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The Journal of Neuroscience, December 17, 2008, 28(51):13856-13865; doi:10.1523/JNEUROSCI.4715-08.2008

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Behavioral/Systems/Cognitive
Dopamine Enhances Fast Excitatory Synaptic Transmission in the Extended Amygdala by a CRF-R1-Dependent Process

Thomas L. Kash,^1 * William P. Nobis,^2 * Robert T. Matthews,^1,3 and Danny G. Winder^1,2,3

¹Department of Molecular Physiology and Biophysics, ²Center for Molecular Neuroscience, and ³Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615

Correspondence should be addressed to Dr. Danny G. Winder, Department of Molecular Physiology and Biophysics, 23rd and Pierce Avenue South, Room 754, RRB, Vanderbilt University School of Medicine, Nashville, TN 37232-0615. Email: danny.winder{at}vanderbilt.edu

A common feature of drugs of abuse is their ability to increase extracellular dopamine levels in key brain circuits. The actions of dopamine within these circuits are thought to be important in reward and addiction-related behaviors. Current theories of addiction also posit a central role for corticotrophin-releasing factor (CRF) and an interaction between CRF and monoaminergic signaling. One region where drugs of abuse promote robust rises in extracellular dopamine levels is the bed nucleus of the stria terminalis (BNST), a CRF-rich component of the extended amygdala. We find that dopamine rapidly enhances glutamatergic transmission in the BNST through activation of a combination of D₁- and D₂-like receptors. This enhancement is activity-dependent and requires the downstream action of CRF receptor 1 (CRF-R1), suggesting that dopamine induces CRF release through a local network mechanism. Furthermore, we found that both in vivo and ex vivo cocaine induced a dopamine receptor and CRF-R1-dependent enhancement of a form of NMDA receptor-dependent short-term potentiation in the BNST. These data highlight a direct and rapid interaction between dopamine and CRF systems that regulates excitatory transmission and plasticity in a brain region key to reinforcement and reinstatement. Because a rise in extracellular dopamine levels in the BNST is a shared consequence of multiple classes of drugs of abuse, this suggests that the CRF-R1-dependent enhancement of glutamatergic transmission in this region may be a common key feature of substances of abuse.

Key words: addiction; cocaine; glutamate; plasticity; neuropeptide; synaptic plasticity

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Received Oct. 1, 2008; revised Nov. 10, 2008; accepted Nov. 11, 2008.

Correspondence should be addressed to Dr. Danny G. Winder, Department of Molecular Physiology and Biophysics, 23rd and Pierce Avenue South, Room 754, RRB, Vanderbilt University School of Medicine, Nashville, TN 37232-0615. Email: danny.winder{at}vanderbilt.edu

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