DAT-NR1 KO mice were implanted with a bilateral cannula in the VTA to deliver specific NMDAR antagonists during a cocaine sensitization regimen, and our results have shown that sensitization can be equally blocked in DAT-NR1 KO and WT animals by simultaneous injection of an NMDAR antagonist in the VTA along with peripheral cocaine. Our experiments are now aimed at ruling out or including the mesocortical DA cell population as the mediator of VTA NMDA dependent sensitization. We are currently performing molecular studies to determine if these dopamine neurons, due to low DAT levels and therefore lack of Cre, may express NMDA receptors. Using an NR1(DATCre) mouse transgenic model, we demonstrate that while the selective inactivation of NMDARs in DA neurons eliminates the induction of molecular changes leading to synaptic strengthening, behavioral measures such as cocaine induced locomotor sensitization and conditioned place preference remain intact in NR1(DATCre) mice. Since VTA DA neurons projecting to the prefrontal cortex and amygdala express little or no detectable levels of the dopamine transporter, it has been speculated that NMDA receptors in DA neurons projecting to these brain areas may have been spared in NR1(DATCre) mice. We have demonstrated that the NMDA receptor gene is ablated in the majority of VTA DA neurons, including those exhibiting undetectable DAT expression levels in our NR1(DATCre) transgenic model, and that application of an NMDAR antagonist within the VTA of NR1(DATCre) animals still blocks sensitization to cocaine. These results eliminate the possibility of NMDAR mediated neuroplasticity in the different DA neuronal subpopulations in our NR1(DATCre) mouse model and therefore suggest that NMDARs on non-DA neurons within the VTA must play a major role in cocaine-related addictive behavior.
| Luo, Yu; Good, Cameron H; Diaz-Ruiz, Oscar et al. (2010) NMDA receptors on non-dopaminergic neurons in the VTA support cocaine sensitization. PLoS One 5: |
