Months, even years, after repentant addicts have said "no" to drugs, asudden craving may re-surface and make them say "yes" all overagain. Cocaine users are particularly prone to such relapses. Whattriggers the late-onset yen for just one more fix?

Any number of sensory cues reminiscent of their former habit mayjump-start ex-addicts' slide backward into renewed drug dependency.Not to mention a single low-dose fix is often enough to fire up the olddesire, and the restless urgency to seek a supply.

Behavioral neuroscientists can describe these triggers of cocainerelapse, but they can't yet interpret them in terms of brain function.What they do know is that a prime cerebral mentor of pleasure andreward in the brain is the chemical messenger, dopamine.

Cocaine is a powerful facilitator of this potent neurotransmitter. Itacts by activating the neurotransmitter's receptors on the neurons thatreceive dopamine's stimuli on the far side of neuronal synapses.

These dopaminergic receptors are thick on the ground, and eachperforms a specific task in the brain, when bound by a molecule ofdopamine. In the past 10 or 15 years, neuropharmacologists havediscovered a series of dopamine-mimicking agonists _ moleculesthat also bind to and activate those same receptors.

In today's Science, two of these dopamine look-alikes, named theD1-like agonist and the D2-like agonist, come closer to elucidatingthe cocaine-relapse phenomenon. The Yale University scientists whotook this latest step on the long journey to clinical therapy for theaddiction, title their report: "Opposite modulation of cocaine-seekingbehavior by D1- and D2-like dopamine receptor agonists."

The paper's first author, behavioral neuroscientist David Self, found_ in laboratory rats _ that "this cocaine relapse, this craving if youwill, is selectively produced by agents acting at the D2 receptorpathway, but not at the D1 pathway."

Self said, "The rat brain is probably the best understood brain of anyanimal. We can never know exactly what the rodents areexperiencing; what's going on in their head, but they do self-administer the same drugs that people do. The neurochemistryinvolved in the addictive property of drugs is similar between ratsand humans."

Self's rats wear a thin plastic tube inserted in their jugular veins.Through this catheter a syringe pumps either cocaine, other drugs orsaline solution. In its cage, a rat can press one of two levers to set offthe syringe.

"During the cocaine session of an experiment," Self explained, "onelever delivered an infusion of cocaine. So the rats formed aconditioned association between that lever and the drug."

After two hours of this bliss, the lever switched to injections ofsaline. "When the animal keeps on pressing that lever, which used todeliver cocaine, we think it may be an index of cocaine-seekingbehavior."

During another two hours of disappointment, the animals evidentlycame to realize that the good times were over, and eventually stoppedsending out for saline.

The experimenters put no pressure on the rats to cultivate theiraddiction. "They have the choice," Self said, "to press one lever,another lever, or go sit in another part of the cage."

Pre-treatment of rats with D2-like agonist, followed by tiny injectionsof cocaine, dramatically increased their cocaine-seeking behavior,while pre-drug administration of D1-like agonist "completelysuppressed the priming effects of cocaine.

"This result was surprising," Self explained, "because we know thatboth D1 and D2 receptors are involved in mediating the reinforcing_ habit-forming _ effects of cocaine. With every other behavioralaspect of the drug, they do the same thing, such as stimulatinglocomotory activity, or substituting for the drug itself in a lot ofanimal tests."

To account for this unexpected dichotomy, Self surmised that "theD2 receptors stimulate the drive to take more cocaine, while the D1sproduce what we think might be some sense of satiation orgratification."

This in effect is what the synthetic morphine analog methadone doesin weaning and treating morphine and heroin addicts. "That's calledreplacement pharmacotherapy," Self observed. "In cocaineaddiction," he added, "there is no effective therapy."

He suggested that the D1 pathway might be a target for use in cocainereplacement pharmacotherapy. "I hope that this study in Science," headded, "will spur interest in the clinical community, at least to givethese drugs a try and to begin to test whether or not they can actuallysuppress the cravings."

So far, he observed, "Companies have been testing D1-like agonistsas therapy for Parkinson's disease but not yet in humans."

Coffee is a psychostimulant that tickles pleasure and satiation centersin the brain, but may or may not involve the dopamine system. WhenSelf fed caffeine to his rats, "we saw that it was more similar to theD2 agonist in terms of cocaine priming. It actually enhanced it."

He cited some current speculation that "cocaine addicts may be tryingto use caffeine and nicotine as replacement therapy for theiraddiction. But other work," he continued, "suggests that caffeine mayactually make matters worse. Although it actually doesn't do much onits own, if a person were to come across relapse-triggeringenvironmental stimuli, caffeine may potentiate those effects." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.