Addiction to drugs of abuse _ alcohol, nicotine, cocaine _ can becalled the dominion of matter over mind. Those substances comprisethe "matter."
Just how their compulsive misuse _ with its highs and crashes,misbehavior and withdrawal _ plays out in the mind, seat of thebrain's higher functions, is under ever-closer scrutiny byneuroscientists focused on addiction research. (See BioWorld Today,Dec. 19, 1995, p. 1.)
In recent years, thanks to PCR and other biotechnological advances,their investigations have advanced from merely studying the erraticlocomotion of rats under the influence, to probing their brains'addictive responses at the molecular level.
Cocaine is a prime target, and with good reason: A recent nationalsurvey found that 1.4 million Americans age 12 or older, shoot, snortor smoke cocaine, and that 640,000 of them are addicted, self-administering it at least once a week. Just saying "no" to suchaddictive drugs hasn't gone very far toward altering this destructiveconduct.
"Fundamental brain research," says Alan Leshner, director of theNational Institute on Drug Abuse (NIDA), "helps us to learn moreabout the addictive nature of cocaine, and moves us even closer toidentifying effective treatment to help the thousands of individualsaffected by cocaine addiction."
Leshner was referring expressly to The Rockefeller University'sNIDA-sponsored Laboratory of the Biology of Addictive Diseases,headed by neuroscientist Mary Jeanne Kreek. She and her co-authorshave a paper in the May 1996 issue of Molecular Brain Researchtitled: "Regulation of kappa opioid receptor [KOR] messenger RNAin the rat brain by `binge' pattern cocaine administration andcorrelation with preprodynorphin mRNA."
KOR is a molecule involved in the brain's handling of pain andemotion at the chemical level. By letting rats binge on injectablecocaine, Kreek found that the drug turns down the activity of a genein the midbrain that encodes that opioid receptor.
"Our study," she said, "is the first report that any drug of abuse, inthis case cocaine, alters the expression of a gene encoding an opioidreceptor in the brain. The finding of a decrease in KOR levels in the[midbrain's] substantia nigra, following `binge' cocaineadministration . . . has not been previously reported."
Binging On Cocaine Rodent Style
Kreek and her team devised their "binge" pattern of cocaine injectionin rats to mimic human addiction, but without overdosing the rodents.Thus the animals received repeated injections of the drug daily for 14days. Saline solution instead of the real thing went into a controlcohort.
In the brains of those who got the fixes, expression of the KOR genein the substantia nigra went down. But it stayed steady in the closelyadjacent caudate-putamen region.
Kreek observed that "the resulting decrease in opiate receptors mayinterfere with how nerves in the region communicate."
Those nerve cells of prime concern to cocaine are the neurons of themidbrain's substantia nigra, which make dopamine. They release thismultipurpose brain chemical at their endings in the caudate-putamen.It's at these synapses that excess dopamine is normally sucked up andshipped back up stream in the neuron for recycling.
Cocaine frustrates this uptake, leaving the dopamine molecule tocontinue firing, as it were. When the drug decreases the expression ofkappa opioid receptors in the substantia nigra, not enough KOR maybe on hand to respond to the dopaminergic feedback signals.Eventually, though, the amount of dopamine pumped out levels off,making the addict feel bad.
At the same time, cocaine also up-regulates expression in thecaudate-putamen of the gene that makes dynorphin. This smallprotein, linked to the endorphin molecule, mimics cocaine's rush ofenergy, euphoria, and numbing of pain. Kreek told BioWorld Todaythat she and her co-authors are now examining whether the increasein dynorphin gene expression relates to the decrease in KOR geneexpression.
"Knowing how cocaine affects the brain's chemistry, she observed,"may eventually be useful in developing a treatment for cocaineaddiction that can block some of its endorphin-like effects withoutinterfering with all of the body's normally occurring endorphins, suchas dynorphin, and its kappa opiate receptor."
Kreek pointed out that "We need these endorphins because they helpus feel normal, cope with pain and stress, and play a role in our use ofenergy."
From Hard Drugs To Therapeutic Drugs
Since submitting their paper to the journal last November, she andher colleagues have been pursuing new rat experiments, seekinganswers to "three critical questions with implications for preventionand also pharmacotherapy of cocaine addiction:
* "First: How long does it take to cause these significant changes inthe opiate receptor's messenger RNA? This is an acute event as wellas a chronic event. It is so incredibly important and exciting to us,because we see it after 14 days of binge-pattern cocaineadministration. What kind of exposure is needed to cause thesechanges?
* "Second: What is the time-course of reversibility after the two-week administration?
* "Third: With longer administration, can you always reverse it? Oris there a critical point of no return?"
Kreek concluded: "With an agent targeted to one of these definedsites of action _ the dopaminergic receptors, the dynorphin systemand the opiate receptors _ would it be possible, down the line, tomodulate or attenuate the cocaine surge effects?" n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.