N-methyl-D-aspartic acid receptors on striatal neurons are essential for cocaine cue reactivity in mice

Abstract

Background: Environmental cues associated with cocaine evoke craving and seeking. This process, termed cue reactivity, is a critical element of cocaine addiction. Although glutamatergic neurotransmission has been implicated in this effect of cocaine, the precise subtype and localization in the brain of the glutamatergic receptor critical for cocaine cue reactivity is not well-understood.

Methods: We used a conditional N-methyl-D-aspartic acid receptor (NMDAR) knockout mouse whose NMDAR gene was deleted by Cre expression restricted to striatal neurons. To evaluate the role of NMDAR in cocaine cue reactivity, conditional knockout mice and control mice (n = 5-8/group) were conditioned for place preference with cocaine (5 and 10 mg/kg SC) for 3 days. Their subsequent place preference was examined in a drug-free state.

Results: Although control mice developed cocaine conditioned place preference, mice deficient for NMDAR on striatal neurons failed to develop conditioned place preference.

Conclusions: The NMDAR on striatal neurons is essential for the development of cocaine cue reactivity in the place conditioning paradigm. Our finding identifies a brain region whose constitutive NMDAR level serves as a determinant for susceptibility to this aspect of cocaine addiction.

Figure 1

Cocaine CPP in conditional NMDAR KO mice. A) Pre-conditioning test. B) Post-conditioning test. *P < 0.0125 and ** P < 0.0025 cocaine- versus saline-paired compartments, as determined by one-way ANOVAs with Bonferroni correction. C, Control; KO, knockout littermates. WT, 5 mg/kg: n = 6, 10 mg/kg: n = 5; KO, 5 mg/kg: n = 8, 10 mg/kg: n = 8.