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Pharmacology

The trails of coke

A compound inhibits the effect of cocaine and helps to elucidate its action on the brain

MIGUEL BOYAYANRecent experiments carried out in Brazil and Germany point towards a possible application for the synthetic compound known by the acronym SR142801. Developed by the French laboratory Sanofi-Aventis, the third largest pharmaceutical company in the world, the compound remained almost ten years without any defined medical use. Now tests with rats and monkeys suggest that the SR142801 – which acts upon the central nervous system and interrupts a specific form of communication between nerve cells – may be effective in combating the extreme agitation and even the exaggerated attention caused by cocaine use.

At the University of Düsseldorf, Germany, a team led by Dr. Joseph Huston treated rats with SR142801 before they were given a cocaine injection. The rodents that received the compound did not walk from side to side without any specific objective nor did they carry out repetitive movements in order to inspect their environment as if there were some threat close by, the behavior demonstrated by the animals that had received only cocaine, a drug that some 1 million Brazilians over the age of 12 years have already tried, according to an estimate from the Brazilian Center for Information About Psychotropic Drugs. In similar tests carried out on monkeys, Carlos Tomaz, from the University of Brasilia (UnB), obtained comparable results. “Throughout the world there is a search for compounds that impede the arrival of cocaine into the central nervous system or block its action on the brain”, says Arthur Guerra de Andrade, the coordinator of the Interdisciplinary Study Group on Alcohol and Drugs of the University of São Paulo.

In spite of its action of blocking the agitation and the attention brought about by the use of cocaine, the SR142801 is probably not the so long awaited medication to combat dependency, capable of transforming well being and euphoria into the compulsive search for more and more drug, capable of de-structuring the user’s life and that of their family. “I don’t believe that the SR142801 has the potential to treat cocaine dependency, since this molecule only blocks excessive movement, but doesn’t interfere in the mechanism of reward associated to the drug consumption”, says Huston, one of the research coordinators.

And it is exactly this mechanism of reward that causes the dependency and makes quitting the drug a challenge almost insuperable for a good part of the users. Seconds after penetrating the nostrils, the cocaine dissolves in the blood vessels, reaches the central nervous system and increases the levels of dopamine, the chemical messenger that activates the nerve cells in the regions of the brain associated with the sensation of pleasure and well being. This is when people start to speak without stopping and remain with energy that seems endless. But, as quickly as they arose, these effects disappear minutes later and give way to anxiety and depression, which leads the person to look for more of the drug in search of more pleasure.

Until a short time ago it was believed that the effects of this alkaloid, extracted for the oval shaped leaves of coca (Erythroxylum coca), a shrub common in Bolivia, Peru and Ecuador, was due only to its interference in the mechanism of the action of dopamine, one of the molecules naturally produced by the organism and responsible for communication between nerve cells (neurons). That satisfaction that emerges with a long awaited salary increase is, to a large extent, the effect of the discharge of dopamine in the brain. The conquest sets off a chemical storm in the central nervous system in which the effective perception of information is associated to the release of dopamine, which carries information from one nerve cell to another. Both the discharge of dopamine and its recapture occur by way of transporters located in the membrane of the neurons that produced the dopamine.

But on arriving at the brain the cocaine produces a short circuit. Like a sluice gate that bars a river and makes the waters back up and overflow, the cocaine impedes the recovery of the dopamine and brings about a type of brain flooding. While the effect of cocaine lasts, it is as if the brain suffers an overdose of dopamine on receiving good news, followed by another and another, until the drug’s effect passes.

Labyrinth
Over the last decade it has been discovered that cocaine also affects the action of other neurotransmitters, such as serotonin and noradrenalin (chemical messengers of the family of monoamines, substances derived from ammonia with a single atom of nitrogen in its composition). More recently at the Psychology Physiology Institute of the University of Düsseldorf, the team headed by Huston and the Brazilian pharmacologist Maria Angelica de Souza Silva demonstrated that cocaine also interferes in the action of a fourth group of neurotransmitters: the neurocinines, via an action as yet little known. Huston and Maria Angelica suspect this interaction when they had found a determined type of receptor of the neurocinines in regions involved in the processing of cocaine in rats’ brains. “Until a short time ago the action of the neurocinines was not investigated because it was not imagined that there were receptors for these molecules in the human brain”, explains Maria Angelica.

On knowing that the Sanofi laboratory developed a molecule that would link itself to these neurocinine receptors, obstructing the action of the neurotransmitter, the Düsseldorf team decided to test it on their rats. In a series of experiments Maria Angelica and Huston gave three different doses of SR142801 to rats, a half an hour before the rats were to receive a cocaine injection. Published in this year’s September edition of the magazine European Journal of Neuroscience, the results show that the SR142801 eliminated the excessive agitation associated with the coke use, but did not alter the feeling of well being. It was clear that, at least for rodents, the cocaine also altered the action of the neurocinines. What was lacking was to discover if the same happened with monkeys, animals evolution wise much closer to human beings.

It was then that the neuroscientists Carlos Tomaz and Marilia Barros and the biologist Eldon Mello Júnior, from the UnB, repeated these experiments with eight black tufted-ear marmosets (Callithrix penicillata), a 20-centimeter monkey with black tufts on its ears, native to the Cerrado (savanna). Again the SR142801 inhibited the agitation and the alert caused by cocaine consumption. But the UnB researchers verified something unexpected. When they gave the black tufted-ear marmosets another compound known as senktide, which should amplify the cocaine effects and leave the monkeys  even more agitated, they observed that nothing changed with the monkeys, as described in September’s issue of the magazine Peptides. This unexpected result indicates, according to Marilia, that the interaction of cocaine with the neurocinines must be more complex than had been imagined. In the face of such varied effects, it would be difficult to arrive at a medicine capable of combating, with efficiency, cocaine dependence.

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