Regulation of cocaine-induced reinstatement by group II metabotropic glutamate receptors in the ventral tegmental area

Lu, Lianyi; Xue, Yue-Qiang; Steketee, Jeffery D.; Rebec, George V.; Sun, Wenlin

doi:10.1007/s00213-011-2455-5

Cited by 16 publications

(15 citation statements)

References 63 publications

(84 reference statements)

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“…Thus, our mice experiments represent a first step toward the dissection between mGluR2 and mGluR3 functions in reward processing. Earlier rat experiments using the same behavioral models that we used with mGluR3 À / À mice reported that LY379268 may block motivation for cocaine in escalated rats (Hao et al, 2010) and decreased cocaine self-administration and cue-induced reinstatement in short-access cocaine-experienced rats (Baptista et al, 2004;Lu et al, 2012). Since LY379268 does not differentiate between mGluR2 and mGluR3, our mice experiments suggest a prominent role of mGluR2 in cocaine-seeking behavior.…”

Section: Discussionmentioning

confidence: 53%

The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior

Cannella

Halbout

Uhrig

et al. 2013

Neuropsychopharmacol

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Medication development for cocaine-addicted patients is difficult, and many promising preclinical candidates have failed in clinical trials. One reason for the difficulty in translating preclinical findings to the human condition is that drug testing is typically conducted in behavioral procedures in which animals do not show addiction-like traits. Recently, a DSM-IV-based animal model has been developed that allows studying the transition to an addiction-like behavior. Changes in synaptic plasticity are involved in the transition to cocaine addiction. In particular, it has been shown that metabotropic glutamate receptor 2/3 (mGluR2/3)-mediated long-term depression is suppressed in the prelimbic cortex in addict-like rats. We therefore hypothesized that cocaine-seeking in addict-like rats could be treated with an mGluR2/3 agonist. Indeed, addict-like rats that were treated systemically with the mGluR2/3 agonist LY379268 (0, 0.3, and 3 mg/kg) showed a pronounced reduction in cue-induced reinstatement of cocaine-seeking. In an attempt to dissect the role played by mGluR2 and mGluR3 in cue-induced reinstatement, we analyzed the mRNA expression patterns in several relevant brain areas but did not find any significant differences between cocaine addict-like and non-addict-like rats, suggesting that the behavioral differences observed are due to translational rather than transcriptional regulation. Another possibility to study the contributions of mGluR2 and mGluR3 in mediating addictive-like behavior is the use of knockout models. Because mGluR2 knockouts cannot be used in operant procedures due to motoric impairment, we only tested mGluR3 knockouts. These mice did not differ from controls in reinstatement, suggesting that mGluR2 receptors are critical in mediating addictive-like behavior.

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Section: Discussionmentioning

confidence: 53%

The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior

Cannella

Halbout

Uhrig

et al. 2013

Neuropsychopharmacol

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“…However, a more recent report demonstrated a reduction in nicotine self-administration by LY379268, but no effect on cocaine self-administration (Justinova et al, 2016). Although few studies have examined the circuitry by which mGlu 2/3 activation reduces drug self-administration, experiments evaluating cocaine and nicotine self-administration have implicated both VTA and NAc receptor populations as potential mediators of reduced drug intake (Liechti et al, 2007; Lu et al, 2012). …”

Section: Group II Metabotropic Glutamate Receptorsmentioning

confidence: 99%

“…Infusion of LY379268 into the rat VTA reduces context-induced reinstatement of heroin seeking (Bossert et al, 2004) and priming-induced resintatement of cocaine seeking (Lu et al, 2012). In addition, activation of group II mGlu receptors in the CeA prevents cue-induced reinstatement of cocaine seeking following prolonged extinction training (incubation of craving; Lu et al, 2007).…”

Section: Group II Metabotropic Glutamate Receptorsmentioning

confidence: 99%

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

Johnson

Lovinger

2016

Front. Cell. Neurosci.

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Drug abuse and addiction cause widespread social and public health problems, and the neurobiology underlying drug actions and drug use and abuse is an area of intensive research. Drugs of abuse alter synaptic transmission, and these actions contribute to acute intoxication as well as the chronic effects of abused substances. Transmission at most mammalian synapses involves neurotransmitter activation of two receptor subtypes, ligand-gated ion channels that mediate fast synaptic responses and G protein-coupled receptors (GPCRs) that have slower neuromodulatory actions. The GPCRs represent a large proportion of neurotransmitter receptors involved in almost all facets of nervous system function. In addition, these receptors are targets for many pharmacotherapeutic agents. Drugs of abuse directly or indirectly affect neuromodulation mediated by GPCRs, with important consequences for intoxication, drug taking and responses to prolonged drug exposure, withdrawal and addiction. Among the GPCRs are several subtypes involved in presynaptic inhibition, most of which are coupled to the Gi/o class of G protein. There is increasing evidence that these presynaptic Gi/o-coupled GPCRs have important roles in the actions of drugs of abuse, as well as behaviors related to these drugs. This topic will be reviewed, with particular emphasis on receptors for three neurotransmitters, Dopamine (DA; D1- and D2-like receptors), Endocannabinoids (eCBs; CB1 receptors) and glutamate (group II metabotropic glutamate (mGlu) receptors). The focus is on recent evidence from laboratory animal models (and some evidence in humans) implicating these receptors in the acute and chronic effects of numerous abused drugs, as well as in the control of drug seeking and taking. The ability of drugs targeting these receptors to modify drug seeking behavior has raised the possibility of using compounds targeting these receptors for addiction pharmacotherapy. This topic is also discussed, with emphasis on development of mGlu2 positive allosteric modulators (PAMs).

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“…Among drugs of abuse, the reinforcing/rewarding properties of cocaine (Sari et al, 2009, Li et al, 2010, Moussawi et al, 2011, Lu et al, 2012), heroin (Bossert et al, 2012) and ethanol (Obara et al, 2009, Cannady et al, 2011, Sari et al, 2011, Bahi et al, 2012) have been shown to interact with the glutamatergic system at various brain reward regions.…”

Section: Introductionmentioning

confidence: 99%

Effects of Ceftriaxone on Chronic Ethanol Consumption: a Potential Role for xCT and GLT1 Modulation of Glutamate Levels in Male P Rats

Rao

Sari

2014

J Mol Neurosci

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Alterations in glutamatergic neurotransmission have been suggested to affect many aspects of neuroplasticity associated with alcohol/drug addiction. We have previously shown that ceftriaxone, a β-lactam antibiotic known to upregulate glutamate transporter 1 (GLT1), reduced ethanol intake after five weeks of free-choice ethanol drinking paradigm in male alcohol-preferring (P) rats. Evidence suggests that differential effects involving alterations of glutamatergic neurotransmission occur after long term ethanol consumption. In this study, we tested whether the efficacy of administration of ceftriaxone persists after 14 weeks of free access to 15% and 30 % ethanol in male P rats. After 14 weeks of ethanol consumption, male P rats were administered ceftriaxone (100 mg/kg, i.p.) or saline vehicle for five days. We found that ceftriaxone treatment resulted in a significant reduction in ethanol intake starting from Day 2 (48 hours after the first i.p. injections of ceftriaxone) through Day 14, 10 days after final injection. Western blot analysis of brain samples from animals euthanized 24 h after treatment with the last dose of ceftriaxone revealed a significant upregulation of cystine/glutamate exchanger (xCT) and GLT1 levels in prefrontal cortex, nucleus accumbens and amygdala as compared to saline vehicle-treated group. These findings demonstrated the effectiveness of ceftriaxone in attenuating ethanol intake in a chronic consumption paradigm. These might be due in part through upregulation of both xCT and GLT1 levels in brain reward regions. Thus, the drug has a potential therapeutic action for the treatment of alcohol dependence.

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Regulation of cocaine-induced reinstatement by group II metabotropic glutamate receptors in the ventral tegmental area

Abstract: Our data support the idea that glutamate release in the VTA is critically involved in cocaine-induced reinstatement and indicate that loss of mGluR2/3-mediated regulation of glutamate release in the VTA may critically contribute to the risk of relapse.

Cited by 16 publications

References 63 publications

The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior

The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

Effects of Ceftriaxone on Chronic Ethanol Consumption: a Potential Role for xCT and GLT1 Modulation of Glutamate Levels in Male P Rats

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