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The Journal of Neuroscience, February 1, 2006, 26(5):1457-1464; doi:10.1523/JNEUROSCI.3786-05.2006

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Cellular/Molecular
The Dopamine D₃ Receptor Is Part of a Homeostatic Pathway Regulating Ethanol Consumption

Jerome Jeanblanc,¹ Dao-Yao He,¹ Nancy N. H. McGough,¹ Marian L. Logrip,^1,2 Khanhky Phamluong,¹ Patricia H. Janak,^1,2,3 and Dorit Ron^1,2,3

¹Ernest Gallo Research Center, ²Neuroscience Graduate Program, and ³Department of Neurology, University of California, San Francisco, Emeryville, California 94608

Correspondence should be addressed to either Dr. Dorit Ron or Dr. Patricia Janak, University of California, San Francisco, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: dorit{at}itsa.ucsf.edu pjanak{at}itsa.ucsf.edu

We recently identified a homeostatic pathway that inhibits ethanol intake. This protective pathway consists of the scaffolding protein RACK1 and brain-derived neurotrophic factor (BDNF). RACK1 translocates to the nucleus after exposure of neurons to ethanol and increases expression of BDNF (McGough et al., 2004). We also found that increasing the levels of BDNF via systemic administration of RACK1 expressed as a Tat-fusion protein (Tat–RACK1) reduces ethanol consumption, whereas reduction of BDNF levels augments this behavior (McGough et al., 2004). Based on these results, we hypothesized that activation of the BDNF receptor TrkB is necessary for the effects of BDNF on ethanol intake and that gene products downstream of BDNF negatively regulate ethanol consumption. Here, we show that inhibition of the BDNF receptor TrkB increases voluntary ethanol consumption in wild-type mice but not in mice lacking one copy of the BDNF gene (BDNF^+/–). We also find that increases in the levels of BDNF, mediated by ethanol or RACK1, lead to increased dorsal striatal levels of the dopamine D₃ receptor (D₃R), a gene downstream of BDNF, via activation of the TrkB receptor. Finally, we show that the Tat–RACK1-mediated reduction of ethanol consumption is attenuated by coinjection with either the Trk inhibitor K252a or the dopamine D₃R-prefering antagonist U-99194A [5, 6-dimethoxy-2-(di-n-propylamino)indan], suggesting that activation of the BDNF pathway via RACK1 leads to increased expression of the dopamine D₃R, which in turn mediates the attenuation of ethanol consumption.

Key words: RACK1; BDNF; dopamine; D₃ receptor; alcohol; addiction

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Received Sept. 7, 2005; revised Dec. 20, 2005; accepted Dec. 20, 2005.

Correspondence should be addressed to either Dr. Dorit Ron or Dr. Patricia Janak, University of California, San Francisco, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: dorit{at}itsa.ucsf.edu pjanak{at}itsa.ucsf.edu

This article has been cited by other articles:

				J. Jeanblanc, D.-Y. He, S. Carnicella, V. Kharazia, P. H. Janak, and D. Ron Endogenous BDNF in the Dorsolateral Striatum Gates Alcohol Drinking J. Neurosci., October 28, 2009; 29(43): 13494 - 13502. [Abstract] [Full Text] [PDF]

				M. L. Logrip, P. H. Janak, and D. Ron Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake FASEB J, July 1, 2008; 22(7): 2393 - 2404. [Abstract] [Full Text] [PDF]

				S. C. Pandey, H. Zhang, R. Ugale, A. Prakash, T. Xu, and K. Misra Effector Immediate-Early Gene Arc in the Amygdala Plays a Critical Role in Alcoholism J. Neurosci., March 5, 2008; 28(10): 2589 - 2600. [Abstract] [Full Text] [PDF]

				T. Flatscher-Bader, N. Zuvela, N. Landis, and P.A. Wilce Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area Hum. Mol. Genet., January 1, 2008; 17(1): 38 - 51. [Abstract] [Full Text] [PDF]

				J. Wang, S. Carnicella, K. Phamluong, J. Jeanblanc, J. A. Ronesi, N. Chaudhri, P. H. Janak, D. M. Lovinger, and D. Ron Ethanol Induces Long-Term Facilitation of NR2B-NMDA Receptor Activity in the Dorsal Striatum: Implications for Alcohol Drinking Behavior J. Neurosci., March 28, 2007; 27(13): 3593 - 3602. [Abstract] [Full Text] [PDF]

				V. Vengeliene, F. Leonardi-Essmann, S. Perreau-Lenz, P. Gebicke-Haerter, K. Drescher, G. Gross, and R. Spanagel The dopamine D3 receptor plays an essential role in alcohol-seeking and relapse FASEB J, November 1, 2006; 20(13): 2223 - 2233. [Abstract] [Full Text] [PDF]

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