Repeated treatment with nicotine induces phosphorylation of NMDA receptor NR2B subunit in the brain regions involved in behavioral sensitization

Nakajima, Akira; Kinugasa, Yukari; Torii, Jun; Hishinuma, Takanori; Tomioka, Y.; Yamada, Kiyofumi; Yamakuni, Tohru

doi:10.1016/j.neulet.2012.07.022

Cited by 13 publications

(8 citation statements)

References 39 publications

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“…Our findings are consistent with prior studies that observed cNIC induced increases in NMDA function, including NR2B current and phosphorylation at tyrosine 1472, in the hippocampus, PFC, and NAc (Ávila-Ruiz et al, 2014;Nakajima et al, 2012;Yamazaki et al, 2006) as well as increased LTP in the hippocampus (Yamazaki et al, 2006) and amygdala (Huang et al, 2008). Increased CREB activity alone can induce an upregulation of silent synapses (Brown et al, 2011;Marie et al, 2005).…”

Section: Discussionsupporting

confidence: 93%

Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses

Xia

Beeler

2017

Neuropsychopharmacol

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Smoking is the leading cause of preventable death in the United States and success rates for quitting remain low. High relapse rates are attributed to pervasive nicotine-reinforced associative learning of incentive cues that is highly resistant to extinction. Why such learning is so persistent is poorly understood but may arise as a consequence of neuroadaptations in synaptic plasticity induced by chronic nicotine. We used whole-cell patch clamp recording to investigate the effect of chronic nicotine (cNIC) on synaptic plasticity in dopamine D2 receptor-expressing medium-spiny neurons in the indirect, striatopallidal pathway in dorsolateral striatum. Mice exposed to cNIC exhibited long-term potentiation in response to high-frequency stimulation instead of the expected depression. cNIC decreased baseline AMPA/NMDA ratio, arising from increased NMDA currents enriched in the NR2B subunit with a concomitant upregulation of NMDA-only, silent synapses. These data demonstrate that cNIC can increase silent synapses in MSNs, as observed with cocaine and opiates, and alter the regulation of corticostriatal plasticity. Prior work has characterized cocaine- and morphine-induced upregulation of silent synapses in the ventral striatum; we show it can occur in the dorsal striatum, a region associated with later stages of addiction, craving, and cue-induced relapse.

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Section: Discussionsupporting

confidence: 93%

Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses

Xia

Beeler

2017

Neuropsychopharmacol

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“…Beginning with the foundational studies of , which connected NMDARs with the development of psychomotor sensitization, more and more evidence has demonstrated that NMDARs are involved in behavioral sensitization induced by psychomotor stimulants, including amphetamine [34,35]. In the current study, three doses of ifenprodil (2.5, 5, 10 mg/kg) was used to prevent behavioral sensitization induced by chronic exposure to METH.…”

Section: Discussionmentioning

confidence: 93%

Ifenprodil Attenuates Methamphetamine-Induced Behavioral Sensitization and Activation of Ras-ERK-∆FosB Pathway in the Caudate Putamen

Liu

Qiao

et al. 2016

Neurochem Res

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Addiction is a debilitating, chronic psychiatric disorder that is difficult to cure completely owing to the high rate of relapse. Behavioral sensitization is considered to may underlie behavioral changes, such as relapse, caused by chronic abuse of psychomotor stimulants. Thus, its animal models have been widely used to explore the etiology of addiction. Recently, increasing evidence has demonstrated that N-methyl-D-aspartate receptors (NMDARs) play an important role in addiction to psychomotor stimulants. However, the role of GluN2B-containing receptors and their downstream signaling pathway(s) in behavioral sensitization induced by methamphetamine (METH) have not been investigated yet. In this study, we used different doses of ifenprodil (2.5, 5, 10 mg/kg), a selective antagonist of the GluN2B subunit, to investigate the role of GluN2B-containing NMDARs in METH-induced behavioral sensitization. We then examined changes in the levels of Ras, phosphorylated extracellular signal-regulated kinase (pERK)/ERK, and ∆FosB in the caudate putamen (CPu) by western blot. We found that 2.5 or 10 mg/kg ifenprodil significantly attenuated METH-induced behavioral sensitization, whereas the mice treated with a moderate dose of ifenprodil (5 mg/kg) displayed no significant changes. Further results of western blot experiments showed that repeated administration of METH caused the increases in the levels of Ras, pERK/ERK and ∆FosB in the CPu, and these changes were inhibited by only the 2.5 mg/kg dose of ifenprodil. In conclusion, these results demonstrated that 2.5 mg/kg ifenprodil could attenuate METH-induced behavioral sensitization. Moreover, GluN2B-containing NMDARs and their downstream Ras-ERK-∆FosB signaling pathway in the CPu might be involved in METH-induced behavioral sensitization.

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“…Nicotine sensitization, with 14 days exposure but no withdrawal, increases NMDAR currents in NAc core and mPFC but not NAc shell, with no changes in GluN2B (Ávila‐Ruiz et al ). In contrast, briefer nicotine exposure (7 days) increases GluN2B phosphorylation in both NAc and striatum (Nakajima et al ). Also, GluN2B but not GluN2A levels are decreased across withdrawal in the striatum (Pistillo et al ).…”

Section: Nmdar Contributions To Nicotine Addictionmentioning

confidence: 99%

Do specific NMDA receptor subunits act as gateways for addictive behaviors?

Hopf

2016

Genes Brain and Behavior

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Addiction to alcohol and drugs is a major social and economic problem, and there is considerable interest in understanding the molecular mechanisms that promote addictive drives. A number of proteins have been identified that contribute to expression of addictive behaviors. NMDA receptors (NMDARs), a subclass of ionotropic glutamate receptors, have been of particular interest because their physiological properties make them an attractive candidate for gating induction of synaptic plasticity, a molecular change thought to mediate learning and memory. NMDARs are generally inactive at the hyperpolarized resting potentials of many neurons. However, given sufficient depolarization, NMDARs are activated and exhibit long-lasting currents with significant calcium permeability. Also, in addition to stimulating neurons by direct depolarization, NMDARs and their calcium signaling can allow strong and/or synchronized inputs to produce long-term changes in other molecules (such as AMPA-type glutamate receptors) which can last from days to years, binding internal and external stimuli in a long-term memory trace. Such memories could allow salient drug-related stimuli to exert strong control over future behaviors and thus promote addictive drives. Finally, NMDARs may themselves undergo plasticity, which can alter subsequent neuronal stimulation and/or the ability to induce plasticity. This review will address recent and past findings suggesting that NMDAR activity promotes drug- and alcohol-related behaviors, with a particular focus on GluN2B subunits as possible central regulators of many addictive behaviors, as well as newer studies examining the importance of non-canonical NMDAR subunits and endogenous NMDAR cofactors.

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Repeated treatment with nicotine induces phosphorylation of NMDA receptor NR2B subunit in the brain regions involved in behavioral sensitization

Cited by 13 publications

References 39 publications

Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses

Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses

Ifenprodil Attenuates Methamphetamine-Induced Behavioral Sensitization and Activation of Ras-ERK-∆FosB Pathway in the Caudate Putamen

Do specific NMDA receptor subunits act as gateways for addictive behaviors?

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