Inactivation of NMDA receptors in the ventral tegmental area during cocaine self-administration prevents GluA1 upregulation but with paradoxical increases in cocaine-seeking behavior

Daniel Guzman, Maria B. Carreira, Allyson K. Friedman, Megumi Adachi, Rachael L. Neve, Lisa M Monteggia, Ming Hu Han, Christopher W. Cowan, David W Self

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Cocaine self-administration increases expression of GluA1 subunits in ventral tegmental area (VTA) dopamine neurons, which subsequently enhance the motivation for cocaine. This increase in GluA1 may be dependent on concomitant NMDA receptor (NMDAR) activation during self-administration, similar to cocaine-induced long-term potentiation in the VTA. In this study, we used viral-mediated expression of a dominant-negative GluN1 subunit (HSV-dnGluN1) in VTA neurons to study the effect of transient NMDAR inactivation on the GluA1 increases induced by chronic cocaine self-administration in male rats. We found that dnGluN1 expression in theVTAlimitedtothe3weeksof cocaineself-administration prevents the subsequent increase in tissue GluA1 levels when compared with control infusions of HSV-LacZ. Surprisingly, dnGluN1 expression led to an enhancement in the motivation to self-administer cocaine as measured using a progressive ratio reinforcement schedule and to enhanced cocaine seeking measured in extinction/reinstatement tests following an extended 3 week withdrawal period. Despite blocking tissue GluA1 increases in cocaine self-administering animals, the HSV-dnGluN1 treatment resulted in increased membrane levels of GluA1 and GluN2B, along with markedly higher locomotor responses to intra-VTA infusions of AMPA, suggesting a paradoxical increase in VTA AMPA receptor responsiveness. Together, these data suggest that NMDARs mediate cocaine-induced increases in VTA GluA1 expression, but such transient NMDAR inactivation also leads to compensatory scaling of synaptic AMPA receptors that enhance the motivational for cocaine.

Original languageEnglish (US)
Pages (from-to)575-585
Number of pages11
JournalJournal of Neuroscience
Volume38
Issue number3
DOIs
StatePublished - Jan 17 2018

Fingerprint

Ventral Tegmental Area
Self Administration
N-Methyl-D-Aspartate Receptors
Cocaine
Up-Regulation
AMPA Receptors
Motivation
Reinforcement Schedule
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Neurotransmitter Receptor
Long-Term Potentiation
Dopaminergic Neurons
Neurons
Membranes

Keywords

  • Cocaine
  • GluA1
  • GluN1
  • Self-administration
  • VTA

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Inactivation of NMDA receptors in the ventral tegmental area during cocaine self-administration prevents GluA1 upregulation but with paradoxical increases in cocaine-seeking behavior. / Guzman, Daniel; Carreira, Maria B.; Friedman, Allyson K.; Adachi, Megumi; Neve, Rachael L.; Monteggia, Lisa M; Han, Ming Hu; Cowan, Christopher W.; Self, David W.

In: Journal of Neuroscience, Vol. 38, No. 3, 17.01.2018, p. 575-585.

Research output: Contribution to journalArticle

Guzman, Daniel ; Carreira, Maria B. ; Friedman, Allyson K. ; Adachi, Megumi ; Neve, Rachael L. ; Monteggia, Lisa M ; Han, Ming Hu ; Cowan, Christopher W. ; Self, David W. / Inactivation of NMDA receptors in the ventral tegmental area during cocaine self-administration prevents GluA1 upregulation but with paradoxical increases in cocaine-seeking behavior. In: Journal of Neuroscience. 2018 ; Vol. 38, No. 3. pp. 575-585.
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AU - Adachi, Megumi

AU - Neve, Rachael L.

AU - Monteggia, Lisa M

AU - Han, Ming Hu

AU - Cowan, Christopher W.

AU - Self, David W

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AB - Cocaine self-administration increases expression of GluA1 subunits in ventral tegmental area (VTA) dopamine neurons, which subsequently enhance the motivation for cocaine. This increase in GluA1 may be dependent on concomitant NMDA receptor (NMDAR) activation during self-administration, similar to cocaine-induced long-term potentiation in the VTA. In this study, we used viral-mediated expression of a dominant-negative GluN1 subunit (HSV-dnGluN1) in VTA neurons to study the effect of transient NMDAR inactivation on the GluA1 increases induced by chronic cocaine self-administration in male rats. We found that dnGluN1 expression in theVTAlimitedtothe3weeksof cocaineself-administration prevents the subsequent increase in tissue GluA1 levels when compared with control infusions of HSV-LacZ. Surprisingly, dnGluN1 expression led to an enhancement in the motivation to self-administer cocaine as measured using a progressive ratio reinforcement schedule and to enhanced cocaine seeking measured in extinction/reinstatement tests following an extended 3 week withdrawal period. Despite blocking tissue GluA1 increases in cocaine self-administering animals, the HSV-dnGluN1 treatment resulted in increased membrane levels of GluA1 and GluN2B, along with markedly higher locomotor responses to intra-VTA infusions of AMPA, suggesting a paradoxical increase in VTA AMPA receptor responsiveness. Together, these data suggest that NMDARs mediate cocaine-induced increases in VTA GluA1 expression, but such transient NMDAR inactivation also leads to compensatory scaling of synaptic AMPA receptors that enhance the motivational for cocaine.

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