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The Journal of Neuroscience, May 20, 2009, 29(20):6535-6544; doi:10.1523/JNEUROSCI.4773-08.2009

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Cellular/Molecular
Chronic Cocaine Enhances Corticotropin-Releasing Factor-Dependent Potentiation of Excitatory Transmission in Ventral Tegmental Area Dopamine Neurons

Junghyun Hahn,² F. Woodward Hopf,^1,2 and Antonello Bonci^1,2

¹Department of Neurology, University of California, San Francisco, San Francisco, California 94143, and ²Ernest Gallo Clinic and Research Center, Emeryville, California 94608

Correspondence should be addressed to Antonello Bonci, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: antonello.bonci{at}ucsf.edu

Current concepts suggest that stress-induced release of neuromodulators such as corticotropin-releasing factor (CRF) can drive drug-dependent behaviors. Although previous drug exposure can enhance behavioral and neurochemical responses to stress, it is unclear how such drug exposure alters the CRF modulation of excitatory synapses onto ventral tegmental area (VTA) dopamine neurons, a key locus of drug- and stress-induced neuroadaptation. Here, we demonstrate that, after repeated cocaine exposure, the magnitude and duration of the CRF-induced potentiation of NMDA receptor (NMDAR)-mediated neurotransmission was significantly increased compared with naive and saline-treated mice. Furthermore, CRF enhanced AMPA receptor (AMPAR)-mediated transmission only in mice that were exposed to cocaine. Increased frequency of AMPAR-mediated spontaneous miniature EPSCs and the intracellular blockade of CRF potentiation of AMPAR-mediated transmission suggest both presynaptic and postsynaptic effects of CRF. Importantly, pharmacological experiments revealed that CRF receptor 1 and protein kinase A pathways were newly recruited after repeated cocaine for the enhancement of CRF-induced NMDAR potentiation and the appearance of AMPAR potentiation. Thus, enhanced CRF-induced potentiation of excitatory synaptic transmission onto VTA dopamine neurons after cocaine preexposure is likely to produce an abnormal increase in dopamine release during stressful events and could augment activation of addictive behaviors in response to stress.

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Received Oct. 3, 2008; revised March 30, 2009; accepted April 9, 2009.

Correspondence should be addressed to Antonello Bonci, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: antonello.bonci{at}ucsf.edu

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