University of Kentucky, USA
Title: Preclinical studies of glucocorticoid receptor antagonists in the treatment of alcohol dependence
Lynda Sharrett-Field received her Bachelor of Science degree in Psychology from the University of Southern Indiana in 2008. She completed Master of Science degree in Experimental Psychology with expertise in behavioral neuroscience in 2010 and a Doctor of Philosophy degree in this discipline in 2013. She has extensive expertise in biochemical, surgical and behavioral approaches in the study of alcohol addiction and its treatment. Her publications reflect a focus on understanding how glucocorticoid hormone receptor systems are altered by alcohol exposure, employing both in vitro and in vivo models, and how these systems may be pharmacologically exploited in the treatment of alcohol dependence.
Glucocorticoid levels are markedly altered by acute and prolonged exposure to intoxicating doses of ethanol, yet the behavioral significance of these alterations are not fully understood. Prior work has shown that ethanol withdrawal associated cognitive deficits in mice can be reduced by acute administration of a glucocorticoid receptor (GR) antagonist and we have also shown that chronic ethanol consumption increases the brain concentrations of corticosterone in rodents. Our in vitro work has shown that corticosterone increases alcohol withdrawal neurotoxicity and calcium accumulation in hippocampal neurons. Our current work focuses on the ability ofglucocorticoid antagonist drugs to reduce the behavioural consequences of alcohol withdrawal. Administration of one dose of the Type 2 GR antagonist, mifepristone, immediately after alcohol withdrawal, prevented the subsequent memory deficits in mice and significantly lowered withdrawal signs. Repeated doses of this drug, given torats during a 4-day binge alcohol treatment, substantially reduced the acute signs of alcohol withdrawal. We have also studied the effects of the mifepristone analogue, ORG34517 that is more selective and lacks progesterone antagonist action. This compound significantly reduced acute withdrawal signs in rats and memory deficits inmice when given prior to withdrawal from chronic alcohol treatment. As a whole, these findings suggest that GR may represent therapeutic targets to be exploited in the treatment of ethanol dependence.
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