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The Journal of Neuroscience, April 29, 2009, 29(17):5389-5401; doi:10.1523/JNEUROSCI.5129-08.2009

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Behavioral/Systems/Cognitive
Protracted Withdrawal from Alcohol and Drugs of Abuse Impairs Long-Term Potentiation of Intrinsic Excitability in the Juxtacapsular Bed Nucleus of the Stria Terminalis

Walter Francesconi,^1,5 Fulvia Berton,¹ Vez Repunte-Canonigo,¹ Kazuki Hagihara,¹ David Thurbon,¹ Dusan Lekic,¹ Sheila E. Specio,² Thomas N. Greenwell,² Scott A. Chen,² Kenner C. Rice,³ Heather N. Richardson,² Laura E. O'Dell,² Eric P. Zorrilla,² Marisela Morales,⁴ George F. Koob,² and Pietro Paolo Sanna¹

¹Molecular and Integrative Neurosciences Department and ²Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, ³National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, ⁴Laboratory of Cellular Neurophysiology, National Institutes on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, and ⁵Department of Biology, University of Pisa, 56126 Pisa, Italy

Correspondence should be addressed to either Walter Francesconi or Pietro Paolo Sanna, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, Email: wfranc{at}scripps.edu or Email: psanna{at}scripps.edu

The juxtacapsular bed nucleus of the stria terminalis (jcBNST) is activated in response to basolateral amygdala (BLA) inputs through the stria terminalis and projects back to the anterior BLA and to the central nucleus of the amygdala. Here we show a form of long-term potentiation of the intrinsic excitability (LTP-IE) of jcBNST neurons in response to high-frequency stimulation of the stria terminalis. This LTP-IE, which was characterized by a decrease in the firing threshold and increased temporal fidelity of firing, was impaired during protracted withdrawal from self-administration of alcohol, cocaine, and heroin. Such impairment was graded and was more pronounced in rats that self-administered amounts of the drugs sufficient to maintain dependence. Dysregulation of the corticotropin-releasing factor (CRF) system has been implicated in manifestation of protracted withdrawal from dependent drug use. Administration of the selective corticotropin-releasing factor receptor 1 (CRF₁) antagonist R121919 [2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine)], but not of the CRF₂ antagonist astressin₂-B, normalized jcBNST LTP-IE in animals with a history of alcohol dependence; repeated, but not acute, administration of CRF itself produced a decreased jcBNST LTP-IE. Thus, changes in the intrinsic properties of jcBNST neurons mediated by chronic activation of the CRF system may contribute to the persistent emotional dysregulation associated with protracted withdrawal.

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Received Oct. 22, 2008; revised Jan. 26, 2009; accepted Jan. 27, 2009.

Correspondence should be addressed to either Walter Francesconi or Pietro Paolo Sanna, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, Email: wfranc{at}scripps.edu or Email: psanna{at}scripps.edu

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