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The dopamine d3 receptor in drug addiction and withdrawal: development of a novel therapeutic approach

Ziel

To perform anatomical localisation studies in rat and human brains to provide information about the systems involved in D3 dopamine receptor (D3R)-drug interactions.
To assess the biological activity of D3R agents in behavioural animal models measuring various aspects of drug addiction and dependence.
To design and synthesise new D3R agonists and antagonists with increased selectivity, biological activity and oral bioavailability and to assess their safety in toxicological studies in animals and in Phase I clinical study.
To seek for genetic association of the D3R gene and alcoholism and drug addiction.

The public and governments recognize substance abuse as one of the most severe problems in Europe, not only for the health of abusers, but also for the well being of society. While substitution products to some drugs exist, there is a need for specific medication to reduce drug-seeking behaviour and withdrawal symptomatology. In addition, while alcohol and possibly other drug-dependences have genetically inherited components, identification of the still unknown factors involved may help manage with high-risk individuals. It is well established that abused drugs (alcohol, heroin and cocaine) share the property to affect dopamine systems in selected brain areas. Pharmacological modulation of the activity of dopaminoceptive neurons may be a novel therapeutic approach to drug addiction. However, this approach could not be envisaged before the recent discovery of the dopamine D3 receptor (D3R). Thus, neuroleptics, the only dopamine receptor blocking compounds presently available for clinical use, all are D2R-preferring agents, which have profound motor and cognitive side-effects that preclude their use in the treatment of drug addiction. In contrast, the D3R is expressed in restricted brain areas that neurochemical studies have identified as anatomical substrates for the actions of drugs of abuse, and the first partially selective D3R antagonists, available at a preclinical stage, have no cataleptogenic or akinetic properties in animals.

In addition, D3R agonists reduce cocaine self-administration inrafs, whereas they are not self-administered. This observation strikingly demonstrates the implication of the D3R in mechanisms by which drugs produce pleasure and reward and also suggests that D3R agents may constitute novel therapeutically agents for treating drug-seeking behaviour and withdrawal symptoms.

In this context, our general objectives are
i) to understand the D3R function in drug addiction by combining pharmacologicaanatomical and genetic approaches;
ii) to design, develop and assess the therapeutic efficacy of novel D3R agents in drug intake and dependence.

To this aim, behavioural studies will be performed in animal models measuring various aspects of drug addiction (sensitisation, reward, craving and anhedonia), with partially selective D3Ragonists and antagonists. Localisation studies in rat and human post-mortem brain tissues will provide information about the systems involved. Ligands for Positron Emission Tomography studies will also be developed to measure D3R level and occupation. New D3R agonists and antagonists with increased selectivity, biological activity and oral bioavailability, will be rationally designed using structure-activity relationship and molecular modelling, synthesised, and screened in binding studies with recombinant receptors already available, or to be cloned during this program. Pharmaceutical development of selected molecules will be made by a SME, which will be in charge of pilot synthesis, toxicological studies and phases I and IIa clinical trials in alcohol addiction.

A genetic association study will be performed in alcoholics to assess the role of D3R gene in the susceptibility to drug dependences and possibly provide a marker for high-risk populations. This program, an extension of a Biomed 1 program, is essentially an applied one aiming at the solution of the critical problem of reduction of compulsive drug intake and craving, through a better understanding of the role and connectivity of a subset of dopamine neurons. It fits perfectly with task 3.8 of Biomed 2, e.g. assessment of "biological effects of illicit drugs on the structure and function of the brain. Role of genetic factors on drug seeking behaviour and "development of treatment".

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CSC - Cost-sharing contracts

Koordinator

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
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2 TER,Centre Paul Broca 2 Ter Rue d'Alesia
75014 PARIS
Frankreich

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Letzte Aktualisierung: 18 November 2002

Mein Booklet

Permalink: https://cordis.europa.eu/project/id/BMH4960203/de

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