NR2A/B-containing NMDA receptors mediate cocaine-induced synaptic plasticity in the VTA and cocaine psychomotor sensitization.
Cocaine-induced modifications of glutamatergic synaptic transmission in the mesolimbic system play a key role in adaptations that promote addictive behaviors. In particular, the activation of ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR) in the ventral tegmental area (VTA) is critical for both cocaine-induced synaptic plasticity induced by a single cocaine injection and for the initiation of cocaine psychomotor sensitization. In this study, we set to determine whether the NR2 subunits of the NMDAR play a specific role in triggering cocaine-induced alterations in synaptic plasticity and the development of psychomotor sensitization. We found that inhibition of NR2A-containing NMDARs by NVP-AAM077, or NR2B-containing receptors by ifenprodil, blocked cocaine-induced increase in the AMPAR/NMDAR currents ratio, a measure of long-term potentiation (LTP) in vivo, in VTA neurons 24h following a single cocaine injection. Furthermore, inhibition of the NR2A subunit during the development of psychomotor sensitization attenuated the enhanced locomotor activity following repeated cocaine injections. Together, these results suggest that NR2-containing NMDA receptors play an important role in the machinery that triggers synaptic and behavioral adaptations to drugs of abuse such as cocaine.
Schumann
Johanna
J
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Matzner
Henry
H
Michaeli
Avner
A
Yaka
Rami
R
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000502:physiology*
D000697:Central Nervous System Stimulants; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D003042:Cocaine