Can diabetes or lipid-lowering medications treat addiction?

Philadelphia, PA, 5 April, 2011 - Thiazolidinediones (TZDs) are a class of medications that are commonly prescribed to treat type-2 diabetes, while fibrates are a structurally-related class of medications that are prescribed to modulate lipid levels in both diabetic and non-diabetic patients to help reduce the risk of cardiovascular disease. These drugs work by binding to peroxisome proliferator-activated receptors (PPARs), with TZDs reducing insulin resistance and lowering the levels of cytokines that promote inflammation, and fibrates reducing low-density lipoprotein (LDL) and triglyceride levels and increasing high-density lipoprotein (HDL) levels to help prevent the development of cardiovascular disease. Another effect of TZDs and fibrates is to raise leptin levels, an effect that may reduce appetite. Recent studies also suggest that PPARs are expressed in the central nervous system, particularly in brain regions implicated in reward.

Two papers recently published in Biological Psychiatry now suggest that drugs that stimulate two different subclasses of PPARs, PPAR- and PPAR-, may play roles in the treatment of nicotine and alcohol addiction by acting in the brain.

The first study, by Mascia and colleagues, used a multi-pronged approach to demonstrate that nicotine's addictive effects can be counteracted by drugs that activate PPAR-α. In both rats and monkeys, these drugs reduced nicotine intake and relapse to nicotine seeking after a period of abstinence. They also prevented nicotine from altering electrical activity and neurochemical levels in addiction-related brain areas.

"Although our research involved highly selective experimental drugs, there are medications (fibrates) used clinically for the treatment of high cholesterol and triglyceride levels, which are selective PPAR-α ligands," further explained senior author Dr. Steven Goldberg. "Drugs that selectively affect PPAR-α receptors, possibly including fibrates, might provide a valuable new approach to the treatment of tobacco dependence in humans."

In the second study, Stopponi and colleagues used pioglitazone to evaluate its effects on alcohol drinking, relapse-like behavior, and withdrawal in rats. Pioglitazone activates PPAR- and is an FDA-approved medication for the treatment of type 2 diabetes.

Corresponding author Dr. Roberto Ciccocioppo detailed their findings, "We demonstrated that activation of PPAR-g receptors by pioglitazone potently reduces alcohol consumption in a rat model of excessive drinking. We also found that pioglitazone abolishes alcohol craving elicited by exposure to stress and prevented the expression of somatic signs of alcohol withdrawal."

"As we learn more about the brain, we are seeing a growing number of examples where medications developed initially for purposes unrelated to psychiatry may have new and otherwise unexpected applications within psychiatry. In this case, the identification of neural PPARs in reward circuits suggested new roles for PPAR stimulators. These new data in animal models suggest that TZDs might be promising new agents in the fight against addiction," commented Dr. John Krystal, Editor of Biological Psychiatry.

It is important to note that these exciting initial findings are only the beginning steps in a line of research that will need to be undertaken before TZDs or fibrates could be used in a clinical setting to treat people with addictions.

The first article mentioned is "Blockade of Nicotine Reward and Reinstatement by Activation of Alpha-Type Peroxisome Proliferator-Activated Receptors" by Paola Mascia, Marco Pistis, Zuzana Justinova, Leigh V. Panlilio, Antonio Luchicchi, Salvatore Lecca, Maria Scherma, Walter Fratta, Paola Fadda, Chanel Barnes, Godfrey H. Redhi, Sevil Yasar, Bernard Le Foll, Gianluigi Tanda, Daniele Piomelli, and Steven R. Goldberg. Mascia, Justinova, Panlilio, Barnes, Redhi, Tanda, and Goldberg are affiliated with the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland. Justinova is also from the University of Maryland School of Medicine, Baltimore, Maryland. Yasar is from Johns Hopkins University School of Medicine, Baltimore, Maryland. Pistis, Luchicchi, Lecca, Scherma, Fratta, and Fadda are affiliated with University of Cagliari, Monserrato, Italy. Le Foll is from the Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada. Piomelli is from the University of California, Irvine, California.

The second discussed article is "Activation of Nuclear PPARγ Receptors by the Antidiabetic Agent Pioglitazone Suppresses Alcohol Drinking and Relapse to Alcohol Seeking" by Serena Stopponi, Lorenzo Somaini, Andrea Cippitelli, Nazzareno Cannella, Simone Braconi, Marsida Kallupi, Barbara Ruggeri, Markus Heilig, Gregory Demopulos, George Gaitanaris, Maurizio Massi, and Roberto Ciccocioppo. Stopponi, Cippitelli, Cannella, Braconi, Kallupi, Ruggeri, Massi, and Ciccocioppo are affiliated with University of Camerino, Camerino, Italy. Somaini is affiliated with Addiction Treatment Centre, Health Local Unit, Biella, Italy. Cippitelli and Heilig are with the National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland. Demopulos and Gaitanaris are from Omeros Corporation, Seattle, Washington.

The articles appear in Biological Psychiatry, Volume 69, Number 7 (April 1, 2011), published by Elsevier.

The authors' disclosures of financial and conflicts of interests are available in their respective articles.

John H. Krystal, M.D. is Chairman of the Department of Psychiatry at the Yale University School of Medicine and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available at http://journals.elsevierhealth.com/webfiles/images/journals/bps/Biological-Psychiatry-Editorial-Disclosures-7-22-10.pdf.

The articles mentioned above are available upon request. Contact Chris J. Pfister at c.pfister@elsevier.com to obtain copies or to schedule an interview.

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