Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Department of Neurobiology; Department of Physiology; Martin Lab; Treistman Lab
Neuroscience and Neurobiology
Tolerance is an important element of drug addiction and provides a model for understanding neuronal plasticity. The hypothalamic-neurohypophysial system (HNS) is an established preparation in which to study the actions of alcohol. Acute application of alcohol to the rat neurohypophysis potentiates large-conductance calcium-sensitive potassium channels (BK), contributing to inhibition of hormone secretion. A cultured HNS explant from adult rat was used to explore the molecular mechanisms of BK tolerance after prolonged alcohol exposure. Ethanol tolerance was intrinsic to the HNS and consisted of: (1) decreased BK potentiation by ethanol, complete within 12 min of exposure, and (2) decreased current density, which was not complete until 24 hr after exposure, indicating that the two components of tolerance represent distinct processes. Single-channel properties were not affected by chronic exposure, suggesting that decreased current density resulted from downregulation of functional channels in the membrane. Indeed, we observed decreased immunolabeling against the BK alpha-subunit on the surface of tolerant terminals. Analysis using confocal microscopy revealed a reduction of BK channel clustering, likely associated with the internalization of the channel.
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Publisher PDF posted after 6 months as allowed by the publisher's author rights policy at http://www.jneurosci.org/sites/default/files/files/JN_License_to_Publish.pdf.
DOI of Published Version
J Neurosci. 2004 Sep 22;24(38):8322-32. Link to article on publisher's site
The Journal of neuroscience : the official journal of the Society for Neuroscience
Pietrzykowski, Andrzej Z.; Martin, Gilles E.; Puig, Sylvie I.; Knott, Thomas K.; Lemos, Jose R.; and Treistman, Steven N., "Alcohol tolerance in large-conductance, calcium-activated potassium channels of CNS terminals is intrinsic and includes two components: decreased ethanol potentiation and decreased channel density" (2004). GSBS Student Publications. 987.