Compulsive heroin use and relapse: Specific molecular substrates and impact of maintenance treatments – HEROMOL

In Western Europe opioids remain the main drugs for which patients seek treatment. The current therapies include maintenance medications: methadone and buprenorphine. However, one of the main problems is the high rate of relapse to drug use. Therefore, it is crucial to better understand the molecular mechanisms of the disease and the influence of maintenance treatments.
One of the core symptoms of addiction is compulsive drug use. In animals, the transition to compulsive drug use can be precipitated by extended, but not limited, access to heroin self-administration. In this project, we will use this drug access model to analyse the molecular regulations involved in compulsive versus controlled drug use. The behavioural effects of drugs are sustained by cellular and molecular regulations. It is well established that heroin induce gene expression regulations in several reward-related brain structures. In the case of cocaine it has recently been shown that in addition to transcriptional regulation other molecules like micro RNAs are also uniquely modulated in the striatum of animals that have developed compulsive cocaine use following extended access to the drug. Whether the regulation of miRNA represents a molecular feature of addiction common to other drugs of abuse, like opioids, is a currently major unanswered question.
The model of drug-primed reinstatement after extinction is a well-validated model of drug relapse in experimental animals. Importantly, sensitivity to heroin-primed reinstatement is considerably increased in animals following extended, but not limited, access to heroin self-administration. An important challenge for future research will be to identify the molecular substrates of this increased vulnerability to relapse, and how and to which extent they can be ameliorated or reversed by opioid maintenance treatments.
Although methadone and buprenorphine are largely prescribed maintenance treatments few studies have examined their efficacy in animal models of compulsive heroin intake. This lack of animal studies has hampered the elucidation of the molecular and cellular mechanisms of action of these molecules. In this project we will study the efficacy of buprenorphine and methadone in facilitating extinction and reducing heroin-primed reinstatement of compulsive drug seeking. We have recently shown that acute and chronic treatments with methadone or buprenorphine induce a pattern of gene regulation distinct from that of morphine in the striatum and nucleus accumbens of rats. In this context, in our model we will set up a maintenance treatment period and test its impact on heroin-primed reinstatement of compulsive drug seeking. In the framework of the project we will then study the influence of buprenorphine and methadone treatments on heroin-induced transcriptional response and heroin-induced miRNA expression regulation following extended versus limited drug use.
The strategy adopted for this project combines cutting-edge behavioural, biochemical and molecular approaches. The main objectives will be to: 1) identify the neuromolecular regulations underlying the differences between controlled and compulsive heroin use; 2) evaluate the efficacy of buprenorphine and methadone in preventing relapse into compulsive heroin seeking as measured in the reinstatement model, 3) develop a more comprehensive perception of molecular regulations induced by compulsive heroin intake and chronic maintenance treatments.
This project should provide entirely new insights into the molecular regulations underlying the differences between controlled and compulsive drug use. It should also contribute to unravel the molecular mechanisms of action of buprenorphine and methadone in reducing compulsive heroin consumption and preventing relapse. This project outlines a novel experimental therapeutics approach for addiction that could be extended to other drugs of abuse in the future.