al., 2013).

Whereas Ro 63–1908 (3.0 mg/kg) pretreatment blocked the acquisition of methamphetamine CPP in male rats (42.312% decrease in time spent in methamphetamine-paired compartment during posttest compared to vehicle pretreated rats), Ro 63–1908 pretreatment only attenuated CPP in females (16.205% and 14.714% decrease from vehicle pretreatment at 1.0 mg/kg and 3.0 mg/kg dose, respectively). To determine if increasing the dose of Ro 63–1908 could fully block the acquisition of CPP in females, we tested an additional group of female rats (see Supplemental Materials and Methods for more details). Pretreatment with a higher dose of Ro 63–1908 (10.0 mg/kg) failed to significantly decrease preference for the methamphetamine-paired compartment during the posttest in females (8.995% decrease compared to vehicle pretreatment). Interestingly, we have previously shown that Ro 63–1908 reduces risky choice in male rats without altering risky choice in female rats (Yates et al., 2021). The blunted effect of Ro 63–1908 on acquisition of methamphetamine CPP and risky choice observed in females may result from sex-related differences in the glutamatergic system. Directly related to the current experiment, female rats have greater GluN2B subunit expression in the hippocampus compared to males (Wang et al., 2015). Given that methamphetamine upregulates GluN2B protein expression in hippocampus (Li et al., 2014), Ro 63–1908 may have blocked a smaller percentage of GluN2B-containing NMDA receptors in females compared to males, resulting in the modest attenuation in acquisition of methamphetamine CPP.

Although Ro 63–1908 blocked the acquisition of methamphetamine CPP, it failed to attenuate the expression of methamphetamine CPP. Some caution is needed when interpreting the null effects of Ro 63–1908 on expression of methamphetamine CPP. Given that methamphetamine and Ro 63–1908 increase locomotor activity, the locomotor-stimulant effects of Ro 63–1908 may have led to a form of generalization during the posttest. That is, Ro 63–1908 may have substituted for methamphetamine during the posttest, eliciting approach behavior toward the compartment paired with methamphetamine. At first glance, the finding that locomotor activity (non-repeating photobeam breaks/s) increased in the methamphetamine-paired compartment following Ro 63–1908 administration relative to vehicle administration provides some support for this hypothesis. However, the number of non-repeating photobeam breaks/s in the saline-paired compartment increased as well and was higher compared to the methamphetamine-paired compartment. Therefore, the current results do not appear to reflect a form of generalization.

In addition to increasing locomotor activity in the expression experiment, Ro 63–1908 (3.0 mg/kg), when administered alone in the control experiment, increased locomotor activity during conditioning sessions. These results are consistent with previous studies (Gill et al., 2002; Higgins et al., 2003; Higgins et al., 2016). Interestingly, other GluN2B-selective antagonists either fail to alter locomotor activity (Anastasio et al., 2009; Higgins et al., 2016; Mikolajczak et al., 2002; Witkin and Acri, 1995) or decrease locomotor activity (Ginski and Witkin, 1994; Mareš and Mikulecká, 2009). Given that Ro 63–1908 increases locomotor activity when administered alone, it was not surprising to observe that rats pretreated with Ro 63–1908 (1.0 mg/kg) were more active following methamphetamine treatment during conditioning sessions. One surprising finding was that pretreating rats with a dose of Ro 63–1908 (3.0 mg/kg) that increased locomotor activity on its own did not augment the locomotor-stimulant effects of methamphetamine. This effect cannot necessarily be attributed to increased stereotypy, as the number of repeating photobeam breaks did not change following administration of Ro 63–1908 (3.0 mg/kg). In fact, Ro 63–1908 (3.0 mg/kg) significantly decreased the number of repeating photobeam breaks/s in the expression experiment and tended to attenuate methamphetamine-induced increases in repeating photobeam breaks in the acquisition experiment. Some caution is needed when interpreting these results as the repeating photobeam breaks measured in our CPP apparatus are not a true measure of stereotypy. Repeating photobeam breaks could measure other behaviors such as grooming.

Collectively, these results highlight a dissociation between Ro 63–1908’s ability to augment the locomotor-stimulant effects of methamphetamine at one dose (1.0 mg/kg) and its ability to block the conditioned rewarding effects of methamphetamine at a higher dose (3.0 mg/kg) in male rats. Typically, pharmacological manipulations that decrease the locomotor-stimulant effects of a drug also attenuate the conditioned rewarding effects of that drug (e.g., Adams et al., 2001; Babosa-Méndez et al., 2021; Baker et al., 1998; Jerlhag et al., 2010; Jerlhag and Engel, 2011; Kim et al., 1996; Kim et al., 2013; Shin et al., 2004; Sun et al., 2016; Velázquez-Sánchez et al., 2009). Additionally, the ability of Ro 63–1908, at least at a lower dose, to enhance the locomotor-stimulant effects of methamphetamine is unique among GluN2B-selective antagonists, as ifenprodil attenuates methamphetamine-induced hyperactivity (Chen et al., 2020; Li et al., 2017; Li et al., 2016a; Li et al., 2016b). Even though Ro 63–1908 and ifenprodil have high affinity for the GluN2B subunit (IC50 of ~0.003–0.01 μM and 0.21–0.81 μM, respectively; Avenet et al., 1996; Gill et al., 2002), they show differential selectively for other receptors. Ifenprodil has higher affinity for adrenergic α1 receptors (IC50 of ~.11 μM; Chenard et al., 1991) compared to Ro 63–1908 (~3.5 μM; Gill et al., 2002), but Ro 63–1908 has weak antagonistic actions at dopamine D2-like receptors and binds to sigma receptors (Gill et al., 2002). It is unlikely that D2-like receptor antagonism accounts for the current results, as D2-like receptor antagonists attenuate the locomotor effects of methamphetamine (Jing et al., 2018; Okuyama et al., 1997). There is a possibility that the dissociative effects of Ro 63–1908 on methamphetamine-induced hyperactivity and its conditioned rewarding effects are mediated partially by sigma receptors. At a low dose, the sigma receptor agonist SA 4503 potentiates the locomotor stimulant effects of methamphetamine but attenuates locomotor activity at higher doses (Rodvelt et al., 2011). Further support for this hypothesis comes from the finding that SA 4503, at a dose that does not potentiate the locomotor-stimulant effects of methamphetamine, is able to attenuate CPP for cocaine and methamphetamine (Mori et al., 2014). As noted by Rodevelt et al. (2011), low concentrations of sigma receptor ligands may lead to enhancements of the dopaminergic system (due to increased intracellular calcium levels), which may account for the increased locomotor activity following methamphetamine administration; conversely, higher concentrations may lead to decreased dopaminergic activity, thus explaining why a higher dose of Ro 63–1908 failed to augment the locomotor-stimulant effects of methamphetamine while blocking its conditioned rewarding effects.

In conclusion, we show that the GluN2B antagonist Ro 63–1908 blocks the acquisition, but not the expression, of methamphetamine CPP in male rats while attenuating the acquisition of methamphetamine CPP in female rats. Considering relapse is a defining feature of substance use disorders, future work should determine if the GluN2B subunit is an important mediator of methamphetamine relapse-like behavior. Previous research has shown that ifenprodil prevents reinstatement of nicotine-seeking behavior (Gipson et al., 2013), but research has not determined if GluN2B-selective antagonists can block reinstatement of methamphetamine-seeking behavior. Because GluN2B-selective antagonists bind to other receptors, such as adrenergic and sigma receptors, studies incorporating siRNA for the GluN2B subunit can be used to further elucidate the contribution of the GluN2B subunit to methamphetamine reward. One study has previously shown that siRNA injected into the nucleus accumbens blocks morphine CPP (Kao et al., 2011). This approach can better isolate how GluN2B-containing NMDA receptors mediate the conditioned rewarding effects of psychostimulants such as methamphetamine, thus increasing the likelihood of developing better interventions for treating methamphetamine use disorder.

Supplementary Material

1

Research Highlights.

  • Ro 63–1908 blocks acquisition of methamphetamine CPP in male rats

  • Ro 63–1908 attenuates acquisition of methamphetamine CPP in female rats

  • Ro 63–1908 does not block expression of methamphetamine-induced place preference

  • Ro 63–1908 (1.0 mg/kg) enhances the locomotor-stimulant effects of methamphetamine

  • Ro 63–1908 was neither rewarding nor aversive when administered alone

Role of Funding Source

None of the funding sources were involved in the study design, analysis, interpretation, or writing of the current manuscript.

The current study was supported by NIH grant R15DA047610 and NIGMS grant P20GM103436. The study was also supported by a Northern Kentucky University Faculty Project Grant and a Northern Kentucky University College of Arts and Sciences Professional Development Award.

Footnotes

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Conflict of Interest

None of the authors have any conflicts of interest.

References

  1. Adams JU, Careri JM, Efferen TR, Rotrosen J, 2001. Differential effects of dopamine antagonists on locomotor activity, conditioned activity and conditioned place preference induced by cocaine in rats. Behav. Pharmacol 12, 603–611. 10.1097/00008877-200112000-00004 [DOI] [PubMed] [Google Scholar]
  2. Ahmadi J, Sahraian A, Biuseh M, 2019. A randomized clinical trial on the effects of bupropion and buprenorphine on the reduction of methamphetamine craving. Trials 20, 468. 10.1186/s13063-019-3554-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anastasio NC, Xia Y, O’Connor ZR, Johnson KM, 2009. Differential role of N-methyl-D-aspartate receptor subunits 2A and 2B in mediating phencyclidine-induced perinatal neuronal apoptosis and behavioral deficits. Neuroscience 163, 1181–1191. 10.1016/j.neuroscience.2009.07.058 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Anggadiredja K, Sakimura K, Hiranita T, Yamamoto T, 2004. Naltrexone attenuates cue-but not drug-induced methamphetamine seeking: a possible mechanism for the dissociation of primary and secondary reward. Brain Res. 1021, 272–276. 10.1016/j.brainres.2004.06.051 [DOI] [PubMed] [Google Scholar]
  5. Anderson AL, Li SH, Markova D, Holmes TH, Chiang N, Kahn R, Campbell J,Dickerson DL, Galloway GP, Haning W, Roache JD, Stock C, Elkashef AM, 2015. Burpropion for the treatment of methamphetamine dependence in non-daily users: a randomized double-blind, placebo-controlled trial. Drug Alcohol Depend. 150, 170–174. 10.1016/j.drugalcdep.2015.01.036 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Avenet P, Léonardon J, Besnard F, Graham D, Frost J, Depoortere H, Langer SZ, Scatton B (1996). Antagonist properties of the stereoisomers of ifenprodil at NR1A/NR2A and NR1A/NR2B subtypes of the NMDA receptor expressed in Xenopus oocytes. Eur. J. Pharamcol 296, 209–213. 10.1016/0014-2999(95)00700-8. [DOI] [PubMed] [Google Scholar]
  7. Baker DA, Fuchs RA, Specio SE, Khroyan TV, Neisewander JL, 1998. Effects of intraaccumbens administration of SCH-23390 on cocaine-induced locomotion and conditioned place preference. Synapse 30, 181–193. [DOI] [PubMed] [Google Scholar]
  8. Balster RL, Schuster CR, 1973. A comparison of d-amphetamine, l-amphetamine, and methamphetamine self-administration in rhesus monkeys. Pharmacol. Biochem. Behav 1, 67–71. 10.1016/0091-3057(73)90057-9 [DOI] [PubMed] [Google Scholar]
  9. Barbosa-Méndez S, Pérez-Sánchez G, Becerril-Villanueva E, Salazar-Juárez A, 2021. Melatonin decreases cocaine-induced locomotor sensitization and cocaine-conditioned place preference in rats. J. Psychiatr. Res 132, 97–110. 10.1016/j.jpsychires.2020.09.027 [DOI] [PubMed] [Google Scholar]
  10. Bustamante D, You ZB, Castel MN, Johansson S, Goiny M, Terenius L, Hökfelt T, Herrera-Marschitz M, 2002. Effect of single and repeated methamphetamine treatment on neurotransmitter release in substantia nigra and neostriatum of the rat. J. Neurochem 83, 645–654. 10.1046/j.1471-4159.2002.01171.x [DOI] [PubMed] [Google Scholar]
  11. Chen B, Freeman M, Kondo K, Ayers C, Montgomery J, Paynter R, Kansagara D, 2019. Pharmacotherapy for methamphetamine/amphetamine use disorder – a systematic review and meta-analysis. Addiction 114, 2122–2136. 10.1111/add.14755 [DOI] [PubMed] [Google Scholar]
  12. Chen G, Li T, Xiao J, Wang J, Shang Q, Qian H, Qiao C, Zhang P, Chen T, Liu X, 2020. Ifenprodil attenuates methamphetamine-induced behavioral sensitization through the GluN2B-PP2A-AKT cascade in the dorsal striatum of mice. Neurochem. Res 45, 891–901. 10.1007/s11064-020-02966-8 [DOI] [PubMed] [Google Scholar]
  13. Chenard BL, Bordner J, Butler TW, Chambers LK, Collins MA, De Costa DL, Ducat MF, Dumont ML, Fox CB, Mena EE, Menniti FS, Nielsen J, Pagnozzi MJ, Richter KEG, Ronau IA, Stemple JZ, White WF, 1995. (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanaol: A potent new neuroprotectant which blocks N-methyl-D-aspartate responses. J. Med. Chem 38, 3138–3145. [DOI] [PubMed] [Google Scholar]
  14. Coffin PO, Santos GM, Hern J, Vittinghoff E, Santos D, Matheson T, Colfax G, Batki SL, 2018. Extended release naltrexone for methamphetamine dependence among men who have sex with men: a randomized placebo-controlled trial. Addiction 113, 268–278. 10.1111/add.13950 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Colfax GN, Santos GM, Das M, Santos DM, Matheson T Gasper J, Shoptaw S, Vittinghoff E, 2011. Mirtazapine to reduce methamphetamine use: a randomized controlled trial. Arch. Gen. Psychiatry 68, 1168–1175. 10.1001/archgenpsychiatry.2011.124/ [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Courtney KE, Ray LA, 2014. Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature. Drug Alcohol Depend. 143, 11–21. 10.1016/j.drugalcdep.2014.08.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Elkashef AM, Rawson RA, Anderson AL, Li SH, Holmes T, Smith EV, Chiang N, Kahn R, Vocci F, Ling W, Pearce VJ, McCann M, Campbell J, Gorodetzky C, Haning W, Carlton B, Mawhinney J, Weis D, 2008. Bupropion for the treatment of methamphetamine dependence, Neuropsychopharmacology 33, 1162–1170. 10.1038/sj.npp.1301481 [DOI] [PubMed] [Google Scholar]
  18. Ernst T, Chang L, 2008. Adaptation of brain glutamate plus glutamine during abstinence from chronic methamphetamine use. J. Neuroimmune Pharmacol 3, 165–172. 10.1007/s11481-008-9108-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Eschleman AJ, Henningsen RA, Neve KA, Janowsky A, 1994. Release of dopamine via the human transporter. Mol. Pharmacol 45, 312–316. [PubMed] [Google Scholar]
  20. Furlong TM, Corbit LH, Brown RA, Balleine BW, 2018. Methamphetamine promotes habitual action and alters the density of striatal glutamate-receptor and -vesicular proteins in dorsal striatum. Addict. Biol 23, 857–867. 10.1111/adb.12534 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Galloway GP, Buscemi R, Coyle JR, Flower K, Siegrist JD, Fiske LA, Baggot MJ, Li L, Polcin D, Chen CY, Mendelson J, 2011. A randomized, placebo-controlled trial of sustained-release dextroamphetamine for treatment of methamphetamine addiction. Clin. Pharmacol. Ther 89, 276–282. 10.1038/clpt.2010.307 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gill R, Alanine A, Bourson A, Buttelmann B, Fischer G, Heitz M-P, Kew JNC, Levet-Trafit B, Lorez H-P, Malherbe P, Miss M-T, Mutel V, Pinard E, Roever S, Scmitt M, Trube G, Wybrecht R, Wyler R, Kemp JA, 2002. Pharmacological characterization of Ro 63–1908 (1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol), a novel subtype-selective N-methyl-D-aspartate antagonist. J. Pharmacol. Exp. Ther 302, 940–948. 10.1124/jpet.102.034322. [DOI] [PubMed] [Google Scholar]
  23. Ginski MJ, Witkin JM, 1994. Sensitive and rapid behavioral differentiation of N-methyl-D-aspartate receptor antagonists. Psychopharmacology 114, 573–582. 10.1007/BF02244987 [DOI] [PubMed] [Google Scholar]
  24. Gipson CD, Reissner KJ, Kupchik YM, Smith AC, Stankeviciute N, Hensley-Simon ME, Kalivas PW, 2013. Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. Proc. Natl. Acad. Sci. U. S. A 110, 9124–9129. 10.1073/pnas.1220591110 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Han W, Wang F, Qi J, Wang F, Zhang L, Zhao S, Song M, Wu C, Yang J, 2012. NMDA receptors in the medial prefrontal cortex and the dorsal hippocampus regulate methamphetamine-induced hyperactivity and extracellular amino acid release in mice. Behav. Brain Res 232, 44–52. 10.1016/j.bbr.2012.03.038 [DOI] [PubMed] [Google Scholar]
  26. Harrod SB, Dwoskin LP, Crooks PA, Klebaur JE, Bardo MT, 2001. Lobeline attenuates d-methamphetamine self-administration in rats. J. Pharmacol. Exp. Ther 298, 172–179. [PubMed] [Google Scholar]
  27. Hart CL, Ward AS, Haney M, Foltin RW, Fischman MW, 2001. Methamphetamine self-administration by humans. Psychopharmacology 157, 75–81. 10.1007/s002130100738 [DOI] [PubMed] [Google Scholar]
  28. Heinzerling KG, Swanson AN, Hall TM, Yi Y, Wu Y, Shoptaw SJ, 2014. Randomized, placebo-controlled trial of bupropion in methamphetamine-dependent participants with less than daily methamphetamine use. Addiction 109, 1878–1886. 10.1111/add.12636 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Hensleigh E, Pritchard LM, 2014. The effect of early environmental manipulation on locomotor sensitivity and methamphetamine conditioned place preference reward. Behav. Brain Res 268, 66–71. 10.1016/j.bbr.2014.03.045 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Higgins GA, Ballard TM, Enderlin M, Haman M, Kemp JA, 2005. Evidence for improved performance in cognitive tasks following selective NR2B NMDA receptor antagonist pre-treatment in the rat. Psychopharmacology 179, 85–98. 10.1007/s00213-005-2203-9 [DOI] [PubMed] [Google Scholar]
  31. Higgins GA, Ballard TM, Huwyler J, Kemp JA, Gill R, 2003. Evaluation of the NR2B-selective NMDA receptor antagonist Ro 63–1908 on rodent behaviour: evidence for an involvement of NR2B NMDA receptors in response inhibition. Neuropharmacology 44, 324–341. 10.1016/S0028-3908(02)00402-1 [DOI] [PubMed] [Google Scholar]
  32. Higgins GA, Silenieks LB, MacMillan C, Sevo J, Zeeb FD, Thevarkunnel S, 2016. Enhanced attention and impulsive action following NMDA receptor GluN2B-selective antagonist pretreatment. Behav. Brain Res 311, 1–14. 10.1016/j.bbr.2016.05.025 [DOI] [PubMed] [Google Scholar]
  33. Jerlhag E, Egecioglu E, Dickson SL, & Engel JA, 2010. Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference. Psychopharmacology 211, 415–422. https://doi/org/10.1007/s00213-010-1907-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Jerlhag E, Engel JA, 2011. Ghrelin receptor antagonism attenuates nicotine-induced locomotor stimulation, accumbal dopamine release and conditioned place preference in mice. Drug Alcohol Depend. 117, 126–131. 10.1016/j.drugalcdep.2011.01.010 [DOI] [PubMed] [Google Scholar]
  35. Jiang M, Chen Y, Li C, Peng Q, Fang M, Liu W, Kang Q, Lin Y, Yung KKL, Mo Z, 2016. Inhibiting effects of rhynchophylline on zebrafish methamphetamine dependence are associated with amelioration of neurotransmitters content and down-regulation of TH and NR2B expression. Prog. Neuropsychopharmacol. Biol. Psychiatry 68, 31–43. 10.1016/j.pnpbp.2016.03.004 [DOI] [PubMed] [Google Scholar]
  36. Jiménez-Sánchez L, Campa L, Auberson YP, Adell A, 2014. The role of GluN2A and GluN2B subunits on the effects of NMDA receptor antagonists in modeling schizophrenia and treating refractory depression. Neuropsychopharmacology 39, 2673–2680. 10.1038/npp.2014.123 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Jing L, Liu B, Zhang M, Liang J-H,J, 2018. Involvement of dopamine D2 receptor in a single methamphetamine-induced behavioral sensitization in C57BL/6J mice. Neurosci. Lett 681, 87–92. 10.1016/j.neulet.2018.02.067 [DOI] [PubMed] [Google Scholar]
  38. Kao J-H, Huang EY-K, Tao P-L, 2011. NR2B subunit of NMDA receptor at nucleus accumbens is involved in morphine rewarding effect by siRNA study. Drug Alcohol Depend. 118, 366–374. 10.1016/j.drugalcdep.2011.04.019 [DOI] [PubMed] [Google Scholar]
  39. Kim HS, Park WK, Jang CG, Oh S, 1996. Inhibition by MK-801 of cocaine-induced sensitization, conditioned place preference, and dopamine-receptor supersensitivity in mice. Brain Res. Bull 40, 201–207. 10.1016/0361-9230(96)00006-8 [DOI] [PubMed] [Google Scholar]
  40. Kim DH, Yang CH, Hwang M, 2013. Sauchinone blocks methamphetamine-induced hyperlocomotion and place preference in mice. Phytomedicine 20, 1071–1075. 10.1016/j.phymed.2013.04.006 [DOI] [PubMed] [Google Scholar]
  41. Kim HS, Jang CG, 1997. MK-801 inhibits methamphetamine-induced conditioned place preference and behavioral sensitization to apomorphine in mice. Brain Res. Bull 44, 221–227. 10.1016/s0361-9230(97)00093-2 [DOI] [PubMed] [Google Scholar]
  42. Kurokawa K, Shibasaki M, Kiyokage E, Mizuno K, Toida K, Ohkuma S, 2011. Involvement of NMDA receptors in ryanodine receptor expression in dopaminergic neurons in the ventral tegmental area of mice with intermittent methamphetamine treatment. Synapse 65, 1156–1165. 10.1002/syn.20953 [DOI] [PubMed] [Google Scholar]
  43. Lee KW, Kim HC, Lee SY, Jang CG, 2011. Methamphetamine-sensitized mice are accompanied by memory impairment and reduction of N-methyl-D-aspartate receptor ligand binding in the prefrontal cortex and hippocampus. Neuroscience 178, 101–107. 10.1016/j.neuroscience.2011.01.025 [DOI] [PubMed] [Google Scholar]
  44. Li J, Liu W, Peng Q, Jiang M, Luo C, Guo Y, Liu Y, Fang M, Mo Z, 2014. Effect of rhynchophylline on conditioned place preference on expression of NR2B in methamphetamine-dependent mice. Biochem. Biophys. Res. Commun 452, 695–700. 10.1016/j.bbrc.2014.08.127 [DOI] [PubMed] [Google Scholar]
  45. Li L, Liu X, Qiao C, Chen G, Li T, 2016a. Ifenprodil attenuates methamphetamine-induced behavioral sensitization and activation of Ras-ERK-ΔFosB pathway in the caudate putamen. Neurochem. Res 41, 2636–2644. 10.1007/s11064-016-1976-z [DOI] [PubMed] [Google Scholar]
  46. Li L, Qiao C, Chen G, Qian H, Hou Y, Li T, Liu X, 2016b. Ifenprodil attenuates the acquisition and expression of methamphetamine-induced behavioral sensitization and activation of Ras-ERK1/2 cascade in caudate putamen. Neuroscience 335, 20–29. 10.1016/j.neuroscience.2016.08.022 [DOI] [PubMed] [Google Scholar]
  47. Li M-H, Underhill SM, Reed C, Phillips TJ, Amara SG, Ingram SL, 2017. Amphetamine and methamphetamine increase NMDAR-GluN2B synaptic currents in midbrain dopamine neurons. Neuropsychopharmacology 42, 1539–1547. 10.1038/npp.2016.278 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Lima-Ojeda JM, Vogt MA, Pfeiffer N, Dormann C, Köhr G, Sprengel R, Gass P, Inta D, 2013. Pharmacological blockade of GluN2B-containing NMDA receptors induces antidepressant-like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain. Prog. Neuropsychopharmacol. Biol. Psychiatry 45, 28–33. 10.1016/j.pnpbp.2013.04.017 [DOI] [PubMed] [Google Scholar]
  49. Lominac KD, Quadir SG, Barrett HM, McKenna CL, Schwartz LM, Ruiz PN, Wroten MG, Campbell RR, Miller BW, Holloway JJ, Travis KO, Rajasekar G, Maliniak D, Thompson AB, Urman LE, Kippin TE, Phillips TJ, Szumlinski KK, 2016. Prefrontal glutamate correlates of methamphetamine sensitization and preference. Eur. J. Neurosci 43, 689–702. 10.1111/ejn.13159 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Ma YY, Guo CY, Yu P, Lee DY, Han JS, Cui CL, 2006. The role of NR2B containing NMDA receptor in place preference conditioned with morphine and natural reinforcers in rats. Exp. Neurol 200, 343–355. 10.1016/j.expneurol.2006.02.117 [DOI] [PubMed] [Google Scholar]
  51. Ma YY, Yu P, Guo CY, Cui CL (2011). Effects of ifenprodil on morphine-induced conditioned place preference and spatial learning and memory in rats. Neurochem. Res 36, 383–391. 10.1007/s11064-010-0342-9 [DOI] [PubMed] [Google Scholar]
  52. Mareš P, Mikulecká A, 2009. Different effects of two N-methyl-D-aspartate receptor antagonists on seizures, spontaneous behavior, and motor performance in immature rats. Epilepsy Behav. 14, 32–39. 10.1016/j.yebeh.2008.08.013 [DOI] [PubMed] [Google Scholar]
  53. Mikolajczak P, Okulicz-Kozaryn I, Kaminska E, Niedopad L, Polanska A, Gebka J, 2002. Effects of acamprosate and some polyamine site ligands of NMDA receptor on short-term memory in rats. Eur. J. Pharmacol 444, 83–96. 10.1016/s0014-2999(02)01276-1 [DOI] [PubMed] [Google Scholar]
  54. Miles SW, Sheridan J, Russell B, Kydd R, Wheeler A, Walters C, Gamble G, Hardley P, Jensen M, Kuoppasalmi K, Tuomola P Föhr J, Kuikanmäki O, Vorma H, Salokangas R, Mikkonen A, Kallio M, Kauhanen J, Kiviniemi V, Tihonen J, 2013. Extendend-release methylphenidate for treatment of amphetamine/methamphetamine dependence: a randomized, double-blind, placebo-controlled trial. Addiction 108, 1279–1286. 10.1111/add.12109 [DOI] [PubMed] [Google Scholar]
  55. Mishra D, Pena-Bravo JI, Leong KC, Lavin A, Reichel CM, 2017. Methamphetamine self-administration modulates glutamate neurophysiology. Brain Struct. Funct 222, 2031–2039. 10.1007/s00429-016-1322-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Mori T, Rahmadi M, Yoshizawa K, Itoh T, Shibasaki M, Suzuki T, 2014. Inhibitory effects of SA4503 on the rewarding effects of abused drugs. Addict. Biol 19, 362–369. 10.1111/j.1369-1600.2012.00488.x [DOI] [PubMed] [Google Scholar]
  57. Munzar P, Baumann MH, Shoaib M, Goldberg SR, 1999. Effects of dopamine serotonin-releasing agents on methamphetamine discrimination and self-administration in rats. Psychopharmacology 141, 287–296. 10.1007/s002130050836 [DOI] [PubMed] [Google Scholar]
  58. Nash JF, Yamamoto BK, 1992. Methamphetamine neurotoxicity and striatal glutamate release: comparison to 3,4-methylendioxymethamphetamine. Brain Res. 581, 237–243. 10.1016/0006-8993(92)90713-j [DOI] [PubMed] [Google Scholar]
  59. National Research Council, 2011. Guide for the care and use of laboratory animals (8th ed.). The National Academies Press. [PubMed] [Google Scholar]
  60. Newton TF, Roache JD De La Garza R 2nd, Fong T, Wallace CL, Li SH, Elkashef A, Chiang N, Kahn R, 2006. Bupropion reduces methamphetamine-induced subjective effects and cue-induced craving. Neuropsychopharmacology 31, 1537–1544. 10.1038/sj.npp.1300979 [DOI] [PubMed] [Google Scholar]
  61. Okuyama S, Chaki S, Kawashima N, Suzuki Y, Ogawa S, Kumagai T, Nakazato A, Nagamine M, Yamaguchi K, Tomksawa K, 1997. The atypical antipsychotic profile of NRA0045, a novel dopamine D4 and 5-hydroxytryptamine2A receptor antagonist, in rats. Br. J. Pharmacol 121, 515–525. 10.1038/sj.bjp.0701164 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Olney JW, Labruyere J, Price MT, 1989. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244, 1360–1362. 10.1126/science.2660263 [DOI] [PubMed] [Google Scholar]
  63. Ozawa S, Kamiya H, Tsuzuki K, 1998. Glutamate receptors in the mammalian central nervous system. Prog. Neurobiol 54, 581–618. 10.1016/s0301-0082(97)00085-3 [DOI] [PubMed] [Google Scholar]
  64. Pena-Bravo JI, Penrod R, Reichel CM, Lavin A, 2019. Methamphetamine self-administration elicits sex-related changes in postsynaptic glutamate transmission in the prefrontal cortex. eNeuro 6, pii:ENEURO.0401–18.2018. 10.1523/ENEURO.0401-18.2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Peter D, Jimenez J, Liu Y, Kim J, Edwards RH, 1994. The chomaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors. J. Biol. Chem 269, 7231–7237. [PubMed] [Google Scholar]
  66. Pike E, Stoops WW, Hays LR, Glaser PE, Rush CR, 2014. Methamphetamine self-administration in humans during D-amphetamine maintenance. J. Clin. Psychopharmacol 34, 675–681. 10.1097/JCP.0000000000000207 [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Rezaei F, Emami M, Zahed S, Morabbi MJ, Farahzadi M, Akhondzadeh S, 2015. Sustained-release methylphenidate in methamphetamine dependence treatment: a double-blind and placebo-controlled trial. Daru 23, 2. 10.1186/s40199-015-0092-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Risca HI, Zuarth-Gonzalez JD, & Baker LE, 2020. Conditioned place preference following concurrent treatment with 3,4-methylenedioxypyrovalerone (MDPV) and methamphetamine in male and female Sprague-Dawley rats. Pharmacol. Biochem. Behav 198, 173032. 10.1016/j.pbb.2020.173032 [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Rodvelt KR, Oelrichs CE, Blount LR, Fan K-H, Lever SZ, Lever JR, Miller DK, 2011. The sigma receptor agonist SA4503 both attenuates and enhances the effects of methamphetamine. Drug Alcohol Depend. 116, 203–210. 10.1016/j.drugalcdep.2010.12.018 [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Rush CR, Stoops WW, Lile JA, Glaser PE, Hays LR, 2011. Subjective and physiological effects of acute intranasal methamphetamine during d-amphetamine maintenance. Psychopharmacology 214, 665–674. 10.1007/s002130-010-2067-5 [DOI] [PubMed] [Google Scholar]
  71. Schindler CW, Bross JG, Thorndike EB, 2002. Gender differences in the behavioral effects of methamphetamine. Eur. J. Pharmacol 442, 231–235. 10.1016/s0014-2999(02)01550-9 [DOI] [PubMed] [Google Scholar]
  72. Shin E-J, Oh K-W, Kim K-W, Kwon YS, Jhoo JH, Jhoo W-K, Cha J-Y, Lim YK, Kim IS, Kim H-C, 2004. Attenuation of cocaine-induced conditioned place preference by Polygala tenuifolia root extract. Life Sci. 75, 2751–2764. 10.1016/j.lfs.2004.04.045 [DOI] [PubMed] [Google Scholar]
  73. Shoptaw S, Heinzerling KG, Rotheram-Fuller E, Steward T, Wang J, Swanson AN, De La Garza R, Newton T, Ling W, 2008. Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence. Drug Alcohol Depend. 96, 222–232. 10.1016/j.drugalcdep.2008.03.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Simões PF, Silva AP, Pereira FC, Marques E, Grade S, Milhazes N, Borges F, Ribeiro CF, Macedo TR, 2007. Methamphetamine induces alterations on hippocampal NMDA and AMPA receptor subunit levels and impairs spatial working memory. Neuroscience 150, 433–441. 10.1016/j.neuroscience.2007.09.044 [DOI] [PubMed] [Google Scholar]
  75. Simões PF, Silva AP, Pereira FC, Marques E, Milhazes N, Borges F, Ribeiro CF, Macedo TR, 2008. Methamphetamine changes NMDA and AMPA glutamate receptor subunit levels in the rat striatum and frontal cortex. Ann. N. Y. Acad. Sci 1139, 232–241. 10.1196/annals.1432.028 [DOI] [PubMed] [Google Scholar]
  76. Stoops WW, Pike E, Hays LR, Glaser PE, Rush CR, 2015. Naltrexone and bupropion, alone or combined, do not alter the reinforcing effects of intranasal methamphetamine. Pharmacol. Biochem. Behav 129, 45–50. 10.1016/j.pbb.2014.11.018 [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Sun L, Song R, Chen Y, Yang R-F, Wu N, Su R-B, Li J, 2016. A selective D3 receptor antagonist YQA14 attenuates methamphetamine-induced behavioral sensitization and conditioned place preference in mice. Acta. Pharmacol. Sin 37, 157–165. 10.1038/aps.2015.96 [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Suzuki O, Hattori H, Asano M, Oya M, Katsumata Y, 1980. Inhibition of monoamine oxidase by d-methamphetamine. Biochem. Pharmacol 29, 2071–2073. 10.1016/00006-2952(80)90493-1 [DOI] [PubMed] [Google Scholar]
  79. Suzuki T, Kato H, Tsuda M, Suzuki H, Misawa M, 1999. Effects of the non-competitive NMDA receptor antagonist ifenprodil on the morphine-induced place preference in mice. Life Sci. 64, PL151–156. 10.1016/s0024-3205(99)00036-3 [DOI] [PubMed] [Google Scholar]
  80. Velázquez-Sánchez C, Ferragud A, Hernández-Rabaza V, Nácher A, Merino V, Cardá M, Murga J, Canales JJ, 2009. The dopamine uptake inhibitor 3 alpha-[bis(4’-fluorophenyl)metoxy]-tropane reduces cocaine-induced early-gene expression, locomotor activity, and conditioned reward. Neuropsychopharmacology 34, 2497–2507. 10.1038/npp.2009.78 [DOI] [PubMed] [Google Scholar]
  81. Wang Y, Ma Y, Hu J, Cheng W, Jiang H, Zhang X, Li M, Ren J, Li X, 2015. Prenatal chronic mild stress induces depression-like behavior and sex-specific changes in regional glutamate receptor expression patterns in adult rats. Neuroscience 301, 363–374. https://doi/org/10.1016/j.neuroscience.2015.06.008 [DOI] [PubMed] [Google Scholar]
  82. White TL, Monnig MA, Walsh EG, Nitenson AZ, Harris AD, Cohen RA, Porges EC, Woods AJ, Lamb DG, Boyd CA, Fekir S, 2018. Psychostimulant drug effects on glutamate, Glx, and creatine in the anterior cingulate cortex and subjective response in healthy humans. Neuropsychopharmacology 43, 1498–1509. 10.1038/s41386-018-0027-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Witkin JM, Acri JB, 1995. Effects of ifenprodil on stimulatory, discriminative stimulus, and convulsant effects of cocaine. Behav. Pharmacol 6, 245–253. [PubMed] [Google Scholar]
  84. Yates JR, Horchar MJ, Ellis AL, Kappesser JL, Mbambu P, Sutphin TG, Dehner DS, Igwe HO, Wright MR, 2021. Differential effects of glutamate N-methyl-D-aspartate receptor antagonists on risky choice as assessed in the risky decision task. Psychopharmacology 238, 133–148. 10.1007/s00213-020-05664-z [DOI] [PMC free article] [PubMed] [Google Scholar]

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