Cocaine-seeking is associated with PKC-dependent reduction of excitatory signaling in accumbens shell D2 dopamine receptor-expressing neurons

Ortinski, Pavel I.; Briand, Lisa A.; Pierce, R. Christopher; Schmidt, Heath D.

doi:10.1016/j.neuropharm.2015.01.002

Cited by 36 publications

(31 citation statements)

References 77 publications

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“…As our mouse model disrupts PKC-mediated phosphorylation of GluA2, the current results may seem to conflict with findings that PKC inhibitors block reinstatement behavior (Famous et al, 2008; Ortinski et al, 2015) and can reverse some forms of cocaine-induced plasticity (McCutcheon et al, 2011a). However, along with its actions on GluA2 subunits, PKC also phosphorylates GluA1 subunits at multiple different residues.…”

Section: Discussioncontrasting

confidence: 90%

“…In contrast to the consequences of PKC-mediated phosphorylation of GluA2, PKC-mediated phosphorylation of GluA1 has been shown to lead to both increased synaptic delivery of AMPA receptors as well as increased conductance of these receptors (Boehm et al, 2006; Jenkins and Traynelis, 2012; Lee et al, 2003; Tao et al, 2014; Wang et al, 2013). Consistent with this, inhibition of PKC leads to a decrease in evoked EPSCs within the nucleus accumbens (Ortinski et al, 2015), demonstrating that disruption of all PKC activity has the opposite effect on both physiology and behavior compared to our findings.…”

Section: Discussionsupporting

confidence: 88%

“…PKC inhibition or disruption of the interaction between GluA2 and PICK1, leads to a blunted reinstatement of cocaine seeking (Famous et al, 2008; Ortinski et al, 2015). Furthermore, disruption of glutamate receptor interacting protein (GRIP), a protein involved in anchoring GluA2 to the membrane, within the nucleus accumbens leads to augmented reinstatement of cocaine seeking (Briand et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Disrupting GluA2 phosphorylation potentiates reinstatement of cocaine seeking

et al. 2016

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Addiction is associated with changes in synaptic plasticity mediated, in part, by alterations in the trafficking and stabilization of AMPA receptors at synapses within the nucleus accumbens. Exposure to cocaine can lead to protein kinase C–mediated phosphorylation of GluA2 AMPA subunits and this phosphorylation event leads to the internalization of GluA2-containing AMPARs, which are calcium-impermeable. However, it is not clear whether this internalization is necessary for the expression of addictive phenotypes. Utilizing a mouse with a point mutation within the GluA2 subunit c-terminus, the current study demonstrates that disrupting PKC-mediated GluA2 phosphorylation potentiates reinstatement of both cue-induced cocaine seeking and cocaine conditioned reward without affecting operant learning, food self-administration or cocaine sensitization. Electrophysiological recordings revealed increased GluA2-mediated AMPA transmission as evidenced by increased sEPSC amplitude without any changes in sEPSC frequency or rectification. In support of this increase in GluA2 activity mediating the augmented cocaine reinstatement, we found that accumbal overexpression of GluA2 recapitulated this behavioral effect in wildtype mice while not altering reinstatement behavior in the GluA2 K882A knock-in mice. In addition, disrupting GluA2 phosphorylation was associated with blunted long-term depression in the nucleus accumbens, mimicking the anaplasticity seen following cocaine self-administration. Taken together these results indicate that disrupting GluA2 phosphorylation and increasing GluA2-mediated transmission in the nucleus accumbens leads to increased vulnerability to cocaine relapse. Further, these results indicate that modulating GluA2-containing AMPAR trafficking can contribute to addictive phenotypes in the absence of alterations in GluA2-lacking receptors. These results highlight the GluA2 phosphorylation site as a novel target for the development of cocaine addiction therapeutics.

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Section: Discussioncontrasting

confidence: 90%

Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Disrupting GluA2 phosphorylation potentiates reinstatement of cocaine seeking

et al. 2016

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“…These findings suggested that D2DR may govern dorsal horn neuronal adaptation during chronic morphine exposure. It should be noted that PKC can be activated by D2DR39. PKC is widely accepted as a downstream of NMDA receptor in morphine tolerance, however, the activated PKC is also reported can activate NMDA receptor to further promote the central sensitization40.…”

Section: Discussionmentioning

confidence: 98%

Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord

Dai

Xiong

Yan

et al. 2016

Sci Rep

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Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Morphine is a highly efficacious agent against chronic severe pain. However, repeated morphine administration leads to antinociceptive tolerance which discontinues morphine therapy for chronic pain. The cellular and molecular mechanisms underlying morphine tolerance are still not fully understood. Morphine is known to exert analgesic effect mainly by activating MOR encoded by the MOR-1 gene. And in MOR-1 knockout mice, the analgesia and tolerance of morphine are absent 1,2 . These results suggested that morphine tolerance may be partly mediated by MOR and it has been reported that MOR desensitization 3,4 contributes to the development of morphine tolerance. In addition, central sensitization also promotes the development and maintenance of morphine tolerance. Chronic morphine treatment can significantly increase the release of different neurotransmitters such as glutamate (Glu), which binds to the NMDA receptor to enhance the excitatory synaptic transmission 5,6 . It also activates the astrocytes and microglia 7-9 , leading to the release of the pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα ) and interleukin-1β (IL-1β ) 10-12 to promote the morphine tolerance.D2DR, a dopamine receptor subtype which affects the locomotion, reward and abuse of opioids [13][14][15][16] has been reported to be involved in morphine-induced nociception modulation in rats. Activation of D2DR by quinpirole in hypothalamic A11 cell group 17 , ventrolateral orbital cortex (VLO) 18 and dorsal hippocampus (CA1) 19 of rats exerts antinociceptive effect. Intraperitoneal injection of quinpirole enhances the antinociceptive effect of morphine 20 . However, Michael A. King and colleagues reported that the effect of opioid analegesia is potentiated in D2DR knock-out mice 21 . Therefore, the apparent analgesia effect and mechanism of D2DR were still not clear. And the effect and mechanism of D2DR on morphine tolerance has also not been elucidated.The present study was performed to investigate the possible role of D2DR in morphine tolerance at spinal levels of mice. Our results indicated that chronic morphine treatment increased the neuronal D2DR expression

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“…88,107 Cocaine reinstatement (a model of relapse) following withdrawal is at least partially due to D2R-dependent increases in PKC signaling in the NAc shell with increased D1R or direct pathway signaling to promote relapse. 108 Indeed, a study of cocaine-primed reinstatement of cocaine-seeking behavior showed an increase in phosphorylated PKCγ. 109 Injection of PKC inhibitors into the NAc core inhibits cocaine-seeking in rats while injection of inhibitors into the ventral tegmental area reduces dopamine release in the NAc as well as cocaine-induced hyperlocomotion.…”

Section: S-glutathionylation Of Pka Pkc Cdk5 and Actin May Inflmentioning

confidence: 99%

S-Glutathionylation and Redox Protein Signaling in Drug Addiction

Womersley

Uys

2016

Progress in Molecular Biology and Translational Science

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Drug addiction is a chronic relapsing disorder that comes at a high cost to individuals and society. Therefore understanding the mechanisms by which drugs exert their effects is of prime importance. Drugs of abuse increase the production of reactive oxygen and nitrogen species resulting in oxidative stress. This change in redox homeostasis increases the conjugation of glutathione to protein cysteine residues; a process called S-glutathionylation. Although traditionally regarded as a protective mechanism against irreversible protein oxidation, accumulated evidence suggests a more nuanced role for S-glutathionylation, namely as a mediator in redox-sensitive protein signaling. The reversible modification of protein thiols leading to alteration in function under different physiologic/pathologic conditions provides a mechanism whereby change in redox status can be translated into a functional response. As such, S-glutathionylation represents an understudied means of post-translational protein modification that may be important in the mechanisms underlying drug addiction. This review will discuss the evidence for S-glutathionylation as a redox-sensing mechanism and how this may be involved in the response to drug-induced oxidative stress. The function of S-glutathionylated proteins involved in neurotransmission, dendritic spine structure, and drug-induced behavioral outputs will be reviewed with specific reference to alcohol, cocaine, and heroin.

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Cocaine-seeking is associated with PKC-dependent reduction of excitatory signaling in accumbens shell D2 dopamine receptor-expressing neurons

Cited by 36 publications

References 77 publications

Disrupting GluA2 phosphorylation potentiates reinstatement of cocaine seeking

Disrupting GluA2 phosphorylation potentiates reinstatement of cocaine seeking

Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord

S-Glutathionylation and Redox Protein Signaling in Drug Addiction

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