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Published in final edited form as: Neurosci Lett. 2022 Dec 21;795:137028. doi: 10.1016/j.neulet.2022.137028

An allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors reduces the cocaine-stimulated ERK1/2 phosphorylation in the mouse striatum

Li-Min Mao 1, Nirav Mathur 2, John Q Wang 1,2,*
PMCID: PMC9870709  NIHMSID: NIHMS1860899  PMID: 36565803

Abstract

Metabotropic glutamate (mGlu) receptors are involved in the experience-dependent neuroplasticity in the mesolimbic reward circuit. A Gαi/o-coupled mGlu2 subtype is distributed presynaptically in the striatum. These autoreceptors may have a significant influence over striatal neurons in their intracellular signaling pathways in response to a psychostimulant. Here we explored the effect of pharmacological potentiation of mGlu2 receptors on cocaine-stimulated phosphorylation (activation) of extracellular signal-regulated kinases (ERK) in the mouse striatum in vivo. We found that an mGlu2 selective positive allosteric modulator (PAM) LY487379 after a systemic injection did not alter basal phosphorylation of ERK1/2 or c-Jun N-terminal kinases in the striatum. However, pretreatment with LY487379 blocked the ERK1/2 phosphorylation induced by cocaine in the two subdivisions of the striatum, i.e., the caudate putamen and nucleus accumbens. LY487379 also blocked the cocaine-induced phosphorylation of Elk-1, a transcription factor downstream to the ERK pathway. Additionally, LY487379 reduced locomotor behavioral responses to cocaine. These results demonstrate that the mGlu2 PAM LY487379 possesses the ability to attenuate the activation of the ERK1/2 pathway in striatal neurons and reduce locomotor activity in response to cocaine in vivo.

Keywords: ERK, JNK, Elk-1, caudate putamen, nucleus accumbens, LY487379

1. Introduction

Group II metabotropic glutamate (mGlu) receptors (mGlu2 and mGlu3) are coupled to Gαi/o proteins and inhibit adenylyl cyclase and cAMP formation upon activation [1]. mGlu2 receptors are primarily presynaptic and usually reside in an area outside of the active zone of axonal terminals where they respond to excessive synaptic glutamate or astrocytic glutamate release to inhibit neurotransmitter release from glutamatergic terminals or other phenotypic terminals [1]. Within the striatum, mGlu2 receptors are distributed on axonal terminals projected from the cerebral cortex and thalamus [2]. Given that cortical and thalamic projection fibers are essentially glutamatergic [3], mGlu2 receptors in axon terminals of these corticostriatal and thalamostriatal fibers are thought to act as autoreceptors to inhibit glutamate release and thereby modulate local glutamatergic transmission and plasticity [4,5].

Mitogen-activated protein kinases (MAPK) are abundantly expressed in the central nervous system. A prototypic subclass of MAPKs is the extracellular signal-regulated kinase (ERK) which has attracted considerable attention in studying synaptic transmission and plasticity [6]. ERK is noticeably sensitive to changing cellular and synaptic input. Once activated (phosphorylated), active ERK translocates from the cytoplasmic compartment into the nucleus where ERK activates distinct transcription factors, including Elk-1, to regulate a discrete set of gene expression [6,7]. Thus, the ERK/Elk-1-mediated signaling super-highway activity-dependently transmits extracellular signals to nuclear gene expression to transcriptionally control synaptic plasticity, while abnormal ERK activity may contribute to the pathogenesis of a variety of neuropsychiatric disorders [6,7].

Psychostimulants (cocaine and amphetamine) after acute systemic administration induced robust behavioral responses in rodents. In addition, these stimulants readily enhanced ERK phosphorylation in the striatum [8–10], a key structure in the mesolimbic reward system critical for addictive properties of drugs of abuse. Between two equally-populated phenotypes of medium spiny projection neurons within the striatum, i.e., dopamine D1 receptor-bearing striatonigral and D2 receptor-bearing striatopallidal neurons, stimulants induced ERK phosphorylation in striatonigral neurons [11,12]. Both D1 and N-methyl-D-aspartate (NMDA) glutamate receptors were required to link stimulants to ERK [11,13–16]. The evoked ERK activity is thought to play a role in mediating the stimulus-transcription coupling in striatal neurons essential for experience-dependent neuroplasticity and stimulant addiction.

In this study, an mGlu2 positive allosteric modulator (PAM) was used to investigate the functional role of mGlu2 receptors in the regulation of ERK and Elk-1 in striatal neurons in vivo. We first examined effects of the mGlu2 PAM on constitutive phosphorylation of ERK in the striatum of adult mice. Another subclass of MAPKs, i.e., c-Jun N-terminal kinases (JNK, also known as stress-activated protein kinase), was examined as comparisons. We then explored whether the mGlu2 PAM has any impact on cocaine-stimulated phosphorylation of 1) ERK, 2) an ERK-directed downstream transcription factor (Elk-1), and 3) the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors in the striatum. Finally, we investigated whether the mGlu2 PAM alters locomotor activity under normal conditions and/or modulates behavioral responses to cocaine.

2. Materials and Methods

2.1. Animals

Young adult male C57BL/6 mice (2–3 months old, 22–28 g) from Charles River (New York, NY) were used in this study. These animals were kept in a 12-h light/12-h dark cycle and at 23°C (humidity: 50% ± 10%). Water and food were available ad libitum. All animal use procedures were in strict accordance with the US National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee.

2.2. Protein extraction

After drug administration, mice were killed by cervical dislocation. Brains were immediately removed and were sectioned into coronal slices. The striatum or the subdivisions of the striatum were dissected from the slices. We then homogenized the collected tissue in a homogenization buffer containing 20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM Na2EDTA, 1 mM EGTA, 1% NP-40, 1% sodium deoxycholate, 0.5% sodium dodecyl sulfate, 2.5 mM sodium pyrophosphate, 1 mM β-glycerophosphate, 1 mM Na3VO4, and 1 μg/ml leupeptin. Protein concentrations were determined. Samples were used in following Western blot assays.

2.3. Western blot

This was performed as described previously [17]. Briefly, proteins were separated on 4–12% SDS NuPAGE gels (Invitrogen, Carlsbad, CA). After transferred to polyvinylidene fluoride membranes, membranes were incubated with a primary antibody overnight at 4°C and were then incubated with a secondary antibody. An enhanced chemiluminescence reagent (GE Healthcare) was used to visualize proteins. The optical density of immunoblots was analyzed with NIH ImageJ. β-Actin was used as a loading control and all optical density values were normalized to β-actin.

2.4. Antibodies and pharmacological agents

Commercially available antibodies were used in this study. They include rabbit antibodies against ERK1/2 (Cell Signaling Technology, Danvers, MA), phosphorylated ERK1/2 (pERK1/2) at Thr202/Tyr204 for ERK1 and Thr185/Tyr187 for ERK2 (Cell Signaling), JNK (Cell Signaling), phosphorylated JNK (pJNK) at Thr183 and Tyr185 (Cell Signaling), GluA1 (Millipore, Burlington, MA), phosphorylated GluA1 at Ser845 (pS845, PhosphoSolutions, Aurora, CO), or β-actin (Sigma-Aldrich, St. Louis, MO), and mouse antibodies against Elk-1 (Santa Cruz Biotechnology, Dallas, TX) or phosphorylated Elk-1 (pElk-1) at Ser383 (Santa Cruz).

Pharmacological agents include N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine (LY487379), a prototypical and highly selective mGlu2 PAM that potently potentiates mGlu2 responses to glutamate while it has no intrinsic agonist activity at mGlu2 receptors [18,19], and cocaine. LY487379 hydrochloride and cocaine hydrochloride were purchased from Tocris (Minneapolis, MN) and Sigma-Aldrich, respectively. LY487379 was dissolved in dimethyl sulfoxide (DMSO) and adjusted with 0.9% NaCl with a final concentration of DMSO at < 0.2%. Cocaine was dissolved in 0.9% NaCl. LY487379 is centrally active after systemic administration [20] and is widely used in animal models to investigate the subtype-specific functional role of mGlu2 receptors [18,20,21]. We selected i.p. doses of LY487379 based on rigorous characterizations of doses of LY487379 after i.p. administration in altering motor responses to acute amphetamine administration (3.2 mg/kg) in mice [21].

2.5. Drug administration and behavioral assessment

Mice received an intraperitoneal (i.p.) injection of vehicle or LY487379 (30 mg/kg) 15 min prior to an i.p. injection of cocaine (30 mg/kg) or saline. Locomotor activity was measured for a 15-min period immediately after the final drug injection. As described in our previous work [22], locomotor activity was measured using an infrared photo-cell-based and automated monitoring system (VersaMax, AccuScan Instruments, Columbus, OH, USA). Briefly, in a sound-attenuated and light-controlled room, mice were placed in acrylic test chambers: 30 cm (H) × 20 cm (L) × 20 cm (W). A 3-h period of habituation was given before testing to exclude the exploratory behavior. Data from the sensors in each chamber were transferred to a computer with operating VersaMax software.

2.6. Statistics

Data in this report are expressed as means ± SEM. These data were statistically analyzed by using GraphPad Prism 6 (GraphPad software, La Jolla, CA). One- or two-way analysis of variance (ANOVA) was performed with a multiple comparison post hoc test. A statistically significant level was defined as a P value < 0.05.

3. Results

3.1. Effects of LY487379 on basal ERK1/2 phosphorylation

We first investigated whether the mGlu2 PAM LY487379 has any impact on constitutive ERK1/2 phosphorylation in the mouse striatum. To this end, a single dose of LY487379 at either 0.5 or 30 mg/kg or vehicle was injected i.p. and mice were then sacrificed 15 min after LY487379 or vehicle injection. Brains were removed and the whole striatum was dissected for Western blot assays. As shown in Fig. 1A, LY487379 at a low dose (0.5 mg/kg) did not alter pERK1/2 levels in the striatum. The PAM at a higher dose (30 mg/kg) still had no significant effect on pERK1/2 levels as compared to vehicle. No change in total cellular levels of ERK1/2 proteins was observed after LY487379 administration

Figure 1. Effects of LY487379 on phosphorylation of kinases and receptors in the mouse striatum.

Figure 1.

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(A) The effect of LY487379 (LY) on ERK1/2 phosphorylation. (B) The effect of LY487379 on JNK phosphorylation. (C) The effect of LY487379 on GluA1-S845 phosphorylation. Data were analyzed by one-way ANOVA and are presented as means±SEM (n=4 per group): pERK2: F(2,9)=0.293, P=0.829; pJNK1: F(2,9)=0.032, P=0.969; pS845: F(2,9)=0.129, P=0.881.

JNK is another subclass of MAPKs [6]. We next assayed changes in spontaneous JNK phosphorylation in the same samples. LY487379 at either dose did not alter basal pJNK levels in the striatum (Fig. 1B). The total amount of JNK proteins remained unchanged following LY487379 administration.

The GluA1 subunit of postsynaptic AMPA glutamate receptors is phosphorylated at the S845 site [23]. GluA1-S845 phosphorylation was readily induced in striatal neurons by cocaine or amphetamine [24]. We thus examined whether the potentiation of presynaptic mGlu2 receptors affects a postsynaptic event, i.e., the GluA1-S845 phosphorylation in striatal output neurons. We found that pS845 and total GluA1 levels in the striatum remained stable in response to the two doses of LY487379 (Fig. 1C).

3.2. Effects of LY487379 on cocaine-stimulated ERK1/2 phosphorylation

To determine the effect of the mGlu2 PAM on ERK1/2 responses to cocaine, we administered LY487379 (0.5 or 30 mg/kg, i.p.) or vehicle 15 min prior to an injection of cocaine (30 mg/kg, i.p.) or saline. Mice were sacrificed 15 min after cocaine or saline administration for analysis of changes in ERK1/2 phosphorylation in the whole striatum with Western blots. As expected, a significant increase in pERK1/2 levels in the striatum was seen in cocaine-treated mice as compared to saline-treated mice (Fig. 2A). Noticeably, pretreatment with LY487379 at 30 mg/kg suppressed this increase, while LY487379 at 0.5 mg/kg had no significant effect.

Figure 2. Effects of LY487379 on cocaine-stimulated ERK1/2 phosphorylation in the mouse striatum.

Figure 2.

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(A) The effect of vehicle (Veh) or LY487379 (LY) on cocaine (Coc)-stimulated ERK1/2 phosphorylation. (B) The effect of LY487379 and/or cocaine on JNK phosphorylation. (C) The effect of LY487379 on cocaine-stimulated GluA1-S845 phosphorylation. Data were analyzed by one-way ANOVA and are presented as means±SEM (n=6 per group): pERK2: F(3,20)=11.320, P<0.001; pJNK1: F(3,20)=0.301, P=0.824; pS845: F(3,20)=5.749, P=0.005. *P<0.05 versus vehicle+saline; +P<0.05 versus vehicle+cocaine.

Acute cocaine administration did not alter JNK phosphorylation in the striatum (Fig. 2B), consistent with the results from previous studies [14,17]. Similarly, pJNK levels showed no change in mice treated with both LY487379 and cocaine. An increase in pS845 levels was seen in the striatum of mice treated with cocaine (Fig. 2C). LY487379 at 0.5 mg/kg did not alter this increase. In mice treated with LY487379 at 30 mg/kg, a marked increase in pS845 proteins persisted, which was not significantly different from that seen in mice treated with cocaine alone.

The striatum contains two major subdivisions, the dorsal caudate putamen (CPu) and the ventral nucleus accumbens (NAc). We thus examined the effect of LY487379 on ERK phosphorylation in these individual subdivisions. Cocaine induced a marked increase in pERK1/2 levels in both the CPu (Fig. 3A) and NAc (Fig. 3B). LY487379 at a dose of 30 but not 0.5 mg/kg (15 min before cocaine) blocked the cocaine-stimulated ERK1/2 phosphorylation in the two regions.

Figure 3. Effects of vehicle (Veh) or LY487379 (LY) on cocaine (Coc)-stimulated ERK1/2 phosphorylation in the mouse CPu and NAc.

Figure 3.

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Data were analyzed by one-way ANOVA and are presented as means±SEM (n=6 per group): CPu-pERK2: F(3,20)=11.62, P<0.001; NAc-pERK2: F(3,20)=16.27, P<0.001. *P<0.05 versus vehicle+saline; +P<0.05 versus vehicle+cocaine.

3.3. Effects of LY487379 on cocaine-stimulated Elk-1 phosphorylation

One of essential functional roles of active ERK1/2 is to phosphorylate (activate) the downstream transcription factor such as Elk-1 [7]. Glutamate signals readily elevated Elk-1 phosphorylation in association with concomitant hyperphosphorylation of ERK1/2 in striatal neurons [7,25–27]. Acute cocaine or amphetamine also enhanced phosphorylation of Elk-1 [8,13,28]. We thus set forth to test the impact of the mGlu2 PAM on Elk-1 phosphorylation in response to cocaine. Cocaine (30 mg/kg, 15 min prior to tissue collection) increased pElk-1 levels in the striatum (Fig. 4A). LY487379 at 30 mg/kg (15 min prior to cocaine) blocked the cocaine-stimulated Elk-1 phosphorylation, although LY487379 at 0.5 mg/kg did not (Fig. 4A). All drug treatments had no effect on cellular levels of total Elk-1 proteins.

Figure 4. Effects of LY487379 on cocaine-stimulated Elk-1 phosphorylation (A) and locomotion (B).

Figure 4.

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Immunoblot data were analyzed by one-way ANOVA and are presented as means±SEM (n=6 per group): pElk-1: F(3,20)=7.452, P=0.002. Behavioral data were analyzed by two-way ANOVA and are presented as means±SEM (n=6 per group): vehicle (Veh) versus LY487379 (LY), F(1,20)=6.019, P=0.023, saline versus cocaine (Coc), F(1,20)=19.83, P<0.001, and interaction, F(1,20)=3.600, P=0.072. *P<0.05 versus vehicle+saline; +P<0.05 versus vehicle+cocaine.

3.4. Effects of LY487379 on locomotor responses to cocaine

To determine whether the mGlu2 PAM affects hyperlocomotion induced by cocaine, locomotor activity in response to cocaine (30 mg/kg, i.p.) was measured in the presence or absence of LY487379 (30 mg/kg, i.p.; 15 min prior to cocaine) in mice. Total distance traveled (cm) for each animal was measured immediately after the final drug injection for a 15-min period. As expected, acute cocaine administration substantially increased total distance traveled (Fig. 4B). Notably, cocaine produced a much less locomotor response in mice pretreated with LY487379 than mice pretreated with vehicle. LY487379 alone did not significantly alter spontaneous motor activity.

4. Discussion

LY487379 is the first reported and prototypical PAM for the mGlu2 subtype [18,19]. A number of mGlu2 PAMs have since been developed with efficacy in animal models of neuropsychiatric disorders [29,30]. By potentiating mGlu2 responses to endogenous glutamate, mGlu2 PAMs constrain excessive glutamatergic signaling through acting at presynaptic sites and thus reshape synaptic transmission and plasticity to mitigate the pathophysiology and symptoms of psychiatric illnesses. Acute cocaine is well known to induce a rapid increase in extracellular dopamine levels in the striatum [31]. A single dose of cocaine also produced a significant rise in glutamate levels in the NAc [32]. Both dopamine signals through D1 receptors and glutamate signals through NMDA receptors are required for the response of ERK1/2 and associated transcription factors to stimulants presumably in a subset of D1-expressing striatonigral projection neurons [8,11,13–16]. In this study, we found that an mGlu2 PAM effectively suppressed the cocaine-stimulated ERK1/2 phosphorylation in the striatum. This implies that, in addition to D1 and NMDA receptors in postsynaptic striatal projection neurons, mGlu2 autoreceptors at corticostriatal and thalamostriatal synapses serve as an essential presynaptic element regulating the outcome of ERK1/2 phosphorylation in response to cocaine. Of note, LY487379 in this study showed no significant effect on the cocaine-stimulated GluA1-S845 phosphorylation. In a previous report, the NMDA receptor antagonist MK801 blocked the acute amphetamine-stimulated ERK1/2 but not GluA1-S845 phosphorylation in the mouse striatum, indicating that, unlike ERK1/2, GluA1 in its S845 phosphorylation in response to amphetamine requires no NMDA receptor stimulation [11]. Given that S845 is phosphorylated by the cAMP-dependent protein kinase A (PKA) [23], the stimulant-induced S845 phosphorylation might be primarily mediated via a signaling mechanism involving the D1 receptor-associated cAMP/PKA pathway.

Despite knowledge about group II mGlu receptor functions extensively analyzed by using nonselective mGlu2/3 agents, it is increasingly intriguing to focus on the mGlu2 subtype to analyze its subtype-specific roles in the modulation of striatal transmitter release in response to stimulants. This can now be pursued by using a pharmacological approach with a number of recently available agents (orthosteric or allosteric) selective for mGlu2 or a genetic approach with mGlu2 knockout mice. At present, studies with pharmacological agents are limited. In mGlu2 null mice, acute cocaine caused a greater increase in dopamine release and a more rapidly increase in glutamate release in the NAc than that seen in wild type mice [33]. This solidifies the model that mGlu2 autoreceptors inhibit neurotransmitter release to limit intracellular signaling responses to cocaine in postsynaptic striatal neurons.

mGlu2 receptors are linked to behavioral activity in response to acute stimulant exposure. In drug-naïve mice, mGlu2 PAMs (JNJ-40411813 and JNJ-42153605) inhibited spontaneous locomotion [29]. In mice treated with a single dose of amphetamine (3.2 mg/kg), LY487379 reduced the amphetamine-stimulated hyperlocomotion at a dose (32 mg/kg, i.p.) that did not disrupt spontaneous locomotor activity [21]. Similarly, LY487379 or the mGlu2 PAM TASP0443294 at doses ineffective in influencing spontaneous locomotion reduced the hyperlocomotion induced by cocaine (30 mg/kg) in mice [this study] or methamphetamine (1 mg/kg) in rats [30]. LY541850, an mGlu2 agonist/mGlu3 antagonist, and another mGlu2 PAM also inhibited the amphetamine- or methamphetamine-induced hyperactivity in mice [34,35]. In mGlu2 knockout mice, hyperlocomotion was observed under novel environmental and stressful conditions, while no change in locomotion existed in a habituated environment [33]. The nonselective mGlu2/3 agonists (LY379268 and LY404039) reversed amphetamine (2.5 or 5 mg/kg)-induced motor activities in mGlu3 but not mGlu2 knockout mice [36,37]. The dual mGlu2/3 agonist LY354740 failed to reverse the amphetamine-induced motor activation in Han Wistar rats lacking mGlu2 expression [38]. Thus, activation of mGlu2 rather than mGlu3 receptors seems more likely to have the acute antipsychotic property.

Highlights:

  • The mGlu2 positive allosteric modulator LY487379 blocked cocaine-stimulated ERK1/2 phosphorylation in the striatum.

  • LY487379 exerted its effects in both the caudate putamen and nucleus accumbens.

  • LY487379 also blocked cocaine-stimulated striatal Elk-1 phosphorylation.

  • Locomotor responses to cocaine was reduced in mice pretreated with LY487379.

Acknowledgements

Authors want to thank Dr. Daozhong Jin for technical assistance.

Funding

This work was supported by the NIH grant R01MH061469 (J.Q.W.).

Footnotes

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Conflict of interest/Competing interest

The authors declare that they have no conflict of interest/competing interest.

Ethics approval

All animal use procedures were in strict accordance with the US National Institutes of Health Guide for the Care and Use of Laboratory Animals. The animal protocol was approved by the Institutional Animal Care and Use Committee (protocol #: 1006).

Availability of Data and Materials

The data sets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data sets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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