Elucidation of the mechanisms which underlie the development of tolerance to ethanol has been difficult because, in general, studies have monitored anatomical or physiological phenomena which could only be loosely tied to behavioral consequences, or measured tolerance of a behavior for which the underlying molecular machinery is not well-understood, or not amendable to analysis. The proposed research analyzes acute ethanol reduction of vasopressin and oxytocin release from the rat posterior pituitary maintained in ethanol-containing organotypic culture, or removed from rats on an ethanol-containing diet. The overall strategy is to correlate the development of tolerance to ethanol-induced reduction of peptide hormone release with underlying changes in electrophysiological parameters of channel function. Previous work has described biophysical mechanisms of acute ethanol action on membrane ion channels critical for release, and recently, we have developed an animal model for the development of tolerance to acute inhibition of release, conditions for the organotypic culture of the hypothalamo-neurohypophysial system (HNS), and isolation and recording parameters for the hypothalamic cell bodies from which the pituitary terminals originate. Thus, we are able to test a number of hypotheses: 1) the channels which are targets of acute ethanol action are modified in response to chronic drug exposure; 2) cellular domains differ in their contribution to drug tolerance, just as they differ in their response to acute drug action; 3) gating parameters of channel function, the parameter affected by chronic exposure; 4) acute tolerance, thought to play a significant role in the development of alcoholism, is affected by chronic drug exposure; 5) The development of long-term tolerance requires that the cell body (the site of transcription, and most likely, translation) be exposed to chronic ethanol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA008003-17
Application #
6731998
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Twombly, Dennis
Project Start
1989-01-01
Project End
2005-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
17
Fiscal Year
2004
Total Cost
$351,000
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pharmacology
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
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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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