Cocaine use disorder is manifested by repeated cycles of drug seeking and drug taking.
Cocaine exposure causes synaptic transmission in the brain to exhibit persistent changes, which are
poorly understood, while the pharmacotherapy of this disease has not been determined. Multiple
potential mechanisms have been indicated to be involved in the etiology of cocaine use disorder.
The glutamatergic system, especially N-methyl-D-aspartate (NMDA) receptors, may play a role in
several physiological processes (synaptic plasticity, learning and memory) and in the pathogenesis
of cocaine use disorder. The composition of the NMDA receptor subunits changes after contingent
and noncontingent cocaine administration and after drug abstinence in a region-specific and timedependent
manner, as well as depending on the different protocols used for cocaine administration.
Changes in the expression of NMDA receptor subunits may underlie the transition from cocaine
abuse to dependence, as well as the transition from cocaine dependence to cocaine withdrawal. In
this paper, we summarize the current knowledge regarding neuroadaptations within NMDA receptor
subunits and scaffolding proteins observed following voluntary and passive cocaine intake, as
well as the effects of NMDA receptor antagonists on cocaine-induced behavioral changes during
cocaine seeking and relapse.