Walter Francesconi1,2, Attila Szücs3,4, Fulvia Berton2,5, George F Koob6,7, Leandro F Vendruscolo6,8, Pietro Paolo Sanna9. 1. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA. 2. Department of Anatomy and Cell Biology, School of Medicine, University of Illinois at Chicago, Chicago, IL, USA. 3. BioCircuits Institute, University of California San Diego, La Jolla, CA, USA. 4. MTA-ELTE NAP-B Neuronal Cell Biology Group, Eötvös Lóránd University, Budapest, Hungary. 5. Dipartimento di Biologia, Universita' degli Studi di Pisa, Pisa, Italy. 6. Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA. 7. National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA. 8. National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA. 9. Department of Immunology and Microbiology and Department ofNeuroscience, The Scripps Research Institute, La Jolla, CA, USA. psanna@scripps.edu.
Abstract
RATIONALE: Drugs of abuse can alter circuit dynamics by modifying synaptic efficacy and/or the intrinsic membrane properties of neurons. The juxtacapsular subdivision of the bed nucleus of stria terminalis (jcBNST) has unique connectivity that positions it to integrate cortical and amygdala inputs and provide feed-forward inhibition to the central nucleus of the amygdala (CeA), among other regions. In this study, we investigated changes in the synaptic and intrinsic properties of neurons in the rat jcBNST during protracted withdrawal from morphine dependence using a combination of conventional electrophysiological methods and the dynamic clamp technique. RESULTS: A history of opiate dependence induced a form of cell type-specific plasticity characterized by reduced inward rectification associated with more depolarized resting membrane potentials and increased membrane resistance. This cell type also showed a lower rheobase when stimulated with direct current (DC) pulses as well as a decreased firing threshold under simulated synaptic bombardment with the dynamic clamp. Morphine dependence also decreased excitatory postsynaptic potential amplification, suggesting the downregulation of the persistent Na+ current (I NaP). CONCLUSION: These findings show that a history of morphine dependence leads to persistent cell type-specific plasticity of the passive membrane properties of a jcBNST neuronal population, leading to an overall increased excitability of such neurons. By altering the activity of extended amygdala circuits where they are embedded, changes in the integration properties of jcBNST neurons may contribute to emotional dysregulation associated with drug dependence and withdrawal.
RATIONALE: Drugs of abuse can alter circuit dynamics by modifying synaptic efficacy and/or the intrinsic membrane properties of neurons. The juxtacapsular subdivision of the bed nucleus of stria terminalis (jcBNST) has unique connectivity that positions it to integrate cortical and amygdala inputs and provide feed-forward inhibition to the central nucleus of the amygdala (CeA), among other regions. In this study, we investigated changes in the synaptic and intrinsic properties of neurons in the rat jcBNST during protracted withdrawal from morphine dependence using a combination of conventional electrophysiological methods and the dynamic clamp technique. RESULTS: A history of opiate dependence induced a form of cell type-specific plasticity characterized by reduced inward rectification associated with more depolarized resting membrane potentials and increased membrane resistance. This cell type also showed a lower rheobase when stimulated with direct current (DC) pulses as well as a decreased firing threshold under simulated synaptic bombardment with the dynamic clamp. Morphine dependence also decreased excitatory postsynaptic potential amplification, suggesting the downregulation of the persistent Na+ current (I NaP). CONCLUSION: These findings show that a history of morphine dependence leads to persistent cell type-specific plasticity of the passive membrane properties of a jcBNST neuronal population, leading to an overall increased excitability of such neurons. By altering the activity of extended amygdala circuits where they are embedded, changes in the integration properties of jcBNST neurons may contribute to emotional dysregulation associated with drug dependence and withdrawal.
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