PET Neuroimaging Reveals How Cocaine Addiction Develops

Media Contacts: Poul Olson, 404-727-9254 -- [email protected]Lilli Kim, 404-727-7709 -- [email protected]

PET Neuroimaging Reveals How Cocaine Addiction Develops Yerkes neuroscientists find that SSRI blocks drug's effects

ATLANTA - OCT. 31, 2001 - Neuroscientists at the Yerkes Regional Primate Research Center of Emory University have for the first time used positron emission tomography (PET) neuroimaging to measure the acute effects of cocaine on blood flow in the brains of awake rhesus monkeys. Furthermore, Yerkes scientists have determined that a particular compound, a selective serotonin reuptake inhibitor (SSRI) called alaproclate, blocks the brain activation induced by cocaine. The findings appear in the Oct. 3 Web edition of Psychopharmacology, and will be published in the journal's print edition at a later date.

The study, led by Leonard Howell, Ph.D., examined cerebral blood flow changes in two male and two female rhesus macaque monkeys that intravenously received similar doses of cocaine while conscious. None of the monkeys had been exposed previously to cocaine. Within five minutes of administration, significant increases in blood flow, indicative of pronounced brain activation, were observed in the dorsolateral region of the prefrontal cortex. This region of the forebrain is believed to control judgment and aspects of personality in humans. In the same monkeys, a control dose of saline also was administered that had no effect on cerebral blood flow.

When Howell treated the monkeys with alaproclate 30 minutes prior to cocaine administration, cerebral blood flow did not increase significantly indicating that the compound blocked cocaine from activating the prefrontal cortex.

The prefrontal cortex, which plays various roles in the brain, is a major component of the dopamine system that controls feelings of pleasure and reward. Cocaine binds to neurons that regulate the chemical dopamine, a neurotransmitter. As a result, the brain is flooded with dopamine, causing the sensation of euphoria.

Addiction researchers have identified a close association between drug-induced functional changes in cerebral blood flow in the prefrontal cortex and the addictive properties of cocaine. Tracking how cocaine alters the brain's neuronal activity, however, has proven challenging because of the variability in levels of cocaine use among people and the tendency of cocaine users to concurrently use other drugs.

For these reasons, the ability to conduct functional MRI or PET neuroimaging in awake monkeys, a technique developed over several years by Howell and a team of Emory scientists, marked a major breakthrough for cocaine addiction research. Because cocaine intake in non-human primates can be standardized, researchers will be able to generate more consistent data.

Howell plans to use PET imaging to develop a profile of addiction in monkeys through each stage of the process. "Our goals is to determine when the brain changes from the non-addicted to the addicted state," said Howell.

In other experiments, Howell has found significant differences in patterns of brain activation between awake monkeys that self-administer cocaine and those that do not.

"We know that environmental factors play a strong role in the addiction process," said Howell. "To be able to image the brain of an awake monkey sets the stage for research studies of cocaine addiction that we can't do in people."

The finding that an SSRI can inhibit cocaine's effects on the brain adds to a growing body of animal and clinical data on serotonin's ability to blunt the activity of psychomotor stimulants such as cocaine.

"But the fact that alaproclate can block the effects of cocaine does not necessarily mean it will be a good medication for controlling addiction," Howell cautions. "Individuals who experience craving for cocaine want relief from the negative feelings of not taking the drug. Alaproclate alone may not control this."

Howell said that SSRIs could potentially be used in combination with cocaine substitutes, such as the phenyltropane compounds, that Yerkes investigators have been developing for the past several years. He also says that the compounds may provide another means for understanding the mechanisms by which cocaine alters neuronal activity and the neurochemical makeup of the brain.

Howell's Yerkes' co-authors on the study were John Hoffman, M.D., John Votaw, Ph.D., Alyson Landrum, Kristin Wilcox, Ph.D., and Kimberly Lindsey. Grants from the National Institutes on Drug Abuse supported the research.

###