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DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens

Nature Neuroscience volume 5, pages 641–648 (2002)Cite this article

Abstract

The medium spiny neurons of the nucleus accumbens receive both an excitatory glutamatergic input from forebrain and a dopaminergic input from the ventral tegmental area. This integration point may constitute a locus whereby the N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors promotes drug reinforcement. Here we investigate how dopaminergic inputs alter the ethanol sensitivity of NMDA receptors in rats and mice and report that previous dopamine receptor-1 (D1) activation, culminating in dopamine and cAMP-regulated phosphoprotein-32 kD (DARPP-32) and NMDA receptor subunit-1 (NR1)-NMDA receptor phosphorylation, strongly decreases ethanol inhibition of NMDA responses. The regulation of ethanol sensitivity of NMDA receptors by D1 receptors was absent in DARPP-32 knockout mice. We propose that DARPP-32 mediated blunting of the response to ethanol subsequent to activation of ventral tegmental area dopaminergic neurons initiates molecular alterations that influence synaptic plasticity in this circuit, thereby promoting the development of ethanol reinforcement.

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Figure 1: Patch clamp analysis reveals D1 receptor modulation of the EtOH sensitivity of accumbal-medium spiny NMDA synaptic currents.
Figure 2: D1 receptors activate a protein kinase A–dependent process that regulates NMDA receptor sensitivity to ethanol in the nucleus accumbens.
Figure 3: Phosphorylation of DARPP-32 and NMDA receptors coincides with the time course of diminished ethanol sensitivity.
Figure 4: Ethanol directly increases DARPP-32 phosphorylation in nucleus accumbens.
Figure 5: Mice lacking DARPP-32 are insensitive to D1 receptor modulation of ethanol sensitivity of NMDA receptors.

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Acknowledgements

This work was supported primarily by NIH R01AA11845 (R.A.M.) and the Integrative Neuroscience Initiative on Alcoholism (INIA, NIH U01AA13CR (R.E.M.)), the Texas Commission on Alcoholism and Drug Abuse (TCADA) and the Waggoner Center on Alcoholism and Addiction Research (WCAAR) (R.A.M.). Additional support was from NIH R01AA11852 (R.A.G.) and R01AA11836 (S.W.L.) and T32AA07471 (K.F-K.). The authors thank R.A. Harris and A. Hendricson for suggestions and discussion, P. Greengard and P. Ingrassia for DARPP-32 antibodies and DARPP-32 modified mice, and A. Miao and M. Jia for technical support.

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Authors and Affiliations

  1. The Waggoner Center for Alcohol and Addiction Research, 2500 Speedway, The University of Texas at Austin, Austin, 78712-1074, Texas, USA

    R. E. Maldve, T. A. Zhang, S. S. Schreiber, M. J. Lippmann, S. W. Leslie, R. A. Gonzales & R. A. Morrisett

  2. The College of Pharmacy, The University of Texas at Austin, Austin, 78712-1074, Texas, USA

    R. E. Maldve, T. A. Zhang, K. Ferrani-Kile, S. S. Schreiber, M. J. Lippmann, S. W. Leslie, R. A. Gonzales & R. A. Morrisett

  3. The Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, 10021, New York, USA

    G. L. Snyder & A. A. Fienberg

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  1. R. E. Maldve
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Correspondence to R. A. Morrisett.

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Maldve, R., Zhang, T., Ferrani-Kile, K. et al. DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens. Nat Neurosci 5, 641–648 (2002). https://doi.org/10.1038/nn877

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