Several million hyperactive schoolchildren and adolescents in theU.S. daily swallow pills of methylphenidate, a.k.a. Ritalin. Thispsychoactive stimulant is a close chemical cousin of cocaine.
Not to worry: Methylphenidate is rarely addictive, and gives its usersa very mild and fleeting high.
Cocaine, in contrast, confers on its abusers a form of hyperactivityknown as binging _ an effort to hang onto the drug's very high high.Cocaine triggers feedback circuits in the brain that render addictionself-perpetuating, self-reinforcing, with a non-stop craving thatdemands instant and repeated rushes of gratification. That accountsfor binging, a frenetic drive to maintain cocaine levels in the brain, bysmoking, snorting or shooting the next fix, and the next, and the next.
By comparing the actions of cocaine and methylphenidate in theawake human brains of cocaine addicts, psychiatrist Nora Volkow, atthe Brookhaven National Laboratory in Upton, N.Y., aimed toconfirm her hunch as to the underlying mechanism of binging, andwhat to do about it
Volkow is chief of Brookhaven's medical department, and director ofnuclear medicine. She is first author of a paper in the current winter1996 edition of the quarterly Journal of Addictive Diseases, an organof the American Society of Addictive Medicine, in Chevy Chase, Md.Its title: "Cocaine addiction: Hypothesis derived from imagingstudies with PET."
She and her co-workers injected sub-pharmacologic _ virtuallyhomeopathic _ doses of radiolabeled cocaine into the veins ofvolunteer addicts, and compared their responses in the brain withshots of methylphenidate.
To do so, they visualized brain sections by PET _ positron-emittingtomography. (See BioWorld Today, Nov. 27, 1996, p. 1.)
"The PET test is extremely sensitive," Volkow explained, "so weinjected cocaine at a concentration totally devoid of pharmacologicalactivity, in order to observe its effect on a system that's not beenperturbed by the action of the drug itself."
First, the Brookhaven team evaluated brain responses in 15 outpatientcocaine addicts during the first week after withdrawal, against 14normal controls. Then they assessed the effects of prolongedwithdrawal, after four months of detoxification, in 22 inpatientcocaine abusers, versus 24 controls.
"Cocaine is very effective in crossing the blood-brain barrier,"Volkow told BioWorld Today. "So it gets into the brain, and outagain, very rapidly. That is, it achieves a high concentration inblocking the dopamine transporter in the brain's pleasure-responsecenter, but for a very short period of time."
This ultra-fast, in-again-out-again pharmacokinetic trajectory,Volkow pointed out, "relates to cocaine's reinforcing properties.
The Cocaine-Ritalin Difference
"Methylphenidate," she added, "has a similar affinity for thedopamine transporter. What's very intriguing is: Here we have twodrugs with similar affinities for the transporter. One is highlyaddictive, the other we give to children. So it provides us a very nicemodel to try to understand where there are other variables thataccount for the pharmacological differences in the addictive potentialof these two compounds."
Those differences proved to be not in their rate of uptake, but in theirrate of clearance from the brain.
The dopamine transporter, Volkow explained, "is a molecule in thedopaminergic cell that functions to clear out the dopamine, once it'sbeen released into the neuronal synapses. Otherwise, it would juststay there, sending out its pleasure signal indefinitely. The only wayit can be terminated is by the transporter."
What cocaine does is trump the transporter, and so allows dopamineconcentration to build up.
"It changes dopamine very dramatically, and very rapidly," Volkowsaid. "And that's crucial for cocaine's reinforcing action. Bingingbehavior," she added, "is classical in the clinical presentation ofcocaine addiction."
Thus, discovering or designing a drug that could sideline this endlessquest for the next fix "would be a tremendous challenge," Volkowsaid, "because that would be an ideal type of drug in the sense thatthe main problem with cocaine is that the subject will take one doseof cocaine after another. To interrupt that binge behavior would be aperfect treatment, but it doesn't exist yet."
Short-Circuiting The Brain Circuit
Long-term binging continually stimulates certain neural circuits in thebrains of chronic cocaine users, Volkow pointed out, which in turnbrings on more chronic binging.
Little is known for sure about what these cerebral circuits do in thebrain normally, except what happens when they're experimentallyextirpated.
"You'll have animals that engage in repetitive behaviors that cannotbe terminated," she observed, "such as a cat's grooming activity. "Acat may lick itself for 15 or 20 minutes. If it didn't have a circuit thatpromoted that automatic behavior, the animal would not engageenough time to achieve its grooming goal."
She continued: "It's the same thing with food. When we start eating,perhaps the first bite is pleasurable, but then the pleasure becomessort of automatic, and we end up eating whatever is on our plate.These circuits can be terminated;" she went on, "otherwise, we'd bebinge-eating, as in bulimia, for example, or binge gambling."
"This neural circuit," she surmised, "which drives a cocaine addict'sbinge behavior, allows us to disconnect and do something automaticwithout having to think about it, and thus be more efficient than weotherwise would be."
She recalled that "at the beginning of the 20th century, there was anepidemic of cocaine use in the U.S. It entailed a behavior describedas `cocainism.' In it, users engaged in repetitive types of motorialmovements, one could say, compulsions.
"Perception of pleasure," Volkow concluded, "is likely to underliebehaviors such as eating, drinking or mating, that need to be repeatedin order for species survival. As a natural reinforcer of such behavior,pleasure has been associated with increased dopamine activity in thebrain." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.