TZDs might serve as new agents for addiction treatment

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-a and PPAR-g, 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-g 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.