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The Journal of Neuroscience, June 8, 2005, 25(23):5553-5562; doi:10.1523/JNEUROSCI.0345-05.2005

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Development/Plasticity/Repair
Regulation of Drug Reward by cAMP Response Element-Binding Protein: Evidence for Two Functionally Distinct Subregions of the Ventral Tegmental Area

Valerie G. Olson,¹ Cyrus P. Zabetian,^1,2 Carlos A. Bolanos,¹ Scott Edwards,¹ Michel Barrot,¹ Amelia J. Eisch,¹ Thomas Hughes,³ David W. Self,¹ Rachael L. Neve,⁴ and Eric J. Nestler¹

¹Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, ²Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516, ³Department of Ophthalmology, Yale University School of Medicine, New Haven, Connecticut 06510, and ⁴Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, Massachusetts 02478

The transcription factor cAMP response element binding protein (CREB) is implicated in the actions of drugs of abuse in several brain areas, but little information is available about a role for CREB in the ventral tegmental area (VTA), one of the key reward regions of the brain. Here, we demonstrate that chronic exposure to drugs of abuse induces CREB activity throughout the VTA. Using viral-mediated gene transfer, we expressed green fluorescent protein (GFP)-tagged CREB or mCREB (a dominant-negative form of CREB) in the VTA and, using a conditioned place-preference paradigm, found that CREB activation within the rostral versus caudal subregions of the VTA produces opposite effects on drug reward. We identified VTA subregion-specific differences in the proportion of dopaminergic and GABAergic neurons and in the dopaminergic projections to the nucleus accumbens, another brain region implicated in drug reward, and suggest that this may contribute to behavioral differences in this study. We also measured expression levels of tyrosine hydroxylase and the AMPA glutamate receptor subunit GluR1, both of which are known to contribute to drug reward in the VTA, and found that both of these genes are upregulated following the expression of CREB-GFP and downregulated following expression of mCREB-GFP, raising the possibility that CREB may exert its effects on drug reward, in part, via regulation of these genes. These results suggest a novel role for CREB in mediating drug-induced plasticity in the VTA and establish two functionally distinct subregions of the VTA in which CREB differentially regulates drug reward.

Key words: cocaine; reward; ventral tegmental area; CREB; mesocortical; mesolimbic; morphine

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Received April 1, 2004; revised April 15, 2005; accepted April 17, 2005.

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