By David N. Leff

When dopamine-2, the second of the neurotransmitter's five versions, docks at its receptor — D2R — in the brain, it probably sets off a sensation of pleasure.

This, neuroscientists surmise, is one mechanism behind the high or bang or rush that may, in part, motivate drug addicts. (Another part of their reward is the sense of relief that a fresh fix affords, by warding off a bout of withdrawal.)

Now a strain of French knockout mice which lack the D2R gene points to that receptor as the worm that baits the hook of narcotic addiction.

The Aug. 6 Nature reports that finding in an article titled "Absence of opiate rewarding effects in mice lacking dopamine D2 receptors." Its senior author, neuroscientist Emiliana Borrelli, constructed the first D2R-minus mouse some three years ago, at the University of Strasbourg, France.

She and her co-authors did so by screening a genomic library for the intron and exon sequences of the gene encoding the receptor, which, by homologous recombination, they then expunged from mouse embryos.

Borrelli directs a neuroscience laboratory in the university's Institute of Molecular Genetics and Cellular Biology (IGBMC).

"A lot of research teams are now working with these mice," neurobiologist Tarek Samad, a co-author of the Nature paper, told BioWorld Today, "but we had them first."

To gauge the reward-seeking effects of the dopamine-2 receptor, Borrelli and her team enlisted two cohorts of mice, one devoid of the D2R gene, the other normal wild-type.

Plus-Minus D2R Spells Preference Vs. Indifference

"We put them through a place-preference test," Samad recounted. "This consisted of a kind of cage with two compartments of different shape. In one we administered morphine every day to the mice; in the other, nothing. After they had become habituated, conditioned," he went on, "a normal mouse would run straight to the compartment where we gave the drug and stay there longer, whereas the knockout animal went indifferently to one or the other. It didn't have a preference."

Injection of morphine triggered an excited pleasurable reaction in the wild-type animals, marked by hyperlocomotion, rearing, running around, licking. "And the next day at the same time," Samad continued, "when the mouse is waiting for the drug again, when the reward starts to appear, we can precipitate withdrawal symptoms in both cohorts — jumping, paw tremor, wet-dog shakes, teeth chattering."

Then, to show that this reward effect was drug-specific, the experimenters put sugar-laced mouse chow rather than morphine into one compartment as a positive control. "We saw," Samad said, "that both the knockout and the wild-type mice preferred the food compartment.

"We separated the reward for food from the one for morphine. This main finding," he added, "the overall idea, the innovative thing in this paper, is that the D2 receptor plays a crucial role in the motivational component of drug addiction."

Route From Mouse To Human: Clear But Fraught

Samad pointed out that these murine responses can be extrapolated to the human brain. "This finding," he observed, "might be useful for the treatment of a lot of addiction cases. If, for example, the absence of the receptors eliminates reward effect, we can conclude very easily that adding some antagonist, which is a ligand for the human dopamine-2 receptor, will eliminate the reward, and so the addiction."

But, he cautioned: "The antagonists have other side effects, which are very strong, such as Parkinsonian symptoms. So we should be very careful at present. This should really be well studied before saying it might be a treatment or not."

Such studies are now under way in Borrelli's lab, he added.

Moreover, "having studied the mouse phenotypes at the behavioral level, now we can go into even more detail and investigate what's happening at the molecular level: which genes are expressed, which are repressed," Samad concluded. *