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- Title
Inactivation of NMD A Receptors in the Ventral Tegmental Area during Cocaine Self-Administration Prevents GluA1 Upregulation but with Paradoxical Increases in Cocaine-Seeking Behavior.
- Authors
Guzman, Daniel; Carreira, Maria B.; Friedman, Allyson K.; Adachi, Megumi; Neve, Rachael L.; Monteggia, Lisa M.; Ming-Hu Han; Cowan, Christopher W.; Self, David W.
- Abstract
Cocaine self-administration increases expression of GluAl subunits in ventral tegmental area (VTA) dopamine neurons, which subsequently enhance the motivation for cocaine. This increase in GluAl 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 viralmediated expression of a dominant-negative GluNl subunit (HSV-dnGluNl) in VTA neurons to study the effect of transient NMDAR inactivation on the GluAl increases induced by chronic cocaine self-administration in male rats. We found that dnGluNl expression in the VT A limited to the 3 weeks of cocaine self-administration prevents the subsequent increase in tissue GluAl levels when compared with control infusions of HSV-LacZ. Surprisingly, dnGluN 1 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 GluAl increases in cocaine self-administering animals, the HSV-dnGluN 1 treatment resulted in increased membrane levels of GluA 1 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 GluAl expression, but such transient NMDAR inactivation also leads to compensatory scaling of synaptic AMPA receptors that enhance the motivational for cocaine.
- Subjects
COCAINE; NEURONS; DOPAMINE analysis; NEURAL transmission; DATA analysis
- Publication
Journal of Neuroscience, 2018, Vol 38, Issue 3, p575
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.2828-16.2017