Withdrawal from Cocaine Self-administration and Yoked Cocaine Delivery Dysregulates Glutamatergic mGlu5 and NMDA Receptors in the Rat Brain

Pomierny-Chamioło, Lucyna; Miszkiel, Joanna; Frankowska, Małgorzata; Pomierny, Bartosz; Niedzielska, Ewa; Smaga, Irena; Fumagalli, Fabio; Filip, Małgorzata

doi:10.1007/s12640-014-9502-z

Cited by 31 publications

(33 citation statements)

References 86 publications

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“…In addition, whereas some brain regions show spontaneous recovery of normal metabolic activity after protracted abstinence, in LgA rats, a few brain structures (the DStr, the ACC, the SN/VTA, the Amyg, the Hipp and the insula) show persistent changes in metabolic activity that may contribute to long-lasting risks of relapse. These results are consistent with separate previous studies that have shown that withdrawal from cocaine self-administration is associated with neuroadaptations in the DStr (Hearing et al, 2008;Pomierny-Chamiolo et al, 2015), ACC (Pomierny-Chamiolo et al, 2015;Zavala et al, 2007;Zorrilla et al, 2001), VTA (mostly with no change in the SN (Arroyo et al, 2000;Chen et al, 2008;Grimm et al, 2003;Lu et al, 2003), Amyg (Lee et al, 2013;Lu et al, 2005a;Zorrilla et al, 2001) and Hipp (Garcia-Fuster et al, 2012;Noonan et al, 2008;Pomierny-Chamiolo et al, 2015;Thompson et al, 2004). Importantly, each of these regions has been shown to be involved in cocaine craving and relapse in animal models (Cosme et al, 2015;Fuchs et al, 2005Fuchs et al, , 2006Grimm and See, 2000;Lu et al, 2005b;McFarland and Kalivas, 2001;Torregrossa et al, 2013).…”

Section: Longitudinal Brain Dysregulations During Abstinence From Cocsupporting

confidence: 92%

Longitudinal Changes in Brain Metabolic Activity after Withdrawal from Escalation of Cocaine Self-Administration

Nicolas

Tauber

Lepelletier

et al. 2017

Neuropsychopharmacol

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The chronic and relapsing nature of addiction suggests that drugs produce persistent adaptations in the brain that make individuals with drug addiction particularly sensitive to drug-related cues and stress and incapable of controlling drug-seeking and drug-taking behavior. In animal models, several long-lasting neuroadaptations have been described. However, few studies have used brain-imaging techniques to provide a complete picture of brain functioning in the course of withdrawal from cocaine. In this study, we allowed rats to self-administer cocaine under short-access (1-h/day) or long-access (6-h/day) conditions and used 2-deoxy-2-(F)fluoro-d-glucose (FDG) positron emission tomography scanning to investigate the longitudinal changes in metabolic activity 1 and 4 weeks after discontinuation of cocaine self-administration. We found that compared to naive rats, both long-access and short-access rats showed significant disruptions in basal brain metabolic activity. However, compared to short-access, long-access rats showed more intense, and long-lasting neuroadaptations in a network of brain areas. In particular, abstinence from extended access to cocaine was associated with decreased metabolic activity in the anterior cingulate cortex, the insular cortex, and the dorsolateral striatum, and increased metabolic activity in the mesencephalon, amygdala, and hippocampus. This pattern is strikingly similar to that described in humans that has led to the proposal of the Impaired Response Inhibition and Salience Attribution model of addiction. These results demonstrate that extended access to cocaine leads to persistent neuroadaptations in brain regions involved in motivation, salience attribution, memory, stress, and inhibitory control that may underlie increased risks of relapse.

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Section: Longitudinal Brain Dysregulations During Abstinence From Cocsupporting

confidence: 92%

Longitudinal Changes in Brain Metabolic Activity after Withdrawal from Escalation of Cocaine Self-Administration

Nicolas

Tauber

Lepelletier

et al. 2017

Neuropsychopharmacol

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“…In fact, the deletion of neuronal A 2A receptors is precognitive, while the deletion of astrocytic A 2A receptors enhances behavioral impairments (Matos et al 2015). The astrocytic A 2A receptor function is linked with the density of NR2B subunits of the glutamatergic NMDA receptors (Matos et al 2015), and the latter receptors are upregulated during cocaine withdrawal with extinction training in rats (Pomierny-Chamiolo et al 2015), what further requires determining the specificity of A 2A receptors not only in brain areas but also in cell type and cell compartment.…”

Section: Discussionmentioning

confidence: 99%

Effects of intra-accumbal or intra-prefrontal cortex microinjections of adenosine 2A receptor ligands on responses to cocaine reward and seeking in rats

et al. 2018

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Rationale and objectivesMany studies indicated that adenosine via its A2A receptors influences the behavioral effects of cocaine by modulating dopamine neurotransmission. The hypothesis was tested that A2A receptors in the nucleus accumbens (NAc) or the prefrontral cortex (PFc) may modulate cocaine reward and/or cocaine seeking behavior in rats.MethodsThe effects of local bilateral microinjections of the selective A2A receptor agonist CGS 21680 or the A2A receptor antagonists KW 6002 and SCH 58261 were investigated on cocaine self-administration on reinstatement of cocaine seeking.ResultsThe intra-NAc shell, but not intra-infralimbic PFc, administration of CGS 21680 significantly reduced the number of active lever presses and the number of cocaine (0.25 mg/kg) infusions. However, tonic activation of A2A receptors located in the NAc or PFc did not play a role in modulating the rewarding actions of cocaine since neither KW 6002 nor SCH 58261 microinjections altered the cocaine (0.5 mg/kg) infusions. The intra-NAc but not intra-PFc microinjections of CGS 21680 dose- dependently attenuated the reinstatement of active lever presses induced by cocaine (10 mg/kg, i.p.) and the drug-associated combined conditioned stimuli using the subthreshold dose of cocaine (2.5 mg/kg, i.p.). On the other hand, the intra-NAc pretreatment with SCH 58261, but not with KW 6002, given alone evoked reinstatement of cocaine seeking behavior.ConclusionThe results strongly support the involvement of accumbal shell A2A receptors as a target, the activation of which exerts an inhibitory control over cocaine reward and cocaine seeking.

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“…Indeed, response-contingent cocaine administration (self-administration group) was shown to produce distinct striatal neuroadaptations when compared to response-independent (yoked) delivery (e.g. : Stefanski et al, 2007, Frankowska et al, 2013, Pomierny-Chamiolo et al, 2015). However this is not a generalized pattern, as in other instances the modality of cocaine exposure did not have effects on post-cocaine pattern of striatal gene/protein expression changes (e.g.…”

Section: Discussionmentioning

confidence: 99%

Post‐cocaine changes in regulator of G‐protein signaling (RGS) proteins in the dorsal striatum: Relevance for cocaine‐seeking and protein kinase C‐mediated phosphorylation

Bilodeau

Schwendt

2016

Synapse

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Persistent cocaine-induced neuroadaptations within the cortico-striatal circuitry might be related to elevated risk of relapse observed in human addicts even after months or years of drug-free abstinence. Identification of these neuroadaptations may lead development of novel, neurobiologically-based treatments of relapse. In the current study, 12 adult male Sprague-Dawley rats self-administered cocaine (or received yoked-saline) for 2 weeks followed by 3 weeks of home-cage abstinence. At this point, we analyzed expression of proteins involved in regulation of Gαi- and Gαq-protein signaling in the dorsal striatum (dSTR). Animals abstinent from chronic cocaine showed decreased expression of regulator of G-protein signaling 2 (RGS2) and RGS4, as well as upregulation of RGS9. These data, together with the increased ratio of Gαq-to-Gαi proteins indicated, ‘sensitized’ Gαq signaling in the dSTR of abstinent cocaine animals. To evaluate activation of Gαq signaling during relapse, another group of abstinent cocaine animals (and yoked saline controls, 22 rats together) was re-introduced to the cocaine context and PKC-mediated phosphorylation in the dSTR was analyzed. Re-exposure to the cocaine context triggered cocaine seeking and increase in phosphorylation of cellular PKC substrates, including phospho-ERK and phospho-CREB. In conclusion, this study demonstrates persistent dysregulation of RGS proteins in the dSTR of abstinent cocaine animals that may produce an imbalance in local Gαq-to-Gαi signaling. This imbalance might be related to augmented PKC-mediated phosphorylation during relapse to cocaine-seeking. Future studies will address whether selective targeting of RGS proteins in the dSTR can be utilized to suppress PKC-mediated phosphorylation and relapse to cocaine-seeking.

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Withdrawal from Cocaine Self-administration and Yoked Cocaine Delivery Dysregulates Glutamatergic mGlu5 and NMDA Receptors in the Rat Brain

Cited by 31 publications

References 86 publications

Longitudinal Changes in Brain Metabolic Activity after Withdrawal from Escalation of Cocaine Self-Administration

Longitudinal Changes in Brain Metabolic Activity after Withdrawal from Escalation of Cocaine Self-Administration

Effects of intra-accumbal or intra-prefrontal cortex microinjections of adenosine 2A receptor ligands on responses to cocaine reward and seeking in rats

Post‐cocaine changes in regulator of G‐protein signaling (RGS) proteins in the dorsal striatum: Relevance for cocaine‐seeking and protein kinase C‐mediated phosphorylation

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