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The Journal of Neuroscience, July 13, 2005, 25(28):6651-6657; doi:10.1523/JNEUROSCI.1474-05.2005

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Behavioral/Systems/Cognitive
Expression of Mutant NMDA Receptors in Dopamine D₁ Receptor-Containing Cells Prevents Cocaine Sensitization and Decreases Cocaine Preference

Carrie L. Heusner¹ and Richard D. Palmiter^1,2

¹Department of Biochemistry and ²Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195

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.

Key words: dopamine; NMDA receptor; conditioned place preference; cocaine; sensitization; transgenic

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Received April 14, 2005; revised June 3, 2005; accepted June 10, 2005.

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