Glutamate and aspartate levels in the nucleus accumbens during cocaine self-administration and extinction: a time course microdialysis study

Miguéns, Miguel; Olmo, Nuria Del; Higuera-Matas, Alejandro; Torres, Isabel; García-Lecumberri, Carmen; Ambrosio, Emilio

doi:10.1007/s00213-007-0958-x

Cited by 72 publications

(69 citation statements)

References 36 publications

(45 reference statements)

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“…Wolf, 1998). More recently, a number of studies have linked the glutamatergic projection from the prefrontal cortex to the NAcore with the expression of cocaine-seeking behavior, using dialysis and pharmacological approaches akin to those in the present study (Cornish and Kalivas, 2000;Di Ciano and Everitt, 2001;Park et al, 2002;McFarland et al, 2003McFarland et al, , 2004Xi et al, 2006;Miguéns et al, 2008). The fact that activation of the prelimbic to NAcore glutamate projection is also critical for heroin seeking supports a contention that activation of this projection may be an essential mechanism mediating drug seeking by many classes of addictive drugs.…”

Section: The Role Of Glutamate Transmission In Drug Seekingsupporting

confidence: 56%

“…It is thought that a key feature of the circuitry underlying cocaine seeking is enhanced glutamate release into the NAcore by afferents from prelimbic cortex. Thus, not only does inactivation of either the NAcore or prelimbic cortex prevent cue-, stress-, or cocaineinduced reinstatement of cocaine seeking (McFarland and Kalivas, 2001;McLaughlin and See, 2003;Di Ciano and Everitt, 2004;Fuchs et al, 2004;Di Ciano et al, 2008), but both cocaine-and stress-induced cocaine seeking are associated with a remarkable overflow of synaptic glutamate into the NAcore from prelimbic afferents (McFarland et al, , 2004Xi et al, 2006;Miguéns et al, 2008). Also, both cocaine-and cue-induced cocaine seeking are blocked by inhibiting AMPA-type glutamate receptors in the NAcore (Cornish and Kalivas, 2000;Di Ciano and Everitt, 2001;Park et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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

LaLumiere¹,

Kalivas²

2008

J. Neurosci.

325

286

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Long-term changes in glutamate transmission in the nucleus accumbens core (NAcore) contribute to the reinstatement of drug seeking after extinction of cocaine self-administration. Whether similar adaptations in glutamate transmission occur during heroin and cueinduced reinstatement of heroin seeking is unknown. After 2 weeks of heroin self-administration and 2 weeks of subsequent extinction training, heroin seeking was induced by a noncontingent injection of heroin or by presentation of light/tone cues previously paired with heroin infusions. Microdialysis was conducted in the NAcore during reinstatement of heroin seeking in animals extinguished from heroin self-administration or in subjects receiving parallel (yoked) noncontingent saline or heroin. Reinstatement by either heroin or cue increased extracellular glutamate in the NAcore in the self-administration group, but no increase was elicited during heroin-induced reinstatement in the yoked control groups. The increase in glutamate during heroin-induced drug seeking was abolished by inhibiting synaptic transmission in the NAcore with tetrodotoxin or by inhibiting glutamatergic afferents to the NAcore from the prelimbic cortex. Supporting critical involvement of glutamate release, heroin seeking induced by cue or heroin was blocked by inhibiting AMPA/kainate glutamate receptors in the NAcore. Interestingly, although a heroin-priming injection increased dopamine equally in animals trained to self-administer heroin and in yoked-saline subjects, inhibition of dopamine receptors in the NAcore also blocked heroin-and cueinduced drug seeking. Together, these findings show that recruitment of the glutamatergic projection from the prelimbic cortex to NAcore is necessary to initiate the reinstatement of heroin seeking.

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Section: The Role Of Glutamate Transmission In Drug Seekingsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

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

LaLumiere¹,

Kalivas²

2008

J. Neurosci.

325

286

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“…Preclinical studies have shown that chronic self-administration of cocaine disrupts synaptic communication between the PFC and the striatum and results in decreased basal levels of non-synaptic, extracellular glutamate in the NAcc. 11,[62][63][64][65] Reduced extracellular glutamate tone in the NAcc core has in turn been associated with downregulation of mGluR5 expression and function in rats, [12][13][14][15][16][17] resulting in disrupted synaptic plasticity, which is assumed to contribute to the persisting nature of addiction. 9 It has been proposed, that the observed down-regulation of mGluR5s and Homer1b/c, post-synaptic scaffolding proteins influencing mGluR5 trafficking and signal transduction, after chronic cocaine administration may constitute a compensatory mechanism, as mGluR5 antagonists attenuate drug-seeking behaviors.…”

Section: Discussionmentioning

confidence: 99%

Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans

et al. 2013

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Long-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users (CU) exhibit altered mGluR5 availability compared with drug-naïve control subjects. Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with 11C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology. CU and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared with non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen (d=1.46, 18%). Duration of smoking abstinence was positively associated with mGluR5 density in all brain regions of interest, indicating that lower mGluR5 availability was particularly pronounced in individuals who had smoked very recently. Specifically tobacco smoking was associated with lower mGluR5 availability in both CU and controls, while cocaine use was not linked to detectable mGluR5 alterations. These findings have important implications regarding the development of novel pharmacotherapies aimed at facilitating smoking cessation. AbstractLong-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users exhibit altered mGluR5 availability compared to drug-naïve control subjects.Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with 11 C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology.Cocaine users and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared to non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen ...

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“…However, in the majority of studies of rats with a history of self-administered cocaine, the cocaine-induced rise in NAC glutamate is very rapid in onset whether micordialysis is performed during subsequent IV self-administration (Miguens et al, 2008;Suto et al, 2010) or before an IP cocaine challenge, following some form of extinction training regardless of testing environment (in the self-administration context: Baker et al, 2003;Li et al, 2010Madayag et al, 2010;Miguens et al, 2008;Xi et al, 2010; or in a neutral context: Kippin et al, 2008;Xi et al, 2006). In studies where the cocaine is self-administered (Miguens et al, 2008;Suto et al, 2010), the cocaine-induced rise in NAC glutamate is maintained, whereas in studies where the cocaine challenge was administered IP to animals with a cocaine self-administration and extinction history, the glutamate rise is transient (Baker et al, 2003;Kippin et al, 2008;Li et al, 2010;McFarland et al, 2003;Xi et al, 2006Xi et al, , 2010; but see also Madayag et al, 2010) and can be blocked completely by N-acetyl-cystine pretreatment (Baker et al, 2003), suggesting a critical role for non-neuronal glutamate sources in this regard (Baker et al, 2002). Although the source of glutamate undergoing methamphetamine-induced plasticity on self-administration remains to be determined, it is clear from the present data that this source is heavily influenced by factors related to the act of drug-taking.…”

Section: Possible Mediators Of Changes In Nac Glutamate Produced By Cmentioning

confidence: 99%

Distinct Neurochemical Adaptations Within the Nucleus Accumbens Produced by a History of Self-Administered vs Non-Contingently Administered Intravenous Methamphetamine

Lominac

Sacramento

Szumlinski

et al. 2011

Neuropsychopharmacol

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Methamphetamine is a highly addictive psychomotor stimulant yet the neurobiological consequences of methamphetamine self-administration remain under-characterized. Thus, we employed microdialysis in rats trained to self-administer intravenous (IV) infusions of methamphetamine (METH-SA) or saline (SAL) and a group of rats receiving non-contingent IV infusions of methamphetamine (METH-NC) at 1 or 21 days withdrawal to determine the dopamine and glutamate responses in the nucleus accumbens (NAC) to a 2 mg/kg methamphetamine intraperitoneal challenge. Furthermore, basal NAC extracellular glutamate content was assessed employing no net-flux procedures in these three groups at both time points. At both 1-and 21-day withdrawal points, methamphetamine elicited a rise in extracellular dopamine in SAL animals and this effect was sensitized in METH-NC rats. However, METH-SA animals showed a much greater sensitized dopamine response to the drug challenge compared with the other groups. Additionally, acute methamphetamine decreased extracellular glutamate in both SAL and METH-NC animals at both time-points. In contrast, METH-SA rats exhibited a modest and delayed rise in glutamate at 1-day withdrawal and this rise was sensitized at 21 days withdrawal. Finally, no net-flux microdialysis revealed elevated basal glutamate and increased extraction fraction at both withdrawal time-points in METH-SA rats. Although METH-NC rats exhibited no change in the glutamate extraction fraction, they exhibited a time-dependent elevation in basal glutamate levels. These data illustrate for the first time that a history of methamphetamine self-administration produces enduring changes in NAC neurotransmission and that non-pharmacological factors have a critical role in the expression of these methamphetamine-induced neurochemical adaptations.

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Glutamate and aspartate levels in the nucleus accumbens during cocaine self-administration and extinction: a time course microdialysis study

Abstract: These data suggest that glutamatergic transmission could be involved in the maintenance of cocaine self-administration and in the early phases of abstinence.

Cited by 72 publications

References 36 publications

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

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

Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans

Distinct Neurochemical Adaptations Within the Nucleus Accumbens Produced by a History of Self-Administered vs Non-Contingently Administered Intravenous Methamphetamine

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