Abstract
Targeting peroxisome proliferator-activated receptors (PPARs) has received increasing interest as a potential strategy to treat substance use disorders due to the localization of PPARs in addiction-related brain regions and the ability of PPAR ligands to modulate dopamine neurotransmission. Robust evidence from animal models suggests that agonists at both the PPAR-α and PPAR-γ isoforms can reduce both positive and negative reinforcing properties of ethanol, nicotine, opioids, and possibly psychostimulants. A reduction in the voluntary consumption of ethanol following treatment with PPAR agonists seems to be the most consistent finding. However, the human evidence is limited in scope and has so far been less promising. There have been no published human trials of PPAR agonists for treatment of alcohol use disorder, despite the compelling preclinical evidence. Two trials of PPAR-α agonists as potential smoking cessation drugs found no effect on nicotine-related outcomes. The PPAR-γ agonist pioglitazone showed some promise in reducing heroin, nicotine, and cocaine craving in two human laboratory studies and one pilot trial, yet other outcomes were unaffected. Potential explanations for the discordance between the animal and human evidence, such as the potency and selectivity of PPAR ligands and sex-related variability in PPAR physiology, are discussed.
Highlights
Substance use disorders (SUDs) continue to represent a significant global public health burden.In 2017, of the estimated 271 million people aged 16–64 years worldwide who had used drugs in the past year, nearly 35 million (~13%) were estimated to suffer from an SUD [1]
When pioglitazone was co-administered with naltrexone, there was an attenuation of cue-induced reinstatement [37]. These results suggest that peroxisome proliferator-activated receptors (PPARs)-γ agonists may be useful in preventing alcohol relapse, possibly to a greater extent when administered concurrently with naltrexone, a non-selective opioid receptor antagonist that is already approved by the United States Food and
The majority of the preclinical behavioral evidence suggesting a role of PPAR agonists in addiction-like behaviors has focused on ethanol
Summary
Substance use disorders (SUDs) continue to represent a significant global public health burden.In 2017, of the estimated 271 million people aged 16–64 years worldwide who had used drugs in the past year, nearly 35 million (~13%) were estimated to suffer from an SUD [1]. Pharmacotherapeutic strategies to treat addictions need to reduce the reinforcing or rewarding properties of drugs, and target the negatively reinforcing states associated with chronic drug-taking that contribute to the significant risk of relapse [7]. Agonist substitution therapies have been successful in mitigating this negative reinforcement in some SUDs, e.g., methadone or buprenorphine for managing withdrawal and craving associated with opioid use disorder [8] and nicotine replacement therapy (NRT) for managing nicotine withdrawal [9]. Other medications, such as naltrexone or acamprosate for alcohol use disorder [10] and varenicline or bupropion for nicotine dependence [9], have demonstrated some efficacy in reducing positive and/or negative reinforcing aspects of drug use. Long-term abstinence rates remain low across SUDs, highlighting the need for novel pharmacological treatment approaches
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