June 26, 2000
Volume 52, No. 36
Scholarship & Resesarch
NIDA, Howell work to break cocaine addiction
By Poul Olson
Yerkes' Leonard Howell knows what it's like to be hooked on a drug. As a pack-a-day smoker for eight years, Howell failed in his first effort to quit. After quitting cold turkey the second time, he said, "I finally had to tell myself that I could never pick up a cigarette again."
Breaking a drug's grip is a battle that millions of people face and many lose. In combination with heavy doses of willpower, some smokers and heroin users have used therapeutic substitutes to control their drug cravings. Similar medications, however, do not exist for cocaine addicts. That may change in as few as four years.
As part of a national push to stem the tide of cocaine addiction, the National Institute on Drug Abuse (NIDA) recently awarded Howell and a coalition of biochemists, and basic and clinical researchers in industry and higher education, a four-year, $3.5 million grant to develop a medication for treating cocaine addiction.
The NIDA grant, awarded under its Strategic Program for Innovative Research on Cocaine Addiction Pharmaco-therapy (SPIRCAP) will build on research that Howell conducted on cocaine addiction for more than a decade. Most recently, the Yerkes researcher has been using squirrel monkeys to test the efficacy of a class of synthetic cocaine analogues, developed by Mike Kuhar, chief of the Yerkes neuroscience division, and researchers at North Carolina's Research Triangle Institute.
Widely considered to hold the best promise for treating cocaine addiction, the compounds called phenyltropanes are similar in structure to cocaine and selectively bind to the same dopamine transporter affected by cocaine. Some promising phenyltropanes, however, don't enter the brain with the rapidity of cocaine or produce its addictive, euphoric rush. The long-lasting duration of the cocaine-like drugs would also facilitate an easy dosing schedule in a treatment setting.
As a chemical therapy used in conjunction with a behavioral treatment program, a phenyltropane compound could be administered during the crucial period of withdrawal immediately after an addict stops using cocaine, when craving for the drug and the urge for compulsive and destructive drug-seeking behaviors are most intense.
In previous studies conducted by Howell, the phenyltropane RTI-113, has shown the most promise in squirrel monkeys in controlling the urge to self-administer cocaine. Toxicity concerns, however, forced Howell to recently suspend studies of the compound.
With the data from Howell's study, the SPIRCAP group will focus on refining the pharmacology of RTI-113 and test several other candidate phenyltropanes in rodent and primate models.
In conjunction with these studies, Howell will continue researching the complex relationship between the serotonin and dopamine systems. Evidence suggests that the neurotransmitter serotonin plays an essential upstream role in the cascade of processes that produce dopamine. Studies have shown that cocaine's effects can be blocked by administrating selective serotonin reuptake inhibitors (SSRIs) such as Prozac.
"Blocking the effects of cocaine won't reduce craving for the drug," explained Howell. "But in combination with a drug like RTI-113, it might provide a way to better reset the brain's chemistry."
Prolonged use of cocaine alters levels of dopamine in the brain, the neurotransmitter responsible for feelings of pleasure and reward, and causes a dysfunction in the brain's chemistry that can take months and sometimes years to correct on its own. "The combined use of an SSRI with a cocaine analogue might provide a means for normalizing the brain chemistry that gives rise to this discomfort," Howell said.
Of the four phenyltropanes he will test for SPIRCAP, Howell plans to take the two lead candidates and study their pharmacology in combination with an SSRI. Given the demonstrated safety of SSRIs, a therapy for cocaine addiction that combines the two drugs could provide a means for synergistically enhancing the effects of the cocaine analogue while minimizing its side effects.
"Although the RTI compounds are designed to be less addictive than cocaine, they are potent substances," Howell said. "The goal of a substitution therapy would be to administer the cocaine analogue at a dose that minimizes its side effects. SSRIs could allow us to do this."
Over the years, Howell and Kuhar have made several significant discoveries related to cocaine addiction, including identifying the neural pathways affected by the drug and the role of environment in encouraging drug-seeking behavior. Howell determined that environmental stimuli can evoke neurochemical changes similar to those produced directly by cocaine.
By 2003, NIDA expects the SPIRCAP group to begin human trials of candidate medications. With fast-track designation, a candidate drug could be fully approved for human use the following year.
"I have never had an opportunity like this to work directly with
the clinical side of medication development for cocaine addiction,"
said Howell. "With the support of NIDA, we all believe that a safe,
effective medication will be discovered."