Effects of the GluN2B-selective antagonist Ro 63-1908 on acquisition and expression of methamphetamine conditioned place preference in male and female rats
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, 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).
Section snippets
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
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
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,
Role of funding source
None of the funding sources were involved in the study design, analysis, interpretation, or writing of the current manuscript.
Contributors
Justin Yates conceptualized the experiments, conducted behavioral testing, analyzed the data, wrote the manuscript, and revised the manuscript. Hunter Campbell and Lauren Hawley conceptualized the experiments, conducted behavioral testing, and wrote the manuscript. Matthew Horchar conducted behavioral testing and revised the manuscript. Joy Kappesser and Makayla Wright conducted behavioral testing.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
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.
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2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Interestingly, Bernheim et al. (2017) have suggested that the attenuating effects of oxytocin on METH-seeking behavior may be dependent on regulation of presynaptic glutamatergic signaling because reinstatement of lever pressing to METH-associated cues was observed after administration of LY341495, metabotropic glutamate receptor (mGluR2/3) antagonist in both male and female rats. The glutamate ionotropic receptor NMDA type subunit 2B (GluN2B) selective antagonist, Ro 63–1908, also completely blocked the conditioned rewarding effects of METH in male, but not female rats (Yates et al., 2021). Whereas administration of Ro 25–6981, another GluN2B selective antagonist, did not exhibit any sex differences in reducing METH seeking behavior (Westbrook and Gulley, 2020).
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2022, Drug and Alcohol DependenceCitation Excerpt :Recent studies have implicated GluN2B-containing NMDA receptors in behavioral phenotypes associated with vulnerability to SUDs, such as risk taking and impulsivity (Yates et al., 2018, 2021b). Furthermore, the GluN2B subunit is an important mediator of methamphetamine reward (Kurokawa et al., 2011; Yates et al., 2021a), as well as reinstatement of heroin- and nicotine-seeking behavior (Shen et al., 2011; Gipson et al., 2013). The primary goal of the current experiment was to determine if the GluN2B subunit-selective antagonist Ro 63–1908 decreases the direct reinforcing effects of cocaine.
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2021, Behavioural Brain ResearchCitation Excerpt :Moreover, whether methamphetamine pharmacokinetic sex differences manifest into behavioral differences in methamphetamine-induced CPP is yet to be determined. However, preliminary work using the 1 mg/kg dose of methamphetamine has not revealed robust sex differences in methamphetamine-induced CPP [34–36]. Although direct comparisons of methamphetamine-induced CPP between the present study with females and our previous study with males is not feasible [20], the magnitude of CPP appears lower in female than in male rats using the 1 mg/kg dose of methamphetamine.
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