New perspectives for treating drug dependence are opening up thanks to work by Pierre Sokoloff's team at INSERM 109 (director Jean-Charles Schwartz), in collaboration with CNRS, Cambridge University and the French pharmaceutical company Bioprojet. A new compound has proved capable of reducing drug seeking in cocaine-dependent rats. This compound, the first specific activator of the D3 dopamine receptor, might help addicts to attenuate their frantic drug-seeking behavior and to reduce the risk of relapse after withdrawal. The effect might extend beyond cocaine to other forms of dependence. These results - the fruit of 10 years' work - have just been published in Nature.
How to overcome dependence on drugs or smoking? Until now only substitution treatments - methadone, SubutexR or nicotine patches - are available. These treatments have limited efficacy and do not tackle the heart of the problem, i.e. craving and compulsive drug-seeking.
For the last 10 years the team led by Pierre Sokoloff at INSERM unit 109 have been examining an original way of inhibiting the drug craving associated with environmental images or signals. It is well established that a person's environment at the time of drug-taking is of capital importance: as the person becomes addicted, he or she gradually links the use of the product to particular signals or images, such as the sight of a spoon, a syringe or a particular atmosphere. Simply encountering these signals can trigger craving and drug-seeking behavior. Many relapses, even years after withdrawal, are due to images evoking the drug.
The story began in 1989 when P. Sokoloff, J.C. Schwartz and coworkers discovered the third receptor for the neurotransmitter dopamine, called the D3 receptor. This receptor is located in a restricted area of the brain, the nucleus acumbens, the key region of dependence: all products that induce dependence in humans, be it cocaine, morphine, heroin, nicotine or alcohol, increase dopamine release in this area. Genetic, pharmacological and physiological evidence argues for the involvement of the D3 receptor in drug dependence.
The idea was forwarded to develop a drug capable of modulating the activity of the receptor and thereby to treat the dependence. The compound would have to specifically bind to the D3 receptor and partially activate it. Thanks to collaboration with the team headed by Camille G. Wermuth (CNRS ERS 655, Illkirch) and scientists from Bioprojet laboratories (Paris), several hundred compounds were synthesized and analyzed. BP 897 successfully passed the battery of in vitro and in vivo tests, and is the first specific and partial D3 receptor agonist to be developed.
BP 897 was then tested by Barry J. Everitt at Cambridge University on cocaine-dependent rats trained to self-administer the drug by pressing a lever. The rats were conditioned to respond to a signal (a light came on at each drug intake). The simple sight of the light, in the absence of available drug, maintained the self-administration behavior (pressing the lever) and even rekindled this behavior after a period of quiescence. This model therefore resembles what happens when people take drugs, as signals or images associated with drug intake suffice to generate an irrepressible desire and to trigger relapse after withdrawal. Thus, the rat's behavior in response to the light signal reasonably reflects frantic drug-seeking and serves as a measure of drug desire and requirements.
Administration of low doses of BP 897 to these dependent rats clearly attenuated their compulsive drug-seeking behavior in response to the light signal. Their cocaine requirements were reduced. BP 897 itself does not act as a drug. Contrary to replacement products, BP 897 does not induce a new type of dependence, and rats do not attempt to self-inject BP 897 when given the possibility.
The implications of this work go beyond cocaine dependence. Indeed, as the D3 receptor is located in the key region for all forms of dependence, BP 897 might conceivably be used for other addictions, to heroin or nicotine for example.
BP 897 is the subject of a joint patent application by INSERM and the French company Bioprojet, which is currently developing the compound as drug. Toxicology results are satisfactory and human trials should start soon.
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Source
Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3
receptor agonist
M. Pilla(1), S. Perachon(2)(3), F. Sautel(2), F. Garrido(4), A. Mann(4), C.G.
Wermuth(4), J.C. Schwartz(2), B.J. Everitt(1) & P. Sokoloff(2)
(1)University of Cambridge, United Kingdom
(2)U109 INSERM, Paris
(3)Laboratoire Bioprojet, Paris
(4)CNRS ERS 655, Illkirch
Journal
Nature