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Volume 21, Number 2, September 2010

It’s the “where’s the beef” question that most animal researchers have heard at least once after describing their findings to a new audience: “Yes, that’s very interesting. But what do your findings mean for humans?” Establishing what scientists call the “translational relevance” of basic science research-that is, its implications for clinical practice-is sometimes challenging. Establishing the translational relevance of basic science research is particularly important in studies of alcohol and alcoholism, where the need for treatments is great and scientists and lay people alike look to animal research to provide clues to potentially useful thera-peutic approaches.

Dr. A. Leslie Morrow, Professor of Psychiatry and Pharmacology and Associate Director of the Bowles Center for Alcohol Studies at UNC, has pioneered studies of an important class of neuromodulators known as neuroactive steroids in alcohol actions. She is also a pioneer in establishing the relevance of neuroactive steroids to the clinic. Produced by various glands and organs including the adrenals and brain, neuroactive steroids modulate the function of the brain’s major inhibitory neurotransmitter, GABA. In experiments spanning more than a decade, the Morrow laboratory has demonstrated that neuroactive steroids are key contributors to alcohol sensitivity, which in humans predicts risk of alcoholism. Morrow and her colleagues demonstrated that administering moderate doses of alcohol in animal models increases concentrations of neuroactive steroids in both the bloodstream and the brain in an amount capable of altering GABAergic functioning. The lab also showed that acute administration of alcohol markedly increases concentrations of specific neuroactive steroids in the bloodstream and in brain areas important in mediating the cognitive and motor effects of alcohol. The increase in neuroactive steroid levels, which is caused by an increase in synthesis of neuroactive steroids by glands such as the adrenals, enhances GABAergic neurotransmission. Blocking the effect of alcohol on neuroactive steroid levels through manipulations such as adrenalectomy or administration of the neuroactive steroid synthesis inhibitor finasteride mitigates a range of alcohol effects, including its relaxing, antidepressant, sedating, and cognitive-impairing properties-findings suggesting that these alcohol effects are at least in part mediated by neuroactive steroids.

Morrow Lab (left to right): Nikki Leonard, Alex Fetzer, Lihan Deng, Ana Maria Dumitru, Todd O’Buckley, Smita Gupta, A. Leslie Morrow, Ph.D., Chandler Walker, Jason Cook, and Patrizia Porcu, Ph.D.

Neuroactive steroids can be synthesized by multiple glands and organs including the adrenals, brain, testes, and ovaries. Morrow demonstrated the particular importance of the adrenals in alcohol enhancement of neuroactive steroids in the bloodstream and the brain by showing that such enhancement does not occur in adrenalectomized animals. In some of their most recent animal work, published in 2010, Morrow’s group established the molecular mechanisms that underlie alcohol enhancement of neuroactive steroid synthesis in the adrenals. They found that release of the adrenocorticotrophic hormone (ACTH) and de novo synthesis of a specific cholesterol transporter known as StAR in the adrenals are both required in order for alcohol to increase levels of neuroactive steroids. In an elegant series of experiments, they demonstrated that ethanol increases both ACTH release and StAR synthesis and that these effects are independent of one another. Further, both ACTH release and StAR synthesis are necessary, but not sufficient, for the occurrence of alcohol-induced elevation of neuroactive steroids in the bloodstream and brain. ACTH is released by the pituitary gland to modulate adrenal gland functioning in response to stress and other stimuli. The results suggest that alcohol-associated increases in neuroactive steroids are caused by stimulation of the hypothalamic-pituitary-adrenal (HPA) axis, the body’s main system for responding to stress.

Chronic exposure to alcohol results in tolerance to its ability to increase neuroactive steroid levels as well as to neuroactive steroid-mediated behavioral effects of alcohol such as relaxation and sedation. In another 2010 publication, Morrow and her colleagues pinpointed the mechanisms of tolerance to alcohol-induced increases in neuroactive steroids as the disruption of ACTH release and StAR phosphorylation. The lab has thus elucidated mechanisms for loss of alcohol-induced increases in neuroactive steroids, a phenomenon that might contribute to behavioral tolerance to alcohol and influence the progression to alcoholism.

Considered in aggregate, the large body of evidence amassed by the Morrow lab through animal studies suggests that alcohol-induced elevation of neuroactive steroids is an important mediator of sensitivity to alcohol. The loss of alcohol-induced responsiveness of neuroactive steroids with chronic alcohol consumption might promote excessive alcohol intake to achieve alcohol’s desired effects. Morrow is now using the evidentiary foundation from her animal research on the mechanisms and roles of neuroactive steroids to guide exciting translational work on neuroactive steroids in humans.

For example, Morrow and colleague Patrizia Porcu, Ph.D., also at UNC Bowles Center for Alcohol Studies, have paved the way for investigations of the potential role of neuroactive steroid responses as a biomarker for alcoholism risk. Consistent with the idea that loss of alcohol-induced responsiveness of neuroactive steroids with chronic alcohol consumption might promote excessive alcohol consumption to achieve alcohol’s desired effects, Morrow postulates that blunted neuroactive steroid responses to physiological and/or pharmacological challenge might predict risk for alcohol abuse and alcoholism. In order to test this hypothesis, it is necessary to measure neuroactive steroids in humans. Until recently, the specific neuroactive steroids of interest could not be measured in humans with available methods. Porcu and Morrow developed a state-of-the-art method for efficient, specific, and sensitive measurement of the relevant neuroactive steroids in human serum. This method promises to have widespread utility in investigating the role of neuroactive steroids in human health and disease and in discovering biomarkers and developing therapeutic agents for alcoholism and other disorders.

The feasibility of using neuroactive steroid responses as biomarkers is illu-strated by Morrow and UNC colleague Dr. Susan Girdler’s recent findings in depression. In a study of 28 women, those in clinical remission from depression had lower concentrations of specific neuroactive steroids in their bloodstream both before and after being administered the steroid progesterone than did women without a history of depression. These results show that abnormalities in neuroactive steroid levels and responses can be indicators of a clinical condition and suggest that a history of clinical depression is associated with persistent neuroactive steroid deficits.

In another line of research, Morrow recently collaborated with UCLA investigators to shed light on the potential role of neuroactive steroids in the mechanism of action of naltrexone, a drug currently in clinical use for treatment of alcoholism. Naltrexone is effective in reducing alcohol craving and drinking and in mitigating the rewarding effects of alcohol, but the mechanisms by which naltrexone effects these changes have not been well characterized. Knowing that an irregularity in a gene known as OPRM1 is associated with enhanced therapeutic effects of naltrexone and that naltrexone disinhibits the HPA axis, Morrow postulated that naltrexone might selectively elevate neuroactive steroid concentrations in drinkers with the OPRM1 irregularity. Among 32 heavy drinkers, naltrexone compared with an inactive placebo increased neuroactive steroid concentrations in those with the OPRM1 irregularity but not among those without it. These results are consistent with a role of neuroactive steroids in the clinical efficacy of naltrexone.

Morrow believes that treatment with neuroactive steroids themselves might be therapeutic in alcoholism and could be helpful in alleviating symptoms of alcohol withdrawal. She is actively seeking collaborators to test potential therapeutic effects of neuroactive steroids and their precursors in human alcoholism. “Our animal research and now our research in humans have yielded numerous findings suggesting that neuroactive steroids could be useful in the treatment of alcoholism,” says Morrow. “Neuroactive steroids increase alcohol sensitivity; they reduce heavy alcohol consumption in animal models of alcoholism; they reduce withdrawal symptoms; they mitigate neuroinflammation-I could go on and on. Converging lines of evidence suggest that the therapeutic potential is there. But we won’t know whether neuroactive steroids are really helpful in alcoholism until we test them in human alcoholics. That’s where we want to go next.” Morrow points to the success of a proof-of-concept trial that showed the potential therapeutic utility of a neuroactive steroid for cognitive symptoms in schizophrenia, noting the presence of cognitive deficits in alcoholism as well. “Where’s the beef? Here’s the beef,” says Morrow. “This is what it’s all about: using our basic science findings to provide rational, evidence-based direction for interventions that help people.”