By David N. Leff
Unlike AIDS, malaria, cancer and heart disease, cocaine abuse is rarely life threatening. But it drains the brains and wallets of its countless aficionados, who snort, smoke and shoot up crack, coke, snow, flake or blow ¿ not to mention the economic and military drain of efforts to suppress the cocaine traffic.
Drug dependence rather than addiction is the specific form of entrapment experienced by cocaine users. ¿Drug dependence activates the brain¿s dopaminergic neurons,¿ explained neuroscientist and molecular geneticist Frangois Conquet, ¿and mediates what¿s called the natural reward system¿ ¿ water, sex, food and maternal behavior. Some people,¿ he added, ¿take cocaine in preference to food, tender loving care or other natural rewards.¿
So did laboratory mice that had been enslaved to cocaine by intravenous injection of the drug. In Conquet¿s lab at GlaxoSmithKline R&D, in Lausanne, Switzerland, these pampered rodents sat in front of two levers. Pressing one lever delivered a self-administered cocaine fix via an indwelling catheter; the other, merely food.
Conquet is senior author of a research paper in the September 2001 issue of Nature Neuroscience. Its title: ¿Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice.¿
¿Our findings point toward a novel understanding of the biological processes underlying drug dependence,¿ Conquet told BioWorld Today. It¿s known that following chronic administration of cocaine, the expression of mGluR5 [metabotropic glutamate receptor subtype 5¿] is increased in a region of the brain ¿ the nucleus accumbens ¿ within the brain¿s natural reward circuit.
¿We used cocaine as a tool to study drug dependence,¿ Conquet recounted. ¿But drugs are all different; they act at various sites in the brain. However, they all come to a common feature, which is dependence. We¿ve been looking for this common dependence mechanism, and ¿ as we report ¿ we think that we have found it. This common mechanism, we think, is mGluR5 ¿ the target that we have discovered.¿
Mutant Mouse Turns Up Snout At Fix
Conquet continued: ¿We knocked out the mGluR5 genes in a mouse, and demonstrated that this mutant null animal was now completely insensitive to cocaine. It could not show a reinforcing effect of the drug, but did have a remaining motivation for food, which is a standard natural reward. In other words, by eliminating mGluR5, the knockout mouse no longer bothered to press the cocaine lever that activated the natural reward system. But that same KO rodent went right on pressing the food lever.
¿Thus, for the first time,¿ Conquet observed, ¿we provided compelling evidence that both systems ¿ artificial activation or natural reward circuits ¿ can be separated from each other experimentally. That¿s the basis of our paper. The significance of this finding is that now we have targets for treatment of drug dependence, which was not the case in the past. Although we have yet to elucidate the exact nature of the mGluR5 contribution to cocaine dependence, these results suggest that the receptor is essential to that dependence.
¿Because mGluR5 is a glutamate receptor that binds ¿ and is activated by ¿ the glutamate neurotransmitter,¿ he went on, ¿this receptor is involved in the brain¿s learning processes. We think that with drug dependence you have a learning contribution. In this case, the mGluR5 receptor is probably involved in emotional learning. And this learning process leads to memory ¿ a sort of memory ¿ and this memory is dependent when activated at this site.
¿The mice in our in vivo experiments were of two types,¿ Conquet recounted. ¿The first one was a genetic mutation gene knockout, so it carried no mGluR5 genes any more. And this mouse was insensitive to cocaine in the self-administration paradigm. It could not enter, could not initiate, the process of dependence on cocaine.
¿Moreover,¿ he continued, ¿we conserved this cocaine insensitivity into normal wild-type mice, without any mutation, but in which we injected an antagonist to this receptor. This antagonist was a drug, a compound called MPEP, that is available on the market for research only ¿ for studying the function of these receptors. There is no available chemical compound to do the same in humans, so far. And with this receptor antagonist we observed that when blocked by MPEP, the normal mice could not get the reinforcing effect of cocaine as well.
¿The mutant mice displayed none of the characteristic stimulant effects of cocaine administration, such as hyperactivity. Their locomotor behavior was unaffected, despite cocaine-induced increases in nucleus accumbens dopamine levels similar to those in wild-type mice. This proves that the dopaminergic system, which mediates the natural reward circuit, remains intact in the mGluR5 mutant mouse.
¿This receptor¿s normal brain function in animals,¿ Conquet surmised, ¿is probably anxiety, but we don¿t know; it¿s not clear. It¿s something linked to anxiety, and sensory mechanisms ¿ emotion, and relationship with the environment. And in relation to cocaine, its function is to mediate the reinforcing effect of the drug ¿ that is, the addictive effect of cocaine. This means that once you take a dose, 30 minutes later you crave a greater, a higher dose. This is called cocaine¿s dependence-reinforcing effect.¿
Which Transmitter Leads? Which Follows?
¿As for the relation of dopamine to the glutamate receptor,¿ Conquet added, ¿this remains to be elucidated. We think that both systems, dopaminergic and mGluR5, act in synergy, which reinforces the reinforcement. We show that, although dopamine levels are still increased by cocaine, the reinforcing and stimulant effects appear to be mediated by glutamate through mGluR5 ¿ while the specific role of dopamine is not clear.¿
Conquet is group leader of the GlaxoSmithKline unit in Lausanne, which focuses on discovery of drug targets. ¿In this direction,¿ he volunteered, ¿we¿re trying to understand the function of the receptor, along with the other putative elements that could be involved in the process.
¿Of the outlook or prospect for addiction treatment, we have no idea. This would be a project that will be decided in the future, of course, but is difficult to foresee now. For now,¿ Conquet concluded, ¿we have new projects ongoing ¿ but not exactly with this particular mouse ¿ on the basic chemical function to determine how this receptor works, in cells or in animals, which is quite unknown.¿