Expression of mutant NMDA receptors in dopamine D1 receptor-containing cells prevents cocaine sensitization and decreases cocaine preference - PubMed (original) (raw)

Comparative Study

Expression of mutant NMDA receptors in dopamine D1 receptor-containing cells prevents cocaine sensitization and decreases cocaine preference

Carrie L Heusner et al. J Neurosci. 2005.

Abstract

The interaction of dopamine and glutamate in limbic brain regions mediates behaviors associated with psychostimulants, which act in part to increase dopamine signaling at both D1 receptors (D1Rs) and D2 receptors. Many addictive behaviors are a result of learned associations, and NMDA receptor activation has been shown to be important for these behaviors. We hypothesized that if NMDA receptor activation in dopamine receptor-containing cells is required for the addictive properties of psychostimulants, then mice with reduced NMDA receptor activity in D1R-containing cells would have attenuated long-term behavioral changes to these drugs. We generated a mouse line in which D1R-containing cells express an NR1 NMDA receptor subunit containing a mutation in the pore that reduces calcium flux. Mice expressing the mutant NMDA receptors in D1R-containing cells have normal basal activity and display similar increases in locomotor activity when treated with acute amphetamine or cocaine. However, the mutant mice fail to display locomotor sensitization to repeated cocaine administration. In addition, these mice also have a decreased ability to form a conditioned place preference to cocaine. These data suggest that intact NMDA receptor signaling in D1R-containing cells is required for the manifestation of behaviors associated with repeated drug exposure.

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Figures

Figure 1.

Figure 1.

Generation of D1R-NR1m mice. A, Targeting strategy for D1R-NR1m mice showing endogenous Drd1a locus (top) targeting vector containing NR1 cDNA (middle) and recombined Drd1a locus (bottom).Primers for genotyping the wild-type allele (a and c) and the targeted allele (a and b) are indicated.B, Southern blot on DNA from wild-type and mutant mouse. Genomic DNA was digested with _Hin_dIII and hybridized with a probe from the Drd1a locus located immediately 5′ to the targeting vector. C, RT-PCR using PCR primers that flank the HA tag. Positive control is a plasmid containing the targeting vector, and the negative control is a plasmid containing the NR1 cDNA without the HA tag.

Figure 2.

Figure 2.

Expression of HA-tagged NR1. A, Expression of HA-tagged NR1 in a the dorsal striatum of a D1R-NR1m mouse. B, Dorsal striatum of a wild-type mouse with no HA-positive staining in neuronal processes.

Figure 3.

Figure 3.

Locomotor activity in wild-type and D1-NR1m mice. A, Ambulations during 3 h in a novel environment, measured in 15 min increments. B, Ambulations for 2 d by both wild-type (n = 8) and D1R-NR1m (n = 8) mice measured in 12 h increments. Error bars represent SEM.

Figure 4.

Figure 4.

Acute responses to amphetamine and cocaine. A, Ambulations in response to vehicle or amphetamine by both wild-type (n = 16) and D1R-NR1m (n = 16) mice. B, Ambulations in response to vehicle or cocaine by wild-type (n = 14) or D1R-NR1m (n = 14) mice. *p < 0.05; **p < 0.01; ***p < 0.005 compared with vehicle dose for that genotype; two-way ANOVA; Fisher's post hoc test. Error bars represent SEM.

Figure 5.

Figure 5.

Sensitization to cocaine. Locomotor response to vehicle (day 0) and repeat injection with cocaine (20 mg/kg) (days 1-5) measured for 2.5 h. **p < 0.01; ***p < 0.005 compared with day 1 of the corresponding genotype; two-way ANOVA; Fisher's post hoc test (wild type, n = 12; D1R-NR1m, n = 13). Error bars represent SEM.

Figure 6.

Figure 6.

Place conditioning for cocaine. A, Percentage of time spent on drug-paired side before pairing sessions (pretest) and after 3 d of pairing (posttest) for 20 mg/kg cocaine. *p < 0.05; paired t test (wild type, n = 12; D1R-NR1m, n = 12). B, Percentage of time spent on drug-paired side both pretest and posttest after pairings with 30 mg/kg cocaine. **p < 0.01; ***p < 0.005; paired t test (wild type, n = 9; D1R-NR1m, n = 10). Error bars represent SEM.

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