Tolerance is an important component of alcohol abuse and alcoholism. We have been using magnocellular neurons from the hypothalamic-neurohypophysial system (HNS) to further our understanding of the acute and chronic actions of alcohol. One of the major advantages of this system is the physical separation of cell bodies in the supraoptic nucleus of the hypothalamus and accessible nerve terminals in the neurohypophysis. This unique property has allowed us to determine that ion channels in the two subcellular compartments differ significantly in their response to alcohol. The work proposed will build on findings that two components of potassium channel tolerance (decreased sensitivity and altered channel density) are present in the terminal, are intrinsic, and demonstrate different kinetics. We will capitalize on the special features of our recently developed HNS explant culture, which allows the independent examination of terminal and cell body compartments, and lends itself to finely-tuned drug exposure protocols and electrophysiological readout of channel function. We now propose to: 1) complete a characterization of tolerance in a functionally coupled Ca channel-potassium channel dyad, allowing a description of this important process in the nerve terminal, compared with the more typically studied cell body, 2) examine the independent capabilities and interdependencies of the somatic and terminal compartments for tolerance development, and 3) test the hypothesis that there are temporally-triggered switches tripped by drug exposure, that are associated with development of channel tolerance in cell bodies and terminals of the HNS. Our findings will provide a cellular model that will illuminate studies of tolerance at the behavioral level, and potentially contribute to effective treatments for alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA008003-20
Application #
7218042
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Twombly, Dennis
Project Start
1989-01-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
20
Fiscal Year
2007
Total Cost
$346,679
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Velázquez-Marrero, Cristina; Ortiz-Miranda, Sonia; Marrero, Héctor G et al. (2014) ?-Opioid inhibition of Ca2+ currents and secretion in isolated terminals of the neurohypophysis occurs via ryanodine-sensitive Ca2+ stores. J Neurosci 34:3733-42
Pietrzykowski, Andrzej Z; Ortiz-Miranda, Sonia; Knott, Thomas K et al. (2013) Molecular tolerance of voltage-gated calcium channels is evident after short exposures to alcohol in vasopressin-releasing nerve terminals. Alcohol Clin Exp Res 37:933-40
Velázquez-Marrero, Cristina; Wynne, Patricia; Bernardo, Alexandra et al. (2011) The relationship between duration of initial alcohol exposure and persistence of molecular tolerance is markedly nonlinear. J Neurosci 31:2436-46
Ortiz-Miranda, Sonia I; Dayanithi, Govindan; Velázquez-Marrero, Cristina et al. (2010) Differential modulation of N-type calcium channels by micro-opioid receptors in oxytocinergic versus vasopressinergic neurohypophysial terminals. J Cell Physiol 225:276-88
Feinberg-Zadek, Paula L; Martin, Gilles; Treistman, Steven N (2008) BK channel subunit composition modulates molecular tolerance to ethanol. Alcohol Clin Exp Res 32:1207-16
Martin, Gilles E; Hendrickson, Linzy M; Penta, Krista L et al. (2008) Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol. Proc Natl Acad Sci U S A 105:17543-8
Pietrzykowski, Andrzej Z; Friesen, Ryan M; Martin, Gilles E et al. (2008) Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol. Neuron 59:274-87
Luo, Feng; Li, Zhixin; Treistman, Steven N et al. (2007) Confounding effects of volatile anesthesia on CBV assessment in rodent forebrain following ethanol challenge. J Magn Reson Imaging 26:557-63
Roberto, Marisa; Treistman, Steven N; Pietrzykowski, Andrzej Z et al. (2006) Actions of acute and chronic ethanol on presynaptic terminals. Alcohol Clin Exp Res 30:222-32
Ortiz-Miranda, S; Dayanithi, G; Custer, E et al. (2005) Micro-opioid receptor preferentially inhibits oxytocin release from neurohypophysial terminals by blocking R-type Ca2+ channels. J Neuroendocrinol 17:583-90

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