Elsevier

Neuropharmacology

Volume 186, 15 March 2021, 108452
Neuropharmacology

mGlu5 function in the nucleus accumbens core during the incubation of methamphetamine craving

https://doi.org/10.1016/j.neuropharm.2021.108452Get rights and content

Highlights

  • Cue-induced methamphetamine craving incubates during forced abstinence.

  • mGlu5-induced synaptic depression is transiently lost in NAc core during abstinence.

  • Surface mGlu5, mGlu5-Homer interactions and DGL-CaMKII interactions are unaltered.

  • Systemic mGlu5 NAM reduces incubated seeking alongside general behavioral reduction.

  • Intra-NAc core mGlu5 NAM does not affect incubated methamphetamine seeking.

Abstract

Many studies have demonstrated that negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGlu5) reduce cocaine and methamphetamine seeking in extinction-reinstatement animal models of addiction. Less is known about effects of mGlu5 NAMs in abstinence models, particularly for methamphetamine. We used the incubation of drug craving model, in which cue-induced craving progressively intensifies after withdrawal from drug self-administration, to conduct the first studies of the following aspects of mGlu5 function in the rat nucleus accumbens (NAc) core during abstinence from methamphetamine self-administration: 1) functionality of the major form of synaptic depression in NAc medium spiny neurons, which is induced postsynaptically via mGlu5 and expressed presynaptically via cannabinoid type 1 receptors (CB1Rs), 2) mGlu5 surface expression and physical associations between mGlu5, Homer proteins, and diacylglycerol lipase-α, and 3) the effect of systemic and intra-NAc core administration of the mGlu5 NAM 3-((2-methyl-4-)ethynyl)pyridine (MTEP) on expression of incubated methamphetamine craving. We found that mGlu5/CB1R-dependent synaptic depression was lost during the rising phase of methamphetamine incubation but then recovered, in contrast to its persistent impairment during the plateau phase of incubation of cocaine craving. Furthermore, whereas the cocaine-induced impairment was accompanied by reduced mGlu5 levels and mGlu5-Homer associations, this was not the case for methamphetamine. Systemic MTEP reduced incubated methamphetamine seeking, but also reduced inactive hole nose-pokes and locomotion, while intra-NAc core MTEP had no significant effects. These findings provide the first insight into the role of mGlu5 in the incubation of methamphetamine craving and reveal differences from incubation of cocaine craving.

Introduction

Methamphetamine is the most widely abused illicit drug in the world after cannabis (Brecht and Herbeck, 2014). The majority of individuals seeking treatment for methamphetamine use disorder relapse within the first year of abstinence (Brecht and Herbeck, 2014). There are no FDA-approved medications to help users of methamphetamine or other psychostimulants maintain abstinence. It is well-established that relapse vulnerability is linked to alterations in brain circuits that respond to drug-associated cues. This vulnerability can be studied using the ‘incubation of craving’ model wherein drug seeking in response to drug-associated cues progressively increases over the course of withdrawal from drug self-administration (Pickens et al., 2011). In rats, incubation of methamphetamine craving occurs during forced abstinence (Shepard et al., 2004; Scheyer et al., 2016; Adhikary et al., 2017) or voluntary abstinence, when rats are provided with mutually exclusive food rewards (Caprioli et al., 2015, 2017; Venniro et al., 2017) or when responding for drug is associated with punishment (Krasnova et al., 2014). Notably, incubation of methamphetamine craving also occurs in humans, with increases in cue-induced drug craving observed during the first 3 months of abstinence (Wang et al., 2013a).

Brain regions important for incubation of methamphetamine craving include the central nucleus of the amygdala (Li et al., 2015b; Venniro et al., 2017; Cates et al., 2018), the dorsal striatum (Li et al., 2015a, 2018a, 2018c; Caprioli et al., 2017), and the nucleus accumbens core (Scheyer et al., 2016; Rossi et al., 2020) (for review, see Altshuler et al., 2020). There is overlap with regions required for cocaine incubation (central nucleus: Lu et al., 2007, 2005; accumbens core: Conrad et al., 2008, Guillem et al., 2014) but also differences. For example, cocaine but not methamphetamine incubation appears to require the prefrontal cortex (Koya et al., 2009; Ma et al., 2014; Li et al., 2015b; Shin et al., 2018; see also Luís et al., 2017, Nicolas et al., 2017) and the nucleus accumbens shell (Lee et al., 2013; Ma et al., 2014; Rossi et al., 2020). One mechanism common to cocaine and methamphetamine incubation is strengthening of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) transmission in the nucleus accumbens (NAc) core. In drug-naïve or saline-treated animals, GluA2-containing Ca2+-impermeable AMPARs are primarily responsible for excitatory transmission onto medium spiny neurons (MSNs), the major cell type and output neurons of the NAc (Kourrich et al., 2007; Conrad et al., 2008). However, after withdrawal from extended-access cocaine or methamphetamine self-administration, there is an accumulation of high conductance Ca2+-permeable AMPA receptors (CP-AMPARs) in NAc core synapses; once this occurs, CP-AMPAR activation is required for the expression of cocaine (Conrad et al., 2008; Loweth et al., 2014) and methamphetamine (Scheyer et al., 2016) incubation. In summary, overlapping but distinct brain regions contribute to cocaine and methamphetamine incubation, and at least one underlying form of plasticity in the NAc – accumulation of CP-AMPARs – is held in common.

For cocaine, the incubation of craving is also associated with group I metabotropic glutamate receptor (mGluR) plasticity. In drug-naïve animals, the major form of long-term depression (LTD) observed in NAc medium spiny neurons (MSN) involves metabotropic glutamate receptor 5 (mGlu5) and cannabinoid receptor type 1 (CB1R) (Robbe et al., 2002; Zlebnik and Cheer, 2016; Araque et al., 2017; Augustin and Lovinger, 2018). Specifically, postsynaptic mGlu5 activation results in the generation of the endocannabinoid 2-arachidonoylglycerol (2-AG), which travels in a retrograde fashion to activate presynaptic CB1Rs thereby reducing glutamate release. The multiprotein mGlu5 complex that mediates 2-AG release is referred to as the 2-AG signalosome (Piomelli, 2014) and requires mGlu5 coupling through Homer scaffolding proteins to diacylglycerol lipase-α (DGL), the enzyme that produces 2-AG. Uncoupling of the signalosome is associated with abolished mGlu5/CB1R-dependent synaptic depression in the NAc (Jung et al., 2012). This synaptic depression is also lost in the NAc after various cocaine regimens (see Discussion) including incubation of cocaine craving (McCutcheon et al., 2011; Scheyer et al., 2018). However, mGlu1 activation, which does not affect excitatory synaptic transmission in drug-naïve MSN, elicits a postsynaptically-expressed LTD after incubation that is mediated by the removal of CP-AMPARs and results in decreased cocaine craving (McCutcheon et al., 2011; Lee et al., 2013; Loweth et al., 2014; Ma et al., 2014; Scheyer et al., 2018). This mGlu1-induced LTD has also been demonstrated in the NAc core after incubation of methamphetamine craving (Scheyer et al., 2016). In summary, cocaine and methamphetamine incubation have in common the emergence of mGlu1-LTD; this is accompanied by loss of mGlu5/CB1R-dependent synaptic depression after cocaine incubation, but whether the latter is impaired after methamphetamine incubation is unknown. Therefore, the first goal of this study was to evaluate mGlu5/CB1R-dependent synaptic depression and components of the 2-AG signalosome after withdrawal from a methamphetamine self-administration regimen that produces incubation of craving.

Given that AMPAR transmission in the NAc is required for expression of incubated cocaine and methamphetamine craving, reducing excitatory transmission through mGlu5/CB1R-dependent LTD might be expected to decrease drug seeking. Contrary to this expectation, some evidence indicates that this LTD mediates reward (Novak et al., 2010; Bilbao et al., 2020) (see Discussion for more detail). Furthermore, many studies have found that reducing mGlu5 transmission through systemic or intra-NAc administration of negative allosteric modulators (NAM) such as 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP) reduces reinstatement of cocaine seeking in extinction-reinstatement models (for reviews, see Caprioli et al., 2018; Mihov and Hasler, 2016; Olive, 2009) and context-induced cocaine seeking in abstinence models (Keck et al, 2013, 2014; Knackstedt et al., 2014; Knackstedt and Schwendt, 2016). Interestingly, mGlu5 NAMs reduce reinstatement of cocaine seeking under conditions in which mGlu5/CB1R-dependent LTD is impaired in the NAc, e.g., cocaine self-administration followed by extinction training (Knackstedt et al., 2010, 2014; Wang et al., 2013b). In summary, intra-NAc administration of mGlu5 NAMs reduces cocaine seeking in multiple addiction models, and results in the reinstatement model suggest that this effect is not attributable to prevention of mGlu5/CB1R-dependent LTD.

Far less is known about methamphetamine. Two studies reported systemic mGlu5 NAM-induced reductions in drug- and cue-primed reinstatement of methamphetamine seeking (Gass et al., 2009; Watterson et al., 2013), but there have been no studies in abstinence models. To fill this gap and provide further insight into the relationship between mGlu5/CB1R-dependent synaptic depression and incubation of methamphetamine craving, the second goal of this study was to determine if MTEP reduces cue-induced methamphetamine seeking before and after incubation. MTEP was selected because of vast preclinical findings with this compound (Mihov and Hasler, 2016), which have been replicated with newer compounds developed to avoid its off-target effects (Caprioli et al., 2018).

Section snippets

Subjects and surgery

All procedures were approved by the Rosalind Franklin University of Medicine and Science and the Oregon Health & Science University Institutional Animal Care and Use Committees in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals. Male Sprague-Dawley rats (Envigo, Indianapolis, IN or South Kent, WA) weighing 275–300 g were housed 3/cage under a reverse 12-h light/dark cycle with food and water available ad libitum. One week after arrival, rats were

Experiment 1: early withdrawal from methamphetamine self-administration is associated with a loss of mGlu5/CB1R-dependent synaptic depression

We have shown previously that DHPG-induced mGlu5/CB1R-dependent synaptic depression (hereafter referred to as DHPG-induced synaptic depression) is abolished in late withdrawal (>WD35) from a cocaine self-administration regimen leading to incubation of craving (McCutcheon et al., 2011; Scheyer et al., 2018). To determine if similar plasticity accompanies methamphetamine incubation, we used rats that self-administered saline (control condition) or methamphetamine (10 sessions of 6 h/day) (Fig. 1

Discussion

Long-lasting adaptations in glutamate transmission within the reward circuitry are a cardinal feature of the enduring vulnerability to relapse captured in animal models of substance use disorders (D’Souza, 2015; Lüscher, 2016; Scofield et al., 2016; Wolf, 2016). While many studies have addressed the role of mGlu5 in reinstatement of psychostimulant seeking after extinction training, less is known about mGlu5's role in drug craving during forced abstinence, and no studies have examined this for

Conclusions

mGlu5/CB1R-dependent synaptic depression in NAc core MSNs was lost during the rising phase of methamphetamine incubation but then recovered, in contrast to its persistent loss during the plateau phase of incubation of cocaine craving. Furthermore, whereas the cocaine-induced loss was accompanied by adaptations related to mGlu5 and Homer proteins, this was not the case for methamphetamine. Finally, behavioral experiments do not rule out a contribution of mGlu5 to the expression of incubated

Funding

This work was supported by the National Institutes of Health [DA009621 (M.E.W.), F32 DA036963 (D.T.C.) and K99 DA038110 (J.A.L.)].

Data statement

Original data are available upon request.

CRediT authorship contribution statement

Conor H. Murray: Conceptualization, Investigation, Writing - original draft, preparation. Daniel T. Christian: Investigation, Writing - review & editing. Mike Milovanovic: Investigation. Jessica A. Loweth: Investigation, Writing - review & editing. Eun-Kyung Hwang: Investigation. Aaron J. Caccamise: Investigation. Jonathan R. Funke: Investigation. Marina E. Wolf: Conceptualization, Writing - review & editing, Project administration, Funding acquisition.

Declaration of competing interest

None.

Acknowledgements

We thank Dr. Ken Mackie at Indiana University, Bloomington for generously supplying the DGL-α antibody.

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    1

    Present address: Dr. Conor H. Murray, Department of Psychiatry and Behavioral Neuroscience, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637, USA.

    2

    Present address: Dr. Daniel T. Christian, Department of Physiology and Pharmacology, Des Moines University, 3200 Grand Ave, Des Moines, IA 50312, USA.

    3

    Present address: Dr. Jessica A. Loweth, Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, 42 E Laurel Rd, Stratford, NJ 08084, USA.

    4

    Present address: Aaron J. Caccamise, Department of Biomedical Sciences, Marquette University, 560 N 16th St, Milwaukee, WI 53233, USA.

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