NMDA Receptors on Non-Dopaminergic Neurons in the VTA Support Cocaine Sensitization

Abstract

BackgroundThe initiation of behavioral sensitization to cocaine and other psychomotor stimulants is thought to reflect N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity in the mesolimbic dopamine (DA) circuitry. The importance of drug induced NMDAR mediated adaptations in ventral tegmental area (VTA) DA neurons, and its association with drug seeking behaviors, has recently been evaluated in Cre-loxp mice lacking functional NMDARs in DA neurons expressing Cre recombinase under the control of the endogenous dopamine transporter gene (NR1DATCre mice).Methodology and Principal FindingsUsing an additional NR1DATCre 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 NR1DATCre 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 NR1DATCre mice. Here we demonstrate that the NMDA receptor gene is ablated in the majority of VTA DA neurons, including those exhibiting undetectable DAT expression levels in our NR1DATCre transgenic model, and that application of an NMDAR antagonist within the VTA of NR1DATCre animals still blocks sensitization to cocaine.Conclusions/SignificanceThese results eliminate the possibility of NMDAR mediated neuroplasticity in the different DA neuronal subpopulations in our NR1DATCre mouse model and therefore suggest that NMDARs on non-DA neurons within the VTA must play a major role in cocaine-related addictive behavior.

Balanced NMDA receptor activity in dopamine D1 receptor (D1R)- and D2R-expressing medium spiny neurons is required for amphetamine sensitization

“…However, we and others have shown that DAT:NR1 knockout mice also develop normal cocaine sensitization, similar to what we describe here (10,11,13). There are multiple possible explanations for this discrepancy.…”

“…First, antagonists affect all cell types in a region, whereas the genetic approach allows only a particular cell type to be affected. Recent evidence strongly suggests that nondopaminergic cells in the VTA are the critical substrate in this region for mediating sensitization (13). Alternatively, it has been shown that not all dopamine neurons express DAT; therefore, Cre-mediated removal of Grin1 in DAT: NR1 knockout mice may be incomplete (33).…”

“…Alternatively, it has been shown that not all dopamine neurons express DAT; therefore, Cre-mediated removal of Grin1 in DAT: NR1 knockout mice may be incomplete (33). It has been shown that application of NMDAR antagonists to the VTA of animals lacking NMDARs on dopamine neurons was able to block cocaine sensitization, suggesting that NMDARs on nondopaminergic cells in this region are important in cocaine sensitization, or that the NMDAR antagonist used has off-target effects (13). Finally, it is possible that DAT:NR1 knockout mice are able to sensitize to psychostimulants due to a compensatory mechanism.…”

“…In contrast, NMDAR antagonists delivered to the VTA prevent cocaine sensitization (12). These disparate results have been recently reconciled by the observation that an NMDAR antagonist injected into the VTA of mice lacking NMDARs on dopamine neurons still blocks cocaine sensitization (13). Thus, NMDARs on nondopamine neurons of the VTA appear to be the critical substrate for cocaine sensitization in this brain region.…”

Neurotensin inhibits glutamate-mediated synaptic inputs onto ventral tegmental area dopamine neurons through the release of the endocannabinoid 2-AG

“…LTP in this area of the brain is otherwise known to occur after injection of cocaine (Ungless et al, 2001) and other drugs of abuse (Saal et al, 2003), and when inhibited in KO mice, causes alterations of drug-seeking behaviors (Engblom et al, 2008;Zweifel et al, 2008). Recent work has also revealed that LTP in nondopaminergic neurons of the VTA is even more directly linked to such drug-seeking behaviors (Luo et al, 2010). Therefore, understanding the mechanisms of LTP in the VTA may prove to be critical to our understanding of drug addiction.…”