Elsevier

Biological Psychiatry

Volume 67, Issue 8, 15 April 2010, Pages 778-780
Biological Psychiatry

Brief Report
N-Methyl-D-Aspartic Acid Receptors on Striatal Neurons Are Essential for Cocaine Cue Reactivity in Mice

https://doi.org/10.1016/j.biopsych.2009.12.023Get rights and content

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.

Section snippets

Animals

Adult male conditional NMDAR KO (RGS9-cre/NR1flox/flox) and control (NR1flox/flox) mice were used in this study. These strains of mice have been used in a previous study (13). Mice were maintained under a 14-hour light/10-hour dark cycle with food and water available ad libitum. Animal handling and use procedures followed a protocol approved by the Animal Care and Use Committee of Albert Einstein College of Medicine, in accordance with National Institutes of Health guidelines.

Drugs

Cocaine

Results

Neither control nor KO mice showed a preconditioning bias to either compartment [Figure 1A; Genotype, F(1,25) = 1.79, NS; Compartment, F(1,25) = 1.65, NS; genotype × compartment, F(1,25) = .04, NS]. The CPP scores on the postconditioning test day showed a significant interaction between Genotype and Compartment [F(1,23) = 5.89, p = .024.]. Exploratory ANOVAs showed that CPP was abolished in KO mice [Dose, F(1,14) = 1.39, NS; Compartment, F(1,14) = .002, NS; dose × compartment, F(1,14) = .004,

Discussion

We assessed the role of NMDAR on striatal neurons in cue reactivity, an element of cocaine addiction, in the place conditioning paradigm. Our results show that mice deficient in NMDAR on striatal neurons failed to show cocaine CPP.

In the conditional KO mice, the excision of NMDAR was restricted by RGS9-dependent Cre expression (13). The RGS9 messenger RNA is expressed in striatal cholinergic interneurons, the striatal indirect pathway projecting to the external segment of the pallidum, and the

References (20)

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