By David N. Leff

¿I can resist everything except temptation.¿ So averred Oscar Wilde¿s temporarily immortal alter ego, Dorian Gray. That boast could apply to the enormous proportion of reformed cocaine addicts who backslide into addiction relapse.

¿Most patients,¿ observed neuroscientist Eliot Gardner, at the National Institute on Drug Abuse (NIDA) in Baltimore, ¿whether alcohol dependent or cocaine or heroine dependent, actually present for treatment sobered up and abstinent. They do it themselves. It¿s well known in addiction medicine,¿ he continued, ¿that it¿s very easy to get patients abstinent and sober. It¿s very difficult to have them stay that way because the tendency to relapse is so enormous. The patients themselves verbalize it when they come for treatment. They repeatedly ask for something to curb the cravings, and protect them against the relapse. With the exception of methadone, which works only for opiate addiction, we have precious little to offer them.¿

Gardner is senior author of a paper in today¿s Science, dated May 11, 2001, titled ¿Relapse to cocaine-seeking after hippocampal theta burst stimulation.¿ The article¿s first author is postdoctoral fellow Stanislav Vorel at Albert Einstein College of Medicine in Bronx, N.Y.

Gardner cites ¿three take-home nuggets¿ described in their Science article:

¿ ¿Identification and location of at least one relapse circuit in the rat brain.

¿ ¿That the relapse circuit is separate from the reward circuit. This came as a bit of a surprise,¿ he told BioWorld Today, ¿but it¿s quite clear that such is the case.

¿ ¿Given that glutamate turns out to be the neurotransmitter in this relapse circuit, we can manipulate the triggered relapse, up or down, by simultaneous injection into the relapse circuit brain areas of compounds that act on glutamate. This opens up the possibility ¿ at least conceptually ¿ of pharmacological development strategies that might ultimately result in anti-relapse or anti-craving medications for folks who have addictive disease problems.¿

Vorel added: ¿We have anatomically located the relapse circuits in the brain. And the main chemical implicated is not dopamine, as generally believed, but glutamate.¿

Mainlining? Go For The Jugular

The co-authors inserted catheters into the jugular veins of rats, and implanted electrodes into various regions of the brain. The animals self-administered cocaine intravenously during daily three-hour sessions in chambers fitted with a lever. Pressing it delivered one fix of the drug.

Then, after one week of this intoxicating nirvana, the co-authors switched the intravenous infusions from cocaine to saline solution. It took the addicted rats between seven and 20 days to get the message ¿ no more fix. At this, the animals lost interest, and stopped pressing. Quitting cold turkey amounted to abstinence.

¿At that point,¿ Gardner went on, ¿we began probing various brain areas with jolts of electrical stimulation that approximated the similar electrical activity recorded from the brain area when animals are in an inquisitive mode ¿ looking and sniffing around, exploring their environment, seeking out things that might be rewarding. The rats with electrodes in the medial forebrain bundle, stimulating that reward circuit, self-administered very eagerly.

¿Animals will do that avidly,¿ Gardner pointed out. ¿It is the most rewarding phenomenon known to biology ¿ right up there on a level with crack cocaine, and probably stronger than the sex urge. Those rats will stimulate this reward circuit at an incredible rate of maximum motoric output ¿ pressing the lever virtually indefinitely.

¿We did not have an a priori hypothesis that the reward and relapse circuits would be different,¿ Gardner recounted. ¿We aimed for the ventral subiculum part of the hippocampus because we felt that relapse would have to involve some kind of an encoded emotional memory. And therefore the deep structures of the temporal lobe would be an appropriate place to go probing around. We thought it equally probable,¿ he went on, ¿that if we stimulated in the reward circuitry that we would also get relapse. However, we could not get relapse in the reward circuitry.

¿The relapse circuit delivers glutamate rather than dopamine. The reward circuit very importantly has a dopamine component. In this Science paper,¿ Gardner continued, ¿we show that while we are activating this relapse circuit with electrical stimulation of the hippocampal subiculum, at the same time we microinject into the ventral tegmental area of the midbrain ¿ the reward center ¿ a relatively nonselective glutamate receptor antagonist ¿ and there is absolutely no relapse.¿

Glutamate Relapse Cure May Be Mission Impossible

¿On the other hand,¿ Gardner continued, ¿if we microinject a relatively nonspecific glutamate agonist we do get relapse. On the basis of those two experiments, we believe that glutamate is playing a major role, and it would not be irrational to pursue glutamate-based drug developmental strategies. But it¿s going to require a real trick, which may take years. Glutamate is an amino acid neurotransmitter ubiquitous throughout the central nervous system. It¿s not used simply in this one relapse circuit. It will require devising some means of getting the medication just to this place in the brain so it won¿t muck up stuff all over the brain, and create horrendous side effects.

¿That will be difficult, if not impossible,¿ he opined, ¿and one might have to think of viral vectors or some such transport mechanism to get the medication just to the cerebral site where you want it to be, without affecting other glutamate circuits all over the brain.

¿Rats, of course, are not people,¿ Gardner observed, ¿but they come close. Reinstatement of cocaine-seeking behavior in the rat,¿ he pointed out, ¿has high validity for relapse in the human addict. Both share common triggers of relapse ¿ stress, life¿s day-to-day hassle ¿ and stimuli conditioned to cocaine. Thus, reinstatement in the rat is a predictive measure of relapse for the human.

¿By and large,¿ he recalled, ¿addiction medicine has been a field with very little to offer patients in the way of pharmacotherapy. The only remedies we had were based on psychosocial group support and behavioral/cognitive therapies, as provided by Alcoholics Anonymous, among others. It works for some people, but a lot of folks need something more. So my emphasis,¿ Gardner concluded, ¿is to help strengthen medication development and discovery programs, such as here at NIDA.¿

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