Cocaine enhances NMDA receptor-mediated currents in ventral tegmental area cells via dopamine D5 receptor-dependent redistribution of NMDA receptors.
Cocaine-induced plasticity of glutamatergic synaptic transmission in the ventral tegmental area (VTA) plays an important role in brain adaptations that promote addictive behaviors. However, the mechanisms responsible for triggering these synaptic changes are unknown. Here, we examined the effects of acute cocaine application on glutamatergic synaptic transmission in rat midbrain slices. Cocaine caused a delayed increase in NMDA receptor (NMDAR)-mediated synaptic currents in putative VTA dopamine (DA) cells. This effect was mimicked by a specific DA reuptake inhibitor and by a DA D1/D5 receptor agonist. The effect of cocaine was blocked by a DA D1/D5 receptor antagonist as well as by inhibitors of the cAMP/cAMP-dependent protein kinase A (PKA) pathway. Furthermore, biochemical analysis showed an increase in the immunoreactivity of the NMDAR subunits NR1 and NR2B and their redistribution to the synaptic membranes in VTA neurons. Accordingly, NMDAR-mediated EPSC decay time kinetics were significantly slower after cocaine, suggesting an increased number of NR2B-containing NMDARs. Finally, pharmacological analysis indicates that NR2B subunits might be incorporated in triheteromeric NR1/NR2A/NR2B complexes rather than in "pure" NR1/NR2B NMDA receptors. Together, our data suggest that acute cocaine increases NMDAR function in the VTA via activation of the cAMP/PKA pathway mediated by a DA D5-like receptor, leading to the insertion of NR2B-containing NMDARs in the membrane. These results provide a potential mechanism by which acute cocaine promotes synaptic plasticity of VTA neurons, which could ultimately lead to the development of addictive behaviors.
Schilström
Björn
B
Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Yaka
Rami
R
Argilli
Emanuela
E
Suvarna
Neesha
N
Schumann
Johanna
J
Chen
Billy T
BT
Carman
Melissa
M
Singh
Vineeta
V
Mailliard
William S
WS
Ron
Dorit
D
Bonci
Antonello
A
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D066298:In Vitro Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000819:agonists; D050641:Receptors, Dopamine D5 / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects; D014018:Tissue Distribution; D017557:Ventral Tegmental Area / Q000502:physiology*
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D018091:Receptors, AMPA; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D050641:Receptors, Dopamine D5; D003042:Cocaine