NMDA receptors on non-dopaminergic neurons in the VTA support cocaine sensitization.
BACKGROUND
The 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 (NR1(DATCre) mice).


RESULTS
Using an additional 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. 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 NR1(DATCre) transgenic model, and that application of an NMDAR antagonist within the VTA of NR1(DATCre) animals still blocks sensitization to cocaine.


CONCLUSIONS
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
Y
Cellular Neurobiology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, United States of America.
Good
Cameron H
CH
Diaz-Ruiz
Oscar
O
Zhang
YaJun
Y
Hoffman
Alexander F
AF
Shan
Lufei
L
Kuang
Serena Y
SY
Malik
Nasir
N
Chefer
Vladimir I
VI
Tomac
Andreas C
AC
Lupica
Carl R
CR
Bäckman
Cristina M
CM
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D055786:Gene Knockout Techniques; D018698:Glutamic Acid / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D009830:Olfactory Bulb / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000502:physiology
D050483:Dopamine Plasma Membrane Transport Proteins; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C045073:Cre recombinase; D019426:Integrases; D003042:Cocaine; D004298:Dopamine
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