Inactivation of NMDA Receptors in the Ventral Tegmental Area during Cocaine Self-Administration Prevents GluA1 Upregulation but with Paradoxical Increases in Cocaine-Seeking Behavior.

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 the VTA limited to the 3 weeks of cocaine self-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.SIGNIFICANCE STATEMENT Dopamine neurons in the ventral tegmental area (VTA) are critical substrates of drug rewards. Animal models indicate that chronic cocaine use enhances excitatory glutamatergic input to these neurons, making them more susceptible to environmental stimuli that trigger drug craving and relapse. We previously found that self-administration of cocaine increases AMPA glutamate receptors in the VTA, and this effect enhances motivation for cocaine. Here we report that the mechanism for this upregulation involves NMDA receptor activity during cocaine use. While interference with NMDA receptor function blocks AMPA receptor upregulation, it also produces a paradoxical enhancement in membrane AMPA receptor subunits, AMPA responsiveness, and the motivation for cocaine. Thus, pharmacotherapy targeting NMDA receptors may inadvertently produce substantial adverse consequences for cocaine addiction.