The Role of mGluR5 in the Effects of Cocaine Implications for Medication Development

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Mark P. Epping-Jordan, PhD

Investigations over the past several years have yielded insights into the contributions of metabotropic glutamate receptors (mGluRs) to the effects of psychostimulants. Recently, an important role was demonstrated for the mGluR subtype 5 in the locomotor stimulant and reinforcing effects of cocaine (1). The data obtained in that report will be summarized here, followed by a brief discussion of the implications of this evidence for the development of medications to treat cocaine dependence.

mGluRs can be divided into three groups based on amino acid sequence homology, receptor pharmacology, and intracellular signal transduction mechanisms (2,3). Group I consists of mGluRl and mGluR5, which stimulate phospholipase C and phosphoinositide hydrolysis, while group II, consisting of mGluR2 and mGluR3, and group III, consisting of mGluR4, 6, 7, and 8, are negatively coupled to adenylyl cyclase. All of the mGluR subtypes, except for mGluR6 and mGluR8, are expressed in widespread regions of the brain, with several subtypes being expressed at high levels in brain regions associated with the behavioral effects of drugs of abuse (4-10).

Direct activation or blockade of mGluRs mediate both baseline and psychomotor stimulant-induced locomotor activity (11,12). Bilateral injections into the nucleus accumbens (NAc) of the non-selective mGluR agonist 1-amino-1,3-cyclopentane-irans-1,3-dicarboxylic acid (ACPD) increased locomotor activity in the rat (11,12), and this effect was blocked by co-injection of mGluR antagonist (RS)-a-methyl-4-carboxyphenylglycine (MCPG) (11). In addition, the locomotor stimulant effects of both the indirect dopamine (DA) agonist amphetamine as well as the direct DA receptor agonist apomorphine were completely blocked by co-injection of MCPG into the NAc (13). Furthermore, bilateral injections of ACPD into the ventral tegmental area, the source of DA projections into the NAc, increased locomotor activity in rats, through activation of both Group I and Group II mGluRs (12). These data support a role for mGluRs in the control of baseline and drug-induced locomotor activation; however, the contributions of specific mGluR subtypes remain unknown.

The expression pattern of mGluR5 suggests a possible role in the effects of drugs of abuse. mGluR5 is highly expressed in both the intrinsic and efferent projection neurons in the NAc and striatum (9), brain regions associated with the behavioral effects of psychostimulants. Approximately 65% of stria-tonigral projection neurons and 50-60% of striatopallidal projection neurons, as well as a majority of striatal interneurons express mGluR5 (10). Over 80% of the NAc core and shell neurons projecting to the ventral pallidum and about 50% of the NAc shell neurons projecting to the ventral tegmental area, the primary efferent accumbal pathways, express mGluR5 mRNA (14). The expression of mGluR5 in significant proportions of accumbal and striatal projection neurons and interneurons suggest that the activity of mGluR5 influences the information that is processed within these structures and that is transmitted to their output pathways.

From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ

Fig. 1. Locomotor response to cocaine administration in mGluR5 (+/+) (n = 14) and (-/-) (n = 16) mice. Horizontal activity was measured during a 45-min period and was calculated as a percentage of baseline locomotor activity (vehicle treatment during the same period). Values represent mean activity counts ± SEM.*, P < 0.05 versus saline vehicle; **, p < 0.01 versus vehicle. (Dunnett's test after two-way repeated measures analysis of variance) [Reprinted with permission from Chiamulera et al. (1).]

Fig. 1. Locomotor response to cocaine administration in mGluR5 (+/+) (n = 14) and (-/-) (n = 16) mice. Horizontal activity was measured during a 45-min period and was calculated as a percentage of baseline locomotor activity (vehicle treatment during the same period). Values represent mean activity counts ± SEM.*, P < 0.05 versus saline vehicle; **, p < 0.01 versus vehicle. (Dunnett's test after two-way repeated measures analysis of variance) [Reprinted with permission from Chiamulera et al. (1).]

While the expression and distribution of mGluR5 have been reasonably well-defined, the specific role played by mGluR5 in the effects of cocaine has been examined only recently. Increases in mGluR5 mRNA in the NAc shell and dorsolateral striatum (15) and decreases in mGluR5 protein levels in the medial NAc were observed 3 wk after cessation of repeated cocaine administration (16). These changes in expression suggest an involvement of mGluR5 in the neuroadaptations resulting from repeated cocaine administration; however, the functional consequences of altered mGluR5 expression remain unknown. In order to determine more specifically the role of mGluR5 to the effects of cocaine, the locomotor stimulant and rewarding effects of cocaine were examined in mGluR5 null mutant (-/-) mice and their wild-type (+/+) siblings. In addition, the effect of the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (17) on cocaine self-administration in C57BL/6J mice was examined [1].

Baseline and cocaine-induced locomotor activity were examined in mGluR5 (-/-) and (+/+) mice. On each test day, all mice received an injection of saline vehicle and were immediately placed into a locomotor activity chamber for 15 min. Mice were then removed from the apparatus and received an injection of either saline or cocaine (10, 20, or 40 mg/kg, ip) and were again placed into the activity chamber for an additional 45 min. Each subject was tested with vehicle alone and all three cocaine doses on different test days with at least 1 wk between test sessions.

Baseline locomotor activity did not differ significantly between (+/+) and (-/-) mice [(+/+), 2393-479; (-/-), 2710-642, mean horizontal activity counts/45-min session - SEM]. Cocaine induced a significant, dose-dependent increase in horizontal activity in (+/+) mice, however, cocaine had no effect on locomotor activity in mGluR5 (-/-) mice at any dose tested (Fig. 1). Because mice received repeated injections of cocaine, it is possible that some of the increase in locomotor activity observed in the (+/+) mice can be attributed to behavioral sensitization (18) Nevertheless, locomotor activity was not altered by cocaine administration in mGluR5 (-/-) mice, under the conditions tested. These results suggest that mGluR5 does not contribute to baseline locomotor activity; however, they indicate that mGluR5 is required for the expression of cocaine-induced locomotor activation (1).

Examination of the effect of mutation of the mGluR5 gene on the reinforcing effects of cocaine in mice may help to establish the role of mGluR5 in human cocaine addiction. Therefore, intravenous cocaine self-administration was investigated in mGluR5 (-/-) and (+/+) mice. Because the self-administration task is complex and requires learning, memory, and motor coordination, which could be disrupted by the mGluR5 mutation, mice were first trained in a discriminated, two-lever, food-reinforced operant task. This training allowed for the assessment of differences in learning rate and/or the ability to perform the operant task separate from the assessment of the reinforcing effects of cocaine. Acquisition of the food-reinforced operant task did not differ between (+/+) and (-/-) mice (Fig. 2A), indicating that the reinforcing properties of food were unchanged in the (-/-) mice.

After the food training, mice were surgically implanted with a catheter in the right jugular vein and, following recovery, were allowed to self-administer cocaine. mGluR5 (+/+) mice acquired stable self-administration across a wide range of cocaine doses; however, (-/-) mice did not acquired cocaine self-administration at any of the doses tested (Fig. 2B). Despite retraining to criterion on the food task between each cocaine dose, lever responding for cocaine in (-/-) mice extinguished within three to five sessions at all doses. Taken together, data from the food training and cocaine self-administration studies suggest that while the reinforcing properties of food remained unchanged, the reinforcing effects of cocaine were absent in mGluR5 (-/-) mice (1).

It is possible that the absence of the reinforcing effect of cocaine in (-/-) mice was due to developmental alterations resulting from the constitutive mutation of the mGluR5 gene rather than to the lack of mGlu5 receptors in the adult mice. Therefore, the effects of the selective mGluR5 antagonist MPEP on cocaine self-administration and operant responding for food in C57BL/6J mice were examined. MPEP dose-dependently reduced cocaine self-administration in C57BL/6J mice (Fig. 2C); however, the most effective MPEP dose (30mg/kg, iv) had no effect on the rate of food-reinforced lever responding in the same mice (Fig. 2D) (1). These data suggest that the effects of MPEP were specific to the reinforcing effects of cocaine and were not due to nonspecific disruption of motivation, to the ability to perform the operant task, or to general malaise induced by MPEP.

Cocaine is known to block the re-uptake of monoamine neurotransmitters, and the locomotor stimulant and reinforcing effects of cocaine have been linked to its ability to increase extracellular levels of DA in the NAc (19,20). Mutation of the mGluR5 gene may have disrupted the ability of cocaine to increase DA levels thereby eliminating cocaine-induced increases in locomotor activity and cocaine self-administration in mGluR5 (-/-) mice. Therefore, extracellular levels of DA in the NAc (Fig. 3A) were examined in awake, freely moving mGluR5 (+/+) and (-/-) mice after injection of either cocaine or saline vehicle. Basal levels of extracellular NAc DA did not differ significantly between mGluR5 (-/-) and (+/+) mice. Cocaine induced significant increases in extracellular DA that did not differ between (-/-) and (+/+) mice (Fig. 3B), suggesting that mutation of the mGluR5 gene did not alter baseline or cocaine-induced increases in NAc DA levels (1).

Because DA neurotransmission appears to be critical to the behavioral effects of cocaine (19,20), the effects of mutation of the mGluR5 gene on the expression and brain distribution of DA receptors and the DA transporter (DAT) were examined. The expression and distribution of DA D1-like and D2-like receptors and the DAT and the expression of D1 and D2 DA receptor mRNA did not differ between mGluR5 (+/+) and (-/-) mice (1). These data suggest that mutation of the mGluR5 gene did not alter the expression or distribution of DA receptors or of the DAT.

The data summarized above indicate an important role for mGluR5 in the locomotor and reinforcing effects of cocaine. However, the specific mechanisms of the mGluR5 contribution to the effects of cocaine are not known. Emerging evidence has identified several possible mechanisms through which mGluR5 may influence pathways involved in the effects of cocaine. This evidence may provide important insights into the development of medications to treat cocaine dependence.

As mentioned above, mGluR5 is highly expressed in several brain regions that contribute to the behavioral effects of cocaine, including the NAc, striatum, ventral tegmental area, and cortex (9).

Fig. 2. Operant responding for food and cocaine reinforcement. (A) Acquisition to criterion of food-reinforced lever pressing in mGluR5 (+/+) (n = 5) and (-/-) (n = 6) mice. Mice earned 50 food reinforcers (whole milk with sucrose, 60 g/L) under each schedule of reinforcement starting with a fixed-ratio 1 time-out 11-s schedule of reinforcement (FRITOlls) through FRITO15s, FRIT020s, and finally FR2T020s, identical to the schedule of reinforcement during cocaine self-administration. Mean number of days to criterion (50 reinforcers in 1 h under FR2T020s) did not differ between genotypes. Values represent mean ± SEM (Student's t test). (B) Mice implanted with jugular catheters were allowed to self-administer cocaine to stability. Mice were given access to various doses of cocaine (0.0, 0.08, 0.4, 0.8, 1.6, and 3.2 mg/kg/injection) during single daily 1 h sessions in a Latin square design, and the number of injections at each dose was determined twice during at least two separate sessions. mGluR5 (-/-) mice failed to acquire self-administration, so they were retrained to lever press for food to criterion in between each cocaine dose so that they had a nonzero response rate during the first one or two sessions of access to each dose. Only mice that completed testing at all doses, including saline, were included in the analyses. Values represent mean number of injections per session ± SEM. *, p < 0.05 versus saline group with same genotype; t, p < 0.05 (+/+) at 0.4 mg/kg/injection dose versus (+/+) at 3.2 mg/kg/injection dose (Student's t tests with Bonferroni correction after two-way repeated measures analysis of variance). (C) Effects of MPEP on cocaine self-administration in C57BI/6J mice (n = 5). Values represent percentage of baseline number of injections per 1 h session. MPEP dose-dependently decreased cocaine self-administration, *, p < 0.05 compared to saline; t, p < 0.05 compared to 3 mg/kg MPEP dose (means comparisons after appropriate one way ANOVA). (D) Effects of MPEP (30 mg/kg, iv) on food-reinforced operant responding in C57Bl/6J mice. MPEP had no effect on the number of lever presses/min in C57Bl/6J mice (n = 5) responding for food under a FR2T020s schedule of reinforcement. [Reprinted with permission from Chiamulera et al. (1).]

Furthermore, the distribution of mGluR5 suggests potential roles in learning, memory, motivation, and motor control, processes involved in the complex behaviors that contribute to the development of cocaine dependence. The locomotor and reinforcing effects of cocaine are regulated by both DA and glutamate transmission in the NAc (11,21) and glutamate and DA may act in synergy to mediate the effects of cocaine (1).

Recent evidence has demonstrated interactions between dopamine and metabotropic glutamate receptor intracellular signaling pathways. These interactions may have important implications for the

Fig. 3. Extracellular DA levels in NAc measured by microdialysis in mGluR5 WT (n = 3) and KO (n = 3) mice. (A) Location of the dialysis probe. Coordinates were calculated to position the probe at the level of the NAc (A: + 1.3 mm, V: -4.6 mm from bregma). The solid and dashed boxes indicate the minimum and maximum extent of the probe placement. Location of the probe was verified in each mouse at the end of the experiment. (B) DA levels analysis: 10 ||L dialysate samples were collected every 20 min from mGluR5 WT (saline, n = 3; cocaine, n = 3) and KO mice (saline, n = 3; cocaine n = 3). Values represent mean pg/sample DA ± SEM. *, p < 0.05; **, p < 0.01 versus saline at the same timepoint. (Student's t test with Bonferroni correction after two-way repeated measures ANOVA for each genotype). Extracellular DA levels were not significantly different between mGluR5 WT and KO groups (analysis of variance for repeated measures on data of mGluR5 WT and KO groups treated with cocaine: not significant). Abbreviations: ac, anterior commissure; CPu, caudate-putamen; LV, lateral ventricle; NAccC, nucleus accumbens core; NAccSh, nucleus accumbens shell. [Reprinted with permission from Chiamulera et al.(7).]

Fig. 3. Extracellular DA levels in NAc measured by microdialysis in mGluR5 WT (n = 3) and KO (n = 3) mice. (A) Location of the dialysis probe. Coordinates were calculated to position the probe at the level of the NAc (A: + 1.3 mm, V: -4.6 mm from bregma). The solid and dashed boxes indicate the minimum and maximum extent of the probe placement. Location of the probe was verified in each mouse at the end of the experiment. (B) DA levels analysis: 10 ||L dialysate samples were collected every 20 min from mGluR5 WT (saline, n = 3; cocaine, n = 3) and KO mice (saline, n = 3; cocaine n = 3). Values represent mean pg/sample DA ± SEM. *, p < 0.05; **, p < 0.01 versus saline at the same timepoint. (Student's t test with Bonferroni correction after two-way repeated measures ANOVA for each genotype). Extracellular DA levels were not significantly different between mGluR5 WT and KO groups (analysis of variance for repeated measures on data of mGluR5 WT and KO groups treated with cocaine: not significant). Abbreviations: ac, anterior commissure; CPu, caudate-putamen; LV, lateral ventricle; NAccC, nucleus accumbens core; NAccSh, nucleus accumbens shell. [Reprinted with permission from Chiamulera et al.(7).]

role of mGluR5 in cocaine dependence and in the development of mGluR agents as therapeutics for the treatment of cocaine addiction.

Incubation of striatal synaptosomes with the Group l mGluR agonist (S)-3,5-dihydroxyphenyl-glycine (DHPG) transiently, but significantly decreased DA uptake through the DAT (22), an effect blocked by the selective mGluR5 antagonist MPEP. This effect appeared to be mediated by mGluR5 activation of protein kinase C and calcium calmodulin-dependent protein kinase II (22). Although the majority of anatomical evidence suggests that mGluR5 is expressed postsynaptically, there is some evidence for localization of mGluR5 in presynaptic axon terminals (9). These results suggest that mGluR5 may interact directly with the DAT to influence DA transmission in the striatum; however, it will be important to evaluate this effect in vivo.

Conflicting evidence exists regarding the interactions between Group l mGluR activation and D1-like DA receptor-induced formation of cyclic adenosine monophosphate (cAMP). Evidence from stri-atal slice preparations showed that D1-like DA receptor agonist-induced cAMP formation was inhibited by the non-selective mGluR agonist ACPD (23), whereas, in cultured striatal neurons, the Group l agonist DHPG potentiates cAMP formation induced by the D1-like agonist SKF 38393 (24). Finally, recent data indicate that stimulation of Group I mGluRs with DHPG activates casein kinase 1 (Ck1) and cyclin-dependent kinase 5 (Cdk5), two kinases involved in dopamine signaling in the neostriatum (25). In addition, DHPG treatment in acutely dissociated neurons was shown to increase the activation of voltage-gated Ca+ channels (25). Taken together these results suggest an interaction between Group I mGluRs and DA receptors, although the specific nature of this interaction remains unclear.

The evidence reviewed in this chapter suggests an important and specific role for the Group I metabotropic glutamate receptor subtype mGluR5 in the effects of cocaine. Mice lacking the mGluR5 gene did not self-administer cocaine and showed no alteration in locomotor activity following cocaine treatment. The selective mGluR5 antagonist MPEP significantly reduced cocaine self-administration, but had no effect on operant responding for food, suggesting that antagonism of mGluR5 does not affect the reinforcing effects of natural reinforcers. This evidence suggests that antagonists of mGluR5 may be developed as effective pharmacological treatments for cocaine addiction. Evidence that mGluR5 plays a modulatory role in both glutamate (3) and DA receptor signaling (22-25) suggests that antagonists of mGluR5 may not induce the aversive side effects associated with direct DA or ionotropic glutamate receptor antagonists. Nevertheless, a significant amount of work remains to be done in order to understand the specific contributions of mGluR5 and the other mGluR subtypes to the effects of cocaine and other drugs of abuse and to the development of addiction.

In conclusion, there are several lines of evidence suggesting that mGluR5 contributes to the effects of cocaine in rodents. mGluR5 is expressed in several brain regions known to contribute to the behavioral effects of cocaine (9, 10, 14). Cocaine did not alter locomotor activity in mice bearing a null mutation of the mGlu5 receptor gene (1). mGluR5 (-/-) mice did not self-administer cocaine, an effect that was not attributable to a learning deficit or to an alteration of brain reward systems (1). Pharmacological blockade of mGluR5 in mice selectively decreases cocaine self-administration (1). Subsequent investigation will lead to a greater understanding of the specific mechanisms through which mGluR5 contributes to the effects of cocaine.

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