By David N. Leff

A certain wannabe presidential candidate has been playing verbal hide-and-seek with the media lately over the question of whether or not, among his "youthful indiscretions," he used cocaine. Nowadays, youthful indiscretion - in the 18 to 25 age group - accounts for the highest rate of cocaine use among the estimated 4 million Americans who regularly shoot, snort or smoke the drug. Half that number are ineluctable addicts.

That 18 to 25 age group also accounts for a probable majority of the nation's competitive athletes - from boxing and wrestling to bike racing and all the spectator ball games. For those of them who take cocaine, the attraction is not merely euphoria but blood-boosting - for the energy rushes their muscles need in order to win.

Psychiatrist Arthur Siegel, at Harvard-affiliated McLean (Psychiatric) Hospital in Belmont, Mass, is lead author of a paper in the twice-monthly journal, Archives of Internal Medicine, dated Sept. 13, 1999. Its title is, "Cocaine-induced erythrocytosis and increase in von Willebrand factor." Those two blood-doping effects of the narcotic explain why cocaine "is the most frequently used illicit drug among patients presenting with chest pain to hospital emergency departments," the paper states, adding, "[The drug] may trigger acute cerebral and myocardial ischemia or infarction."

To get a handle on these blood-thickening and clot-clogging menaces of cocaine use, Siegel and his co-authors mounted a double-blind clinical trial involving 21 long-term cocaine abusers, ages 21 to 35. Seven participants received the narcotic intravenously; 14 inhaled it intranasally. In both cohorts, this treatment raised their hemoglobin, hematocrit and red blood cell counts from 4 percent baseline levels to 6 percent.

"This increase," the journal paper pointed out, "was quantitatively similar to infusion of 2 units of packed RBCs [red blood cells], use of erythropoietin [EPO] every day for 6 weeks in doses of 20 units per kilogram, or chewing coca leaf during exercise."

These blood-doping effects - erythrocytosis - the co-authors added, "have been associated with sudden death in athletes." To athletes, seemingly more intent on winning than on life itself - human recombinant EPO's special attraction was that no urine or other test could detect it. The drug couldn't be told apart from the normal bodily function of replenishing red blood cells.

Separately, Siegel's journal article reported that in the cocaine trial recipients, von Willebrand factor (vWF) levels went up 40 percent above baseline. The factor promotes blood clotting by causing platelets to stick together.

Gene Regulator In Brain Guilty Of Drug Addiction

To paraphrase Mark Twain, everyone researches cocaine addiction, but no one has yet done anything to treat it. Molecular psychiatrist Eric Nestler, at Yale University in New Haven, Conn., thinks he may be coming close to an addiction remedy. He is senior author of a research article in the current issue of Nature, dated Sept. 16, 1999, titled: "Expression of the transcription factor deltaFosB."

"I think the important upshot of this paper," Nestler told BioWorld Today, "is that it really does identify the possibility that deltaFosB pathways could be targeted in drug discovery efforts. There are currently no effective treatments for addiction. As we learn more about the underlying biology, we'll be able to be smarter about how we go about finding the treatments." (See BioWorld Today, Dec. 22, 1998, p. 1.)

Nestler continued, "The basic phenomenon that the paper addresses is this protein, deltaFosB, which is induced by chronic exposure to a drug of abuse, but not by acute exposure. It's been an intriguing phenomenon because of this temporal feature.

"The question is," he continued, "By what mechanism does cocaine cause addiction? People have been interested by a molecular switch in the brain, that somehow switches from casual, infrequent use to a chronic, compulsive addiction. DeltaFosB has been intriguing because it is induced by chronic exposure to a drug of abuse, but not by acute exposure. It's induced to only very low levels after acute intake, and therefore with infrequent use it doesn't build up. But with more intensive exposure to drugs of abuse, it does begin to build up to a point where it can reach very high levels.

"However, despite that insight," Nestler went on, "we had no inkling as to what functional effect deltaFosB might produce related to addiction. So in order to answer the question, what aspects of addiction are mediated by deltaFosB, we made genetic mutant mice in which we could turn on the gene for deltaFosB in the same nerve cells where cocaine induces the protein - namely, the brain's nucleus accumbens region. It's thought to be an important brain-reward center, not only for cocaine, but also for other drugs of abuse - such as amphetamine, morphine and nicotine.

"We observed that the animals, upon expression of deltaFosB in these nerve cells, become much more sensitive to cocaine," Nestler recounted. "That is a phenomenon seen in many addicts; it's called sensitization. So our hypothesis now is that deltaFosB represents a mechanism for inducing relatively long-lived sensitization - that is, addiction."

His mutant mice confirmed, in in vivo experiments, that deltaFosB does seem to be a mechanism that causes relatively long-lived changes in the brain, and increases an animal's sensitivity to the rewarding properties of cocaine."

The co-authors then went on to identify some of the target genes through which deltaFosB - a transcription factor - acts. As such, it regulates other genes.

"In the paper," Nestler recalled, "we identified one such gene through which it produces these effects. So deltaFosB now provides a new pathway in the biology of addiction. It can be targeted for the development of novel drugs. For example, if we could prevent the induction of deltaFosB, or once induced if we could prevent its consequences, we might be able to arrest or reverse the addiction process, and thereby treat it more effectively than we can today."

Yale has a patent pending on deltaFosB, and, Nestler confides, "Its Office of Cooperative Development is in conversations with companies that might pursue it further."