The mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine decreases ethanol consumption via a protein kinase C epsilon-dependent mechanism

Glutamatergic neurotransmission plays a critical role in addictive behaviors, and recent evidence indicates that genetic or pharmacological inactivation of the type 5 metabotropic glutamate receptor (mGluR5) reduces the self-administration of cocaine, nicotine, and alcohol. Because mGluR5 is coupled to activation of protein kinase C (PKC), and targeted deletion of the epsilon isoform (PKCepsilon) in mice reduces ethanol self-administration, we investigated whether there is a functional link between mGluR5 and PKCepsilon. Here, we show that acute administration of the mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine to mice increases phosphorylation of PKCepsilon in its activation loop (T566) as well as in its C-terminal region (S729). Increases in phospho-PKCepsilon are dependent not only on mGluR5 stimulation but also on phosphatidylinositol-3 kinase (PI3K). In addition, the selective mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) reduced basal levels of phosphorylation of PKCepsilon at S729. We also show that MPEP dose dependently reduced ethanol consumption in wild-type but not in PKCepsilon-null mice, suggesting that PKCepsilon is an important signaling target for modulation of ethanol consumption by mGluR5 antagonists. Radioligand binding experiments using [(3)H]MPEP revealed that these genotypic differences in response to MPEP were not a result of altered mGluR5 levels or binding in PKCepsilon-null mice. Our data indicate that mGluR5 is coupled to PKCepsilon via a PI3K-dependent pathway and that PKCepsilon is required for the ability of the mGluR5 antagonist MPEP to reduce ethanol consumption.     

Inhibitory effects of MPEP,an mGluR5 antagonist,and memantine,an <Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="SmallCaps">D</Emphasis>-aspartate receptor antagonist,on morphine antinociceptive tolerance in mice

Abstract Rationale. Inhibition of N-methyl-D-aspartate (NMDA) receptors by memantine, an NMDA-receptor antagonist, and other antagonists of ionotropic receptors for glutamate inhibit the development of opiate antinociceptive tolerance. The role of metabotropic receptors for glutamate (mGluR) in opiate tolerance is less known. Objective. In the present study, we examined the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the mGluR type-I (subtype mGluR5) antagonist, as well as the effect of co-administration of low doses of memantine and MPEP on morphine antinociceptive tolerance in mice. Methods. Morphine antinociceptive activity was tested twice, before and after chronic morphine administration, in the tail-flick test using a cumulative dose–response protocol. Tolerance was induced by six consecutive days of b.i.d. administration of morphine (10 mg/kg, s.c.). Saline, memantine (7.5 mg/kg and 2.5 mg/kg, s.c.), MPEP (30 mg/kg and 10 mg/kg, i.p.) and the combination of both antagonists at low doses was given 30 min prior to each morphine injection during its chronic administration. A separate experiment assessed the effects of memantine, MPEP and their combination on acute morphine antinociception using a tail-flick test. Results. MPEP (30 mg/kg but not 10 mg/kg) as well as memantine (7.5 mg/kg but not 2.5 mg/kg) attenuated the development of tolerance to morphine-induced antinociception. When given together, the low doses of MPEP (10 mg/kg) and memantine (2.5 mg/kg) also significantly attenuated opiate tolerance. None of the treatments with glutamate antagonists produced antinociceptive effects or significantly affected morphine-induced antinociception. Conclusions. The data suggest that both mGluR5 and NMDA receptors may be involved in the development of morphine antinociceptive tolerance. Electronic Publication     

The mGluR5 antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-administration in C57BL/6J mice

Rationale Many of the biochemical, physiological, and behavioral effects of ethanol are known to be mediated by ionotropic glutamate receptors. Emerging evidence implicates metabotropic glutamate receptors (mGluRs) in the biobehavioral effects of ethanol and other drugs of abuse, but there is little information regarding the role of mGluRs in the reinforcing effects of ethanol. Materials and methods Male C57BL/6J mice were trained to lever-press on a concurrent fixed ratio 1 schedule of ethanol (10% v/v) vs water reinforcement during 16-h sessions. Effects of mGluR1, mGluR2/3, and mGluR5 antagonists were then tested on parameters of ethanol self-administration behavior. Results The mGluR5 antagonist MPEP (1–10 mg/kg, i.p.) dose-dependently reduced ethanol-reinforced responding but had no effect on concurrent water-reinforced responding. Analysis of the temporal pattern of responding showed that MPEP reduced ethanol-reinforced responding during peak periods of behavior occurring during the early hours of the dark cycle. Further analysis showed that MPEP reduced the number of ethanol response bouts and bout-response rate. MPEP also produced a 13-fold delay in ethanol response onset (i.e., latency to the first response) with no corresponding effect on water response latency or locomotor activity. The mGluR1 antagonist CPCCOEt (1–10 mg/kg, i.p.) or the mGluR2/3 antagonist LY 341495 (1–30 mg/kg, i.p.) failed to alter ethanol- or water-reinforced responding. Conclusions These data indicate that mGlu5 receptors selectively regulate the onset and maintenance of ethanol self-administration in a manner that is consistent with reduction in ethanol’s reinforcement function.     

Behavioral and neurochemical interactions between Group 1 mGluR antagonists and ethanol: potential insight into their anti-addictive properties

Blockade of the mGluR5 subtype of Group 1 metabotropic glutamate receptor (mGluRs) reduces the rewarding effects of ethanol (EtOH), while the effects of mGluR1a blockade remain under-investigated. The present study compared the effects of pretreatment with the mGluR5 antagonist MPEP and the mGluR1a antagonist CPCCPOEt upon behavioral and neurochemical variables associated with EtOH reward in alcohol-preferring C57BL/6J mice. Pretreatment with either antagonist (0-10 mg/kg, IP) dose-dependently reduced measures of EtOH reward in an operant self-administration paradigm and the maximally effective antagonist dose (10 mg/kg) also blocked the expression of EtOH-induced place conditioning, as well as EtOH consumption under 24-h free-access conditions. MPEP pretreatment did not significantly alter the EtOH dose-locomotor response function; however, it prevented EtOH-induced changes in extracellular dopamine, glutamate and GABA in the nucleus accumbens (NAC). In contrast, CPCCOEt shifted the EtOH dose-response function downwards, enhanced the capacity of higher EtOH doses to elevate NAC levels of GABA and lowered extracellular dopamine and glutamate below baseline following EtOH injection. It is suggested that the "anti-alcohol" effects of MPEP may involve an attenuation of the neurochemical signals mediating EtOH reward, whereas those of CPCCOEt may involve an increased sensitivity to the inhibitory effects of EtOH upon brain and behavior.     

Metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) microinfusions into the nucleus accumbens shell or ventral tegmental area attenuate the reinforcing effects of nicotine in rats

Systemic administration of the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was previously shown to selectively attenuate nicotine self-administration without affecting food-maintained responding in rats. Glutamatergic neurotransmission in the ventral tegmental area (VTA) and nucleus accumbens (NAcc) shell plays an important role in the reinforcing effects of nicotine. To determine the brain sites that may mediate the systemic effects of MPEP on nicotine self-administration, the present study investigated the effects of MPEP microinfusions into the VTA or the NAcc shell on nicotine and food self-administration in separate groups of rats. Administration of low MPEP doses (0, 0.5, 1, and 2 μg/0.5 μl/side) microinfused into the NAcc shell had no effect on nicotine self-administration, whereas higher MPEP doses (0, 10, 20, and 40 μg/0.5 μl/side) microinfused into the NAcc shell dose-dependently attenuated nicotine self-administration without affecting food-maintained responding. Microinfusions of MPEP into the VTA (0, 10, 20, and 40 μg/0.5 μl/side) significantly decreased both nicotine and food self-administration at 20 μg/0.5 μl/side but did not affect responding for either reinforcer at 40 μg/0.5 μl/side. This lack of effect of 40 μg/0.5 μl/side MPEP on either nicotine or food self-administration when administered into the VTA may be attributable either to actions of MPEP at presynaptic mGlu5 receptors or at targets other than mGlu5 receptors. Importantly, anatomical control injections 2 mm above the NAcc shell or the VTA using the most effective MPEP dose in the two regions did not result in attenuation of nicotine self-administration. In conclusion, MPEP microinfusions in the VTA or NAcc shell attenuates the reinforcing effects of nicotine possibly via blockade of mGlu5 receptors located in these regions.     

The mGluR5 antagonist MPEP decreases operant ethanol self-administration during maintenance and after repeated alcohol deprivations in alcohol-preferring (P) rats

Rationale Recent research indicates that blockade of mGluR5 modifies the reinforcing properties of ethanol.Objectives The present studies examined the effects of mGluR5 receptor blockade in a genetic model of high ethanol intake, the alcohol-preferring (P) rat, on the maintenance of operant ethanol self-administration. In addition, we determined the effect of 2-methyl-6-(phenylethyl)-pyridine (MPEP) on the repeated alcohol deprivation effect.Methods Twelve male (P) rats were trained in experimental sessions to self-administer 10% w/v ethanol via a sucrose-fading procedure. After the establishment of operant ethanol self-administration, subjects were treated with various metabotropic glutamate receptor (mGluR) subtype antagonists immediately prior to experimental sessions: the mGluR5 antagonist MPEP (1, 3, and 10 mg/kg); the mGluR2–3 antagonist LY-341495 (1, 3, and 10 mg/kg); and the mGluR1 antagonist CPCCOEt (1, 3, and 10 mg/kg). After determining the role of mGluR5 in the maintenance of operant ethanol self-administration, we examined the role of this receptor in relapse following repeated periods of alcohol deprivation by depriving subjects of ethanol exposure for three 2-week deprivation periods.Results The mGluR5 antagonist MPEP dose-dependently decreased operant ethanol self-administration. In addition, rats that received saline immediately prior to repeated alcohol deprivation sessions self-administered ethanol at increasing levels that were above those achieved in the last operant-conditioning session prior to the initial 2-week deprivation period. This repeated alcohol deprivation effect was prevented in subjects pretreated with MPEP (10 mg/kg).Conclusions These findings suggest that mGluR5 receptors may modulate both the maintenance of operant ethanol self-administration and abstinence-induced increases in ethanol intake.     

Behavioral sensitization due to social defeat stress in mice: antagonism at mGluR5 and NMDA receptors

Rationale Repeated administration of psychostimulants progressively augments the behavioral response to and increases self-administration behavior of these drugs. Experience of repeated intermittent social defeat stress episodes also leads to a sensitized locomotor response following psychostimulant challenge. Both metabotropic and ionotropic glutamate receptors have been shown to be critical in the induction and expression of stimulant sensitization, but their role in sensitization due to social defeat stress remains unclear.Objective We evaluated the role of mGluR5 and NMDA glutamate receptors in the development of amphetamine-induced and social defeat stress-induced sensitization, using the non-competitive mGluR5 antagonist, MPEP, and the non-competitive NMDA antagonist, dizocilpine (MK-801).Methods In adult, male CFW mice, sensitization was induced by either ten daily injections of d-amphetamine (1 mg/kg) or ten daily brief episodes of social defeat. Mice were pretreated with MPEP (3 mg/kg or 10 mg/kg) or dizocilpine (0.1 mg/kg) prior to amphetamine injections. Mice subjected to social defeat were pretreated with MPEP (10 mg/kg) or dizocilpine (0.1 mg/kg). Ten days after induction, the expression of locomotor sensitization to amphetamine was determined.Results The induction of sensitization due to social defeat stress was prevented by MPEP, yet MPEP did not inhibit the development of behavioral sensitization to amphetamine. Confirming and extending earlier results, dizocilpine pretreatment blocked both amphetamine-induced and stress-induced sensitization.Conclusions These data indicate that behavioral sensitization to social defeat stress is dependent on mGluR5 receptors, whereas low-dose amphetamine sensitization may not be.     

Phosphorylation of GluA1-Ser831 by CaMKII Activation in the Caudate and Putamen Is Required for Behavioral Sensitization After Challenge Nicotine in Rats

BackgroundPhosphorylation of the glutamate receptor (GluA1) subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor plays a crucial role in behavioral sensitization after exposure to psychostimulants. The present study determined the potential role of serine 831 (Ser831) phosphorylation in the GluA1 subunit of the caudate and putamen (CPu) in behavioral sensitization after challenge nicotine.MethodsChallenge nicotine (0.4 mg/kg) was administered subcutaneously (s.c.) after 7 days of repeated exposure to nicotine (0.4 mg/kg, s.c.) followed by 3 days of withdrawal in rats. Bilateral intra-CPu infusions of drugs were mainly performed to test this hypothesis.ResultsChallenge nicotine increased both phosphorylated (p)Ser831 immunoreactivity (IR) and pCa²⁺/calmodulin-dependentprotein kinases II (pCaMKII)-IR in the medium spiny neurons (MSNs) of the CPu. These increases were prevented by bilateral intra-CPu infusion of the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP (0.5 nmol/side) and the N-methyl-D-aspartate (NMDA) receptor antagonist MK801 (2 nmol/side). However, the dopamine D1 receptor (D1R) antagonist SCH23390 (7.5 nmol/side) prevented only pSer831-IR alone. Bilateral intra-CPu infusion of the Tat-GluA1_D peptide (25 pmol/side), which interferes with the binding of pCaMKII to GluA1-Ser831, decreased the challenge nicotine–induced increase in locomotor activity.ConclusionsThese findings suggest that the GluA1-Ser831 phosphorylation in the MSNs of the CPu is required for the challenge nicotine–induced behavioral sensitization in rats. CaMKII activation linked to mGluR5 and NMDA receptors, but not to D1R, is essential for inducing the CaMKII-Ser831 interaction.     

Effect of 2-methyl-6-(phenylethynyl) pyridine on intravenous self-administration of ketamine and heroin in the rat

The mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP) may be beneficial for drug abuse treatment, as it has been found to reduce self-administration of ethanol, nicotine and cocaine in preclinical models. This study investigated whether this finding can be extended to dissociative anaesthetics and opioids. Long Evans rats were trained to intravenously self-administer ketamine (0.5 mg/kg/infusion, 2 h sessions, fixed ratio 3) or heroin (0.05 mg/kg/infusion, 1 h sessions, fixed ratio 10). After reaching stable responding, the effect of MPEP pretreatment (1.25-20 mg/kg, intraperitoneal; t=-30 min) on intravenous self-administration (IVSA) of each compound was investigated. Behavioural specificity of MPEP on IVSA was assessed using a food-reinforcement procedure. IVSA of ketamine was dose-dependently reduced by MPEP pretreatment, with a minimal effective dose of 5 mg/kg and a 75% reduction at the highest dose tested. IVSA of heroin was only modestly reduced by the highest dose of MPEP (20% reduction). Food-reinforced behaviour was not altered by MPEP, either given alone or in combination with ketamine or heroin, indicating that the effect in the IVSA paradigm was behaviourally specific. It is suggested that the differential effect of MPEP on IVSA of ketamine and heroin is related to the particular class of the self-administered drug or its relative reinforcing efficacy.     

The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine,cocaine and food in rats

Rationale The metabotropic glutamate (mGlu5) receptor subtype 5 antagonist MPEP attenuates self-administration of numerous drugs of abuse.Objectives The purpose of the present study was to explore whether MPEP-induced decreases in nicotine and cocaine self-administration reflect attenuation of the reinforcing and incentive motivational effects of nicotine and cocaine. The effects of MPEP on breaking points maintained by nicotine, cocaine or food were assessed using a progressive ratio schedule of reinforcement. Breaking points obtained under such schedules are postulated to reflect both the reinforcing and incentive motivational properties of reinforcers.Methods Rats were allowed to respond for nicotine (0.05 mg/kg per infusion, free base), cocaine (0.18 mg/kg per infusion, salt), or food (45 mg pellets) under a progressive ratio schedule of reinforcement. After establishing stable and equivalent levels of responding for all three reinforcers, rats underwent one test session where no rewards were presented to assess the effects of 1-day extinction, similar to 1-day pharmacological-induced extinction, on performance in this schedule. Subsequently, rats were again allowed to respond for nicotine, cocaine or food until reestablishment of stable levels of responding. Then, MPEP (1–9 mg/kg) was administered intraperitoneally according to a within-subjects Latin square design, 30 min prior to the testing sessions.Results Responding in the absence of a primary reinforcer was significantly decreased compared to responding under baseline conditions. Further, MPEP decreased break points maintained by nicotine, cocaine and food.Conclusions The mGlu5 receptor is implicated in mediating the reinforcing and incentive motivational properties of nicotine, cocaine and food.     

Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking

Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indicated the importance of this receptor in the self-administration of cocaine and locomotor sensitisation to this stimulant. Both ionotropic and metabotropic receptors have been implicated in drug-seeking and drug-taking behaviours, but the specific role of each subtype of metabotropic glutamate receptors (mGlu receptors) is still unknown. In the present series of experiments we further investigated the role of mGlu5 receptors on nicotine, cocaine- and food-taking behaviour. We also investigated the effects of the mGlu5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) on the acute locomotor activating effects of nicotine, the expression of sensitisation to its repeated, intermittent administration, and nicotine-triggered relapse to nicotine-seeking behaviour. The results indicate that MPEP treatment reduced nicotine-induced drug-seeking behaviour in a model of nicotine-triggered relapse to nicotine seeking. Furthermore, MPEP decreased both nicotine and cocaine self-administration without affecting food self-administration under similar schedules of reinforcement. Finally, MPEP reduced both the acute locomotor stimulant effects of nicotine as well as the expression of behavioural sensitisation to its repeated administration. Although the intravenous administration of MPEP at 1 and 10 mg/kg transiently reduced spontaneous locomotor activity during the first 25 min post-administration, we also demonstrated that performance on the accelerating rotarod was not affected when MPEP was given 5 and 30 min prior to the test. Altogether, the present findings strengthen the hypothesis that selective antagonism at mGlu5 receptors may be a new potential pharmacotherapeutic approach for the treatment of drug dependence and addiction.     

Metabotropic glutamate receptor 5 (mGluR5) regulation of ethanol sedation, dependence and consumption: relationship to acamprosate actions

Recent studies have demonstrated that metabotropic glutamate receptor 5 (mGluR5) antagonists decrease alcohol self-administration and suggest that the anti-craving medication, acamprosate, may also act to decrease mGluR5 function. To address the role of mGluR5 in behavioural actions of ethanol and acamprosate, we compared mutant mice with deletion of the mGluR5 gene and mice treated with a mGluR5 antagonist (MPEP) or acamprosate. Lack of mGluR5 or administration of MPEP reduced the severity of alcohol-induced withdrawal (AW), increased the sedative effect of alcohol (duration of loss of righting reflex; LORR), and increased basal motor activity. The motor stimulation produced by ethanol was blocked by deletion of mGluR5, but not by injection of MPEP. Both acamprosate and MPEP increased ethanol-induced LORR and reduced AW. Importantly, the protective effects of both MPEP and acamprosate on AW were found when the drugs were injected before, but not after, injection of ethanol. This indicates that the drugs prevented development of dependence rather than merely producing an anticonvulsant action. No effects of acamprosate or MPEP on ethanol-induced LORR and AW were found in mGluR5 knockout mice, demonstrating that mGluR5 is required for these actions. mGluR5 null mutant mice showed decreased alcohol consumption in some, but not all, tests. These data show the importance of mGluR5 for several actions of alcohol and support the hypothesis that some effects of acamprosate require mGluR5 signalling.     

Interactive effects of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine self-administration and reward deficits associated with nicotine withdrawal in rats

Stimulatory actions of nicotine on mesocorticolimbic dopamine transmission are partly mediated by nicotine-induced glutamate release acting on ionotropic and metabotropic glutamate (mGlu) receptors. Because both presynaptic inhibitory mGlu2/3 and postsynaptic excitatory mGlu5 receptors provide potential targets for treatment of aspects of nicotine dependence, we examined interacting effects of mGlu5 (2-methyl-6-(phenylethynyl)-pyridine, MPEP) and mGlu2/3 (LY341495) receptor antagonists on nicotine self-administration and brain reward threshold elevations associated with spontaneous nicotine withdrawal in rats. We hypothesized that increasing glutamate transmission by blocking presynaptic inhibitory mGlu2/3 autoreceptors would antagonize MPEP-induced decreases in nicotine self-administration. We also hypothesized that blocking postsynaptic actions of glutamate on mGlu5 receptors would exacerbate nicotine withdrawal-induced reward deficits, and that this effect would be attenuated by co-administration of the mGlu2/3 receptor antagonist LY341495. MPEP selectively decreased nicotine, but not food, self-administration in rats. LY341495 slightly decreased both nicotine and food self-administration. Co-administration of LY341495 with MPEP attenuated the effectiveness of MPEP in decreasing nicotine intake, although MPEP was still effective. Spontaneous nicotine withdrawal induced somatic signs of withdrawal and reward threshold elevations indicating reward deficits. MPEP increased somatic signs and reward deficits in both nicotine- and saline-withdrawing rats. Thus, while mGlu5 receptor antagonists may be therapeutically useful in decreasing tobacco smoking, they worsen nicotine withdrawal. Co-administration of LY341495 reduced MPEP-induced reward deficits in both nicotine- and saline-withdrawing rats. Thus, increasing glutamate transmission via mGlu2/3 autoreceptor blockade reduces the effects of mGlu5 receptor blockade on nicotine self-administration and MPEP-induced exacerbation of brain reward deficits associated with nicotine withdrawal.     

The effects of the mGluR5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) on behavioural responses to nicotine

Rationale  

Previous studies have shown that blockade of metabotropic glutamate 5 receptors (mGluR5) results in inhibition of nicotine self-administration in experimental animals. However, these studies have not established the behavioural mechanisms which mediate these effects or the extent to which the effects of mGluR5 antagonism on nicotine self-administration reflect a selective attenuation of nicotine reinforcement.     

Nicotine potentiation of brain stimulation reward reversed by DHβE and SCH 23390, but not by eticlopride, LY 314582 or MPEP in rats

RATIONALE: Systemic nicotine administration increases dopamine and glutamate levels in reward-related brain areas. Nicotine-induced increases of dopamine in the nucleus accumbens are in part mediated by glutamatergic projections to the ventral tegmental area dopamine neurons. OBJECTIVES: To assess the effects of actions at acetylcholine, dopamine, presynaptic (mGluR(2/3)) and postsynaptic (mGluR(5)) metabotropic glutamate receptors (mGluRs) on the potentiation of brain stimulation reward induced by systemically administered nicotine (0.125-0.5 mg/kg; free base) in rats. METHODS: A discrete-trial current-threshold s stimulation reward procedure (electrodes placed in the posterior lateral hypothalamus) was used to assess the effects of DH beta E (0.5-5 mg/kg), an acetylcholine nicotinic receptor antagonist, SCH 23390 (1.25-5 microg/kg), a dopamine D(1) receptor antagonist, eticlopride (2.5-20 microg/kg), a dopamine D(2) receptor antagonist, LY 314582 (1-20 mg/kg), an mGluR(2/3) agonist, and MPEP (1-9 mg/kg), an mGluR(5) antagonist, on the reward potentiating effects of nicotine (0.25 mg/kg). RESULTS: DH beta E had no effect on reward thresholds when administered alone, but dose-dependently reversed the nicotine-induced potentiation of brain stimulation reward. SCH 23390 (5 microg/kg) elevated thresholds when administered alone, and reversed the nicotine-induced potentiation of brain stimulation reward even at a dose (2.5 microg/kg) that had no effect on reward thresholds. Eticlopride (10-20 microg/kg), LY 314582 (10-20 mg/kg) and MPEP (9 mg/kg) elevated thresholds when administered alone but had no effect on the nicotine-induced potentiation of brain stimulation reward. CONCLUSIONS: These results indicate that nicotinic and dopamine D(1) receptors are involved in the nicotine-induced potentiation of brain stimulation reward, while actions at dopamine D(2), mGlu(2/3) and mGlu(5) receptors did not modulate this effect of nicotine.     

Lobeline does not serve as a reinforcer in rats

Abstract Rationale. Previous results demonstrated that pretreatment with lobeline attenuates d-methamphetamine self-administration in rats. Objective. The present experiments determined if lobeline serves as a reinforcer, if it decreases d-methamphetamine-induced reinstatement of d-methamphetamine self-administration, and if it activates the mesolimbic and nigrostriatal dopamine (DA) pathways in Sprague-Dawley male rats. Methods. The ability of intravenous (IV) lobeline (0.015–0.15 mg/kg per infusion) to engender responding and the ability of lobeline (0.015 and 0.05 mg/kg per infusion) to substitute for d-methamphetamine was determined using the self-administration paradigm. Experiments were also performed to determine if lobeline (1.0 and 3.0 mg/kg) reinstates responding for d-methamphetamine or alters the ability of d-methamphetamine (1.0 mg/kg per infusion) to reinstate responding following extinction. The effect of lobeline (3.0 mg/kg) or d-methamphetamine (1.0 and 3.0 mg/kg) on DA and dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens and striatum were also determined. Results. Lobeline was not self-administered and did not substitute for d-methamphetamine. Also, lobeline did not reinstate responding for d-methamphetamine following extinction nor did it alter d-methamphetamine-induced reinstatement. Furthermore, lobeline did not alter DA or DOPAC levels in the either the nucleus accumbens or striatum. Conclusions. Taken together, the present results indicate that lobeline decreases d-methamphetamine self-administration by decreasing reward, not by acting as a substitute reinforcer. Electronic Publication     

Interaction between the mGlu receptors 5 antagonist, MPEP, and amphetamine on memory and motor functions in mice

Rationale

Metabotropic glutamate mGlu receptors 5 (mGluR5) receptors are abundant in corticolimbic circuitry where they modulate glutamate and dopamine signal transduction.

Objectives

In this study, we explored the hypothesis that mGluR5 antagonist, (2-methyl-6-(phenylethynyl)pyridine hydrochloride) (MPEP), facilitates dopamine-dependent effects on memory and motor functions.

Methods

To this aim, we examined the effects of different doses (from 0 to 24 mg/kg) of the mGluR5 antagonist, MPEP, on the modulation of amphetamine-dependent behaviors, namely passive avoidance, locomotor activity, and rotation behavior in intact and dopamine-depleted CD1 male mice.

Results

We demonstrated that a low dose (3 mg/kg) of MPEP, which is void of behavioral effects on its own, facilitates amphetamine-induced effects independently on the behavior measured both in naïve and in dopamine-lesioned mice; this synergistic effect is lost when higher doses of MPEP are used.

Conclusion

The results are discussed in terms of possible balance between dopamine and glutamate activity in regulating the proper fine tuning of information processing.     

Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behavior in rats

Previous studies suggested that metabotropic glutamate 5 (mGlu5) receptors play an important role in the reinforcing effects of abused drugs. The present experiments evaluated the effects of the mGlu5 receptor antagonist, MPEP (2-methyl-6-(phenylethynyl)-pyridine hydrochloride; 1-10 mg/kg, salt, i.p.), in rat models of nicotine-seeking behavior that may have relevance to relapse to drug-taking. Male Wistar rats (with restricted access to food) were trained to nose-poke to receive intravenous infusions of nicotine (0.03 mg/kg per infusion, base) under a fixed ratio 5 time out 60 s schedule of reinforcement. After stable nicotine self-administration was acquired, nose-poking behavior was extinguished in the absence of nicotine-associated cues. During the reinstatement test phase, independent groups of animals were exposed to: (a) response-contingent nicotine-associated cues (cue-induced reinstatement); or (b) response-noncontingent presentations of 45-mg food pellets under fixed time 2 min schedule (schedule-induced reinstatement). Additional control experiments were conducted to demonstrate that in nicotine-na?ve animals MPEP does not affect cue-induced reinstatement of food-seeking behavior and has no effects on operant behavior maintained by a simple fixed interval 2 min schedule of food reinforcement. Pretreatment with MPEP (10 mg/kg) significantly attenuated the reinstatement of nicotine-seeking in both experiments. Further, MPEP (10 mg/kg) significantly attenuated polydipsia induced by a fixed time 2 min food schedule. In conclusion, the present findings indicate that the blockade of mGlu5 receptors attenuates cue-induced reinstatement of nicotine self-administration behavior (but not food-seeking) and may produce a general inhibition of schedule-induced behaviors, including schedule-induced nicotine-seeking.     

Effect of the mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant properties of cocaine, <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine,and the dopamine reuptake inhibitor GBR12909 in mice

Rationale Recent evidence suggests that, in addition to ascending monoaminergic systems, glutamate systems also play a role in psychostimulant-induced locomotor activity. The present study was conducted to examine the effects of the selective type-5 metabotropic glutamate receptor (mGluR5) antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant effects of cocaine, d-amphetamine, and the dopamine reuptake inhibitor GBR12909.Methods Male DBA/2J mice were treated with saline or MPEP (1, 5, 20 or 30 mg/kg i.p.) 10 min prior to the administration of cocaine (15 mg/kg or 30 mg/kg i.p.), d-amphetamine (3 mg/kg or 5 mg/kg i.p.) or GBR12909 (10 mg/kg or 20 mg/kg i.p.). Locomotor activity was then monitored in an open-field environment for 30 min. The effects of MPEP alone (1, 5, 20 and 30 mg/kg i.p.) on locomotor activity were also examined.Results MPEP dose dependently inhibited the acute locomotor stimulant effects of cocaine, d-amphetamine, and the 10-mg/kg dose of GBR12909. However, MPEP had no effect on the locomotor stimulant effects of the higher (20 mg/kg) dose of GBR12909. When tested alone, MPEP increased locomotor activity at doses of 5 mg/kg and 20 mg/kg.Conclusions Our data suggest that mGluR5 receptors not only mediate spontaneous locomotor activity in DBA/2J mice but also the acute locomotor stimulant effects of cocaine, d-amphetamine and lower doses of GBR12909. However, the fact that MPEP did not attenuate the locomotor stimulant effects of the high (20 mg/kg) dose of GBR12909 suggests complex interactions between metabotropic glutamate receptors, dopamine transporters and possibly other monoamines in the regulation of psychostimulant-induced locomotor activity.     

Effect of the metabotropic glutamate receptor type 5 antagonists MPEP and MTEP in parkinsonian monkeys

Brain glutamate overactivity is well documented in Parkinson's disease (PD) and antiglutamatergic drugs have been proposed to relieve PD symptoms and decrease dyskinesias. Metabotropic glutamate receptors are topics of recent interest in PD. This study investigated the effects of the metabotropic glutamate receptors type 5 (mGluR5) antagonists MPEP and MTEP on motor behavior in monkeys with a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion to model PD and treated with l-Dopa the gold standard therapy. Six Macaca fascicularis MPTP monkeys were initially treated repeatedly with l-Dopa; this treatment increased their locomotion and reduced their parkinsonian scores but also induced dyskinesias. Then, a dose-response of MPEP and MTEP (1.5-30 mg/kg) administered 15 and 30 min respectively prior to l-Dopa, showed that the antiparkinsonian activity of l-Dopa was generally maintained as measured with locomotion and antiparkinsonian scores as well as the onset and duration of the l-Dopa response. Interestingly the mean dyskinesia score during all the duration of the l-Dopa motor effect, the 1 h peak period dyskinesias scores as well as the maximal dyskinesias scores were dose-dependently reduced with both drugs reaching statistical significance at 10 and 30 mg/kg. Our results showed a beneficial antidyskinetic effect of blocking mGluR5 in l-Dopa-treated MPTP monkeys. This supports the therapeutic use of an mGluR5 antagonist to restore normal brain glutamate neurotransmission in PD and decrease dyskinesias.