Glutamate Release in the Nucleus Accumbens Core Is Necessary for Heroin Seeking

LaLumiere, Ryan T.; Kalivas, Peter W.

doi:10.1523/jneurosci.5129-07.2008

Cited by 330 publications

(313 citation statements)

References 49 publications

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“…Although these findings are consistent with the localization of accumbal D 2 -likeRs on local glutamate terminals (see above), they are quite surprising considering that the extracellular glutamate levels in the nucleus accumbens are mainly sustained by nonvesicular glutamate release . In line with this view, several studies reported that the basal levels of extracellular glutamate in the nucleus accumbens are only modestly reduced or unaffected by tetrodotoxin perfusion or by the depletion of extracellular Ca + + levels Saulskaya and Mikhailova, 2002;Saulskaya and Soloviova, 2004;LaLumiere and Kalivas, 2008). Therefore, it seems unlikely that inhibition of synaptic release of glutamate is the main mechanism responsible for the reported extracellular glutamate reduction during quinpirole perfusion.…”

Section: Discussionmentioning

confidence: 85%

A Novel Mechanism of Cocaine to Enhance Dopamine D2-Like Receptor Mediated Neurochemical and Behavioral Effects. An In Vivo and In Vitro Study

Ferraro

Frankowska

Marcellino

et al. 2012

Neuropsychopharmacol

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Recent in vitro results suggest that cocaine may exert direct and/or indirect allosteric enhancing actions at dopamine (DA) D 2 receptors (D 2 Rs). In the present paper we tested the hypothesis that cocaine in vivo can enhance the effects of the D 2 -likeR agonist quinpirole in rats by using microdialysis and pharmacological behavioral studies. Furthermore, in vitro D 2 -likeR binding characteristics and Ga i/o -protein coupling, in the absence and in the presence of cocaine, have been investigated in rat striatal membranes. Intra-nucleus accumbens perfusion of the D 2 -likeR agonist quinpirole (10 mM) reduced local dialysate glutamate levels, whereas cocaine (10 and 100 nM) was ineffective. At a low concentration (100 nM), cocaine significantly enhanced quinpirole-induced reduction of accumbal extracellular glutamate levels. The behavioral experiments showed that cocaine (0.625 mg/kg), but not the DA uptake blocker GBR 12783 (1.25 mg/ kg), enhanced quinpirole (1 mg/kg)-induced hyperlocomotion. Finally, cocaine (100 nM), but not GBR 12783 (200 nM), produced a small, but significant increase in the efficacy of DA to stimulate binding of GTPgS to striatal D 2 -likeRs, whereas the D 2 -likeR binding characteristics were unchanged in striatal membranes by cocaine in the nM range. The significant increase in the maximal response to DA-stimulated GTPgS binding to D 2 -likeRs by 100 nM cocaine remained in the presence of GBR 12783. The observed cocaine-induced enhancement of the Ga i/o -protein coupling of D 2 Rs may be in part because of allosteric direct and/or indirect enhancing effects of cocaine at these receptors. These novel actions of cocaine may have relevance for understanding the actions of cocaine upon accumbal DA, and/or glutamate transmission and thus its rewarding as well as relapsing effects.

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Section: Discussionmentioning

confidence: 85%

A Novel Mechanism of Cocaine to Enhance Dopamine D2-Like Receptor Mediated Neurochemical and Behavioral Effects. An In Vivo and In Vitro Study

Ferraro

Frankowska

Marcellino

et al. 2012

Neuropsychopharmacol

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“…Oneway ANOVA revealed no significant effect of MPEP treatment on the active (F (3,20) =1.90, P=0.16) or inactive (F (3,20) =0.22, P=0.88) responses induced by cues ( Figure 4A). In addition, there was no significant effect of MPEP treatment on the active (F (3,20) =0.095, P=0.97) or inactive (F (3,20) =0.059, P=0.98) responses induced by heroin priming (0.25 mg per kg) with conditioned cues ( Figure 4B). …”

Section: Effects Of Mpep Microinfusions Into the Nac Shell On Heroin mentioning

confidence: 94%

Blockade of mGluR5 in the nucleus accumbens shell but not core attenuates heroin seeking behavior in rats

et al. 2014

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Aim: Glutamatergic neurotransmission in the nucleus accumbens (NAc) is crucial for the relapse to heroin seeking. The aim of this study was to determine whether mGluR5 in the NAc core or shell involved in heroin seeking behavior in rats. Methods: Male SD rats were self-administered heroin under a fixed-ratio 1 (FR1) reinforcement schedule for 14 d, and subsequently withdrawn for 2 weeks. The selective mGluR5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 5, 15 and 50 nmol per side) was then microinjected into the NAc core or shell 10 min before a heroin-seeking test induced by context, cues or heroin priming. Results: Microinjection of MPEP into the NAc shell dose-dependently decreased the heroin seeking induced by context, cues or heroin priming. In contrast, microinjection of MPEP into the NAc core did not alter the heroin seeking induced by cues or heroin priming. In addition, microinjection with MPEP (15 nmol per side) in the NAc shell reversed both the percentage of open arms entries (OE%) and the percentage of time spent in open arms (OT%) after heroin withdrawal. Microinjection of MPEP (50 nmol per side) in the striatum as a control location did not affect the heroin seeking behavior. Microinjection of MPEP in the 3 locations did not change the locomotion activities. Conclusion: Blockade of mGluR5 in NAc shell in rats specifically suppresses the relapse to heroin-seeking and anxiety-like behavior, suggesting that mGluR5 antagonists may be a potential candidate for the therapy of heroin addiction.Keywords: heroin; addiction; relapse; mGluR5; MPEP; the nucleus accumbens; striatum Acta Pharmacologica Sinica (2014Sinica ( ) 35: 1485Sinica ( -1492 doi: 10.1038/aps.2014 published online Nov 17 2014 Original Article IntroductionRelapse is the most important manifestation of heroin addiction following prolonged periods of abstinence [1] . Relapse arises from intense craving that can be triggered by a single drug-taking experience or exposure to an environmental stimulus [2] . The pre-clinical literature indicates that longterm drug-induced alterations in glutamatergic transmission within the NAc may underlie relapse to drug-seeking behavior following the re-exposure to drugs and drugassociated stimuli during abstinence of the drug [3,4] . Type 5 metabotropic glutamate receptor (mGluR5) as a postsynaptic element is abundantly present throughout in the NAc, where it is positively coupled to NMDA receptor function and mediates various forms of synaptic plasticity [5,6] . The deletion of mGluR5 results in marked deficits in responding to the reinforcing and locomotor stimulating effects of cocaine [7] . Furthermore, the administration of the noncompetitive selective mGluR5 antagonist 2-methyl-6 (phenyethynyl) pyridine (MPEP) decreased the self-administration and/or relapse of nicotine [8,9] , cocaine [10,11] , ethanol [12][13][14] , and heroin [15,16] . MTEP, another antagonist of mGluR5, also can attenuate opiate selfadministration and opiate-seeking behavior in mice [17] . These data indicate mGluR5 plays a...

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“…It remains to be determined if these properties translate in the attenuation of symptoms for other anxiety disorders than social phobia (e.g., post-traumatic stress disorder, panic disorder) [66]. There are contradictory results as to CBD's effect on sleep (similar to results from animal studies) as it has been associated with both wake-inducing and hypnotic properties in humans [11,67,68]. Altogether, many pharmacological, preclinical, and clinical properties (e.g., antipsychotic, anxiolytic) of CBD that had been demonstrated over roughly the last decade all point towards a potential role for CBD in alleviating behaviors relevant to addiction disorder.…”

Section: Cbd and Neurobiological Targets/effectsmentioning

confidence: 99%

“…The glutamatergic system and particularly GluR1 receptors are known to contribute to neuroplasticity underlying drug-seeking behavior [67,73], and treatments targeting glutamates are being developed for addiction intervention.…”

Section: Cbd In Preclinical Addiction Modelsmentioning

confidence: 99%

Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage

et al. 2015

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Multiple cannabinoids derived from the marijuana plant have potential therapeutic benefits but most have not been well investigated, despite the widespread legalization of medical marijuana in the USA and other countries. Therapeutic indications will depend on determinations as to which of the multiple cannabinoids, and other biologically active chemicals that are present in the marijuana plant, can be developed to treat specific symptoms and/or diseases. Such insights are particularly critical for addiction disorders, where different phytocannabinoids appear to induce opposing actions that can confound the development of treatment interventions. Whereas Δ 9 -tetracannabinol has been well documented to be rewarding and to enhance sensitivity to other drugs, cannabidiol (CBD), in contrast, appears to have low reinforcing properties with limited abuse potential and to inhibit drug-seeking behavior. Other considerations such as CBD's anxiolytic properties and minimal adverse side effects also support its potential viability as a treatment option for a variety of symptoms associated with drug addiction. However, significant research is still needed as CBD investigations published to date primarily relate to its effects on opioid drugs, and CBD's efficacy at different phases of the abuse cycle for different classes of addictive substances remain largely understudied. Our paper provides an overview of preclinical animal and human clinical investigations, and presents preliminary clinical data that collectively sets a strong foundation in support of the further exploration of CBD as a therapeutic intervention against opioid relapse. As the legal landscape for medical marijuana unfolds, it is important to distinguish it from Bmedical CBD^and other specific cannabinoids, that can more appropriately be used to maximize the medicinal potential of the marijuana plant.

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Glutamate Release in the Nucleus Accumbens Core Is Necessary for Heroin Seeking

Cited by 330 publications

References 49 publications

A Novel Mechanism of Cocaine to Enhance Dopamine D2-Like Receptor Mediated Neurochemical and Behavioral Effects. An In Vivo and In Vitro Study

A Novel Mechanism of Cocaine to Enhance Dopamine D2-Like Receptor Mediated Neurochemical and Behavioral Effects. An In Vivo and In Vitro Study

Blockade of mGluR5 in the nucleus accumbens shell but not core attenuates heroin seeking behavior in rats

Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage

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