NR2A/B-containing NMDA receptors mediate cocaine-induced synaptic plasticity in the VTA and cocaine psychomotor sensitization

Schumann, Johanna; Matzner, Henry; Michaeli, Avner; Yaka, Rami

doi:10.1016/j.neulet.2009.06.002

Cited by 21 publications

(13 citation statements)

References 30 publications

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“…GRIN2A regulates reward-related associative learning, cognition, memory, and structural and behavioral plasticity in the context of drug addiction [13]–[16], [21], [25], [26], suggesting that GRIN2A acts upon the brain’s reward system, which plays a key role in drug addiction. In the past decade, accumulated evidence indicates that NMDA receptors play a pivotal role in the development of tolerance and physical dependence to opiates [27]–[29].…”

Section: Discussionmentioning

confidence: 99%

Analysis of Variations in the Glutamate Receptor, N-Methyl D-Aspartate 2A (GRIN2A) Gene Reveals Their Relative Importance as Genetic Susceptibility Factors for Heroin Addiction

et al. 2013

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The glutamate receptor, N-methyl D-aspartate 2A (GRIN2A) gene that encodes the 2A subunit of the N-methyl D-aspartate (NMDA) receptor was recently shown to be involved in the development of opiate addiction. Genetic polymorphisms in GRIN2A have a plausible role in modulating the risk of heroin addiction. An association of GRIN2A single-nucleotide polymorphisms (SNPs) with heroin addiction was found earlier in African Americans. To identify markers that contribute to the genetic susceptibility to heroin addiction, we examined the potential association between heroin addiction and forty polymorphisms of the GRIN2A gene using the MassARRAY system and GeneScan in this study. The frequency of the (GT)26 repeats (rs3219790) in the heroin addiction group was significantly higher than that in the control group (χ2 = 5.360, P = 0.021). The allele frequencies of three polymorphisms (rs1102972, rs1650420, and rs3104703 in intron 3) were strongly associated with heroin addiction (P<0.001, 0.0002, and <0.001, after Bonferroni correction). Three additional SNPs from the same intron (rs1071502, rs6497730, and rs1070487) had nominally significant P values for association (P<0.05), but did not pass the threshold value. Haplotype analysis revealed that the G-C-T-C-C-T-A (block 6) and T-T (block 10) haplotypes of the GRIN2A gene displayed a protective effect (P = <0.001 and 0.003). These findings point to a role for GRIN2A polymorphisms in heroin addiction among the Han Chinese from Shaanxi province, and may be informative for future genetic or neurobiological studies on heroin addiction.

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Section: Discussionmentioning

confidence: 99%

Analysis of Variations in the Glutamate Receptor, N-Methyl D-Aspartate 2A (GRIN2A) Gene Reveals Their Relative Importance as Genetic Susceptibility Factors for Heroin Addiction

et al. 2013

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“…One of the immediate molecular effects that underlies single and multiple injections of cocaine are long-term changes in synaptic plasticity in the VTA (Ungless et al , 2001; Borgland et al , 2004; Schumann et al , 2009). This area is implicated in the development of drug addiction (Ikemoto & Wise, 2004; Kauer, 2004; Self, 2004) and sensitization (Kalivas et al , 1993; Wolf & Xue, 1998).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Protein Kinase Mζ (PKMζ) in the Mesolimbic System Alters Cocaine Sensitization in Rats

Vélez-Hernández

Vázquez-Torres

Velásquez-Martinez

et al. 2013

Journal of Drug and Alcohol Research

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Chronic cocaine use produces long-lasting changes in reward circuits that may underlie the transition from casual to compulsive patterns of drug use. Although strong neuroadaptations within the mesocorticolimbic system are known to occur, the specific role of these drug-induced plasticities on sensitization remains to be elucidated. Here we investigate whether PKMζ, a protein involved in maintaining long-term potentiation (LTP), plays a role in these cocaine-induced changes in synaptic strengthening. We performed whole-cell voltage clamp recordings of putative ventral tegmental area (VTA) dopamine (DA) cells 24 hours after five days of 15 mg/kg i.p. cocaine or isovolumetric saline injections. We observed that superfusion of 5µM ZIP (PKMζ inhibitory peptide) decreased AMPA currents and AMPA/NMDA ratios only in cocaine sensitized rats. In vivo ZIP microinfusions (10 nmol) into the VTA after cocaine sensitization decreased locomotor activity on a subsequent cocaine challenge only if given ZIP is given before the withdrawal period. On the other hand, ZIP microinfusions into the nucleus accumbens (NAc) core after a seven days withdrawal period disrupt the expression of locomotor sensitization. The present data provide a potentially relevant region, and time-specific PKMζ-dependent brain mechanism that enables sensitization. Our results support the vision that addiction involves a pathological learning process. They imply that if this synaptic strengthening is reversed, changes in the behavioral response may also be overturned.

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“…Cocaine-induced changes in NMDAR expression differ between brain areas, but are also highly sensitive to the choice of cocaine administration paradigm and the history of cocaine exposure. This is particularly evident in the nucleus accumbens (NAc), where short withdrawal (3 days or less) from experimenter-administered (non-contingent) cocaine is reported to decrease the NMDAR subunit levels or leave them unchanged (Yamaguchi et al, 2002; Yamamoto and Zahniser, 2012), whereas longer periods of withdrawal from non-contingent cocaine is associated with an increase in NMDAR subunit expression (Ghasemzadeh et al, 2009a, Schumann and Yaka, 2009; Zhang et al, 2007). This pattern of decreased to increased expression of NMDARs with abstinence from non-contingent cocaine is different for animals that are trained to self-administer cocaine.…”

Section: Cocaine Effects On Nmdar Expressionmentioning

confidence: 99%

Cocaine-Induced Changes in NMDA Receptor Signaling

Ortinski

2014

Mol Neurobiol

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Addictive states are often thought to rely on lasting modification of signaling at relevant synapses. A long-standing theory posits that activity at N-methyl-D-aspartate receptors (NMDARs) is a critical component of long-term synaptic plasticity in many brain areas. Indeed, NMDAR signaling has been found to play a role in the etiology of addictive states, in particular following cocaine exposure. However, no consensus is apparent with respect to the specific effects of cocaine exposure on NMDARs. Part of the difficulty lies in the fact that NMDARs interact extensively with multiple membrane proteins and intracellular signaling cascades. This allows for highly heterogeneous patterns of NMDAR regulation by cocaine in distinct brain regions and at distinct synapses. The picture is further complicated by findings that cocaine effects on NMDARs are sensitive to the behavioral history of cocaine exposure, such as the mode of cocaine administration. This review provides a summary of evidence for cocaine-induced changes in NMDAR expression, cocaine-induced alterations in NMDAR function and cocaine effects on NMDAR control of intracellular signaling cascades.

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NR2A/B-containing NMDA receptors mediate cocaine-induced synaptic plasticity in the VTA and cocaine psychomotor sensitization

Cited by 21 publications

References 30 publications

Analysis of Variations in the Glutamate Receptor, N-Methyl D-Aspartate 2A (GRIN2A) Gene Reveals Their Relative Importance as Genetic Susceptibility Factors for Heroin Addiction

Analysis of Variations in the Glutamate Receptor, N-Methyl D-Aspartate 2A (GRIN2A) Gene Reveals Their Relative Importance as Genetic Susceptibility Factors for Heroin Addiction

Inhibition of Protein Kinase Mζ (PKMζ) in the Mesolimbic System Alters Cocaine Sensitization in Rats

Cocaine-Induced Changes in NMDA Receptor Signaling

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