Team Reveals Major Role for Novel Neurotransmitter System in Regulating Drug Intake

By Anna Sobkowski

A team of researchers at The Scripps Research Institute has provided strong new evidence that a novel neurotransmitter system in the brain is involved in alcohol and opiate addiction. The group found that levels of endogenous cannabinoids increase or decrease in direct proportion to the amount of alcohol or opiates consumed. By providing insight into possible new targets for drug therapy, this work opens up novel avenues for regulating addiction.

The research was published on April 4 in an online edition of The Journal of Neuroscience.

Since the 1990s, scientists have known of the existence of CB1, a brain receptor for marijuana-like substances known as endogenous—or endo—cannabinoids (eCB), that participate in such functions as learning, memory, and habit formation. The eCBs and eCB receptors are part of an "eCB system" that has been thought to be involved in some of the pharmacologic effects of alcohol and opiates. The Scripps Research scientists have shown that the relative change in eCB levels in the brain plays a major role in mediating the rewarding effects of these drugs. Until now, direct in vivo evidence that alcohol and opiates alter brain eCB formation was lacking.

To evaluate the role of the eCB system in the modulation of drug consumption, Loren "Larry" Parsons, a Scripps Research chemist and neuropharmacologist, and postdoctoral fellows Stéphanie Caillé and Lily Alvarez-Jaimes used in vivo microdialysis to study the extracellular eCB levels in the nucleus accumbens, which is a brain region that has long been implicated in the mediation of drug reward. The microdialysis technique monitors ongoing changes in brain chemistry while an animal is awake and engaged in activities such as drug taking. This provides a relatively non-disruptive means for tracking changes in brain chemistry that underlie behavior.

"We found that consumption of either alcohol or heroin results in large increases in brain endocannabinoid levels," says project leader Parsons, "Importantly, blocking the effects of these endocannabinoids at CB1 receptors in the nucleus accumbens reduces the motivation to consume both alcohol and heroin."

The Parsons group used the drug Rimonabant (also known as Acomplia) to block CB1 receptors. This drug has been successfully used outside the United States for weight loss and smoking cessation, although FDA approval for its use in this country is still pending. Previous work has shown that systemic Rimonabant reduces alcohol and opiate intake. The Scripps Research group extended these observations by demonstrating that blockade of CB1 receptors specifically in the nucleus accumbens lowers both alcohol and heroin consumption. Together with their microdialysis findings this provides a direct link between drug-induced increases in nucleus accumbens cannabinoid levels and the motivation to consume these drugs. The Parsons group found, however, that cocaine self-administration does not alter brain endocannabinoid levels and that CB1 receptor blockade does not alter cocaine intake. This suggests that endocannabinoids are not involved in the addictive effects of all abused substances.

Parsons notes the possibility that long-term drug or alcohol exposure may alter endocannabinoid function in a manner that contributes to escalating drug use and eventual drug dependence. There is evidence that brain chemistry differs between non-dependent individuals who use drugs to obtain the pleasure of a "buzz" and drug-dependent individuals who drink or take drugs not to feel pleasure but simply to feel "normal." Identifying the neurochemical mechanisms involved in this distinction of dependence is an important step in the treatment of addiction. Parsons also notes work by Scripps Research Associate Professor Jack Sipe suggesting that genetic disruption of endocannabinoid signaling is associated with a predisposition toward problem drug and alcohol use, indicating this system may be involved in familial addictive disorders.

"While our present study highlights an endocannabinoid component in the effects of alcohol and heroin, there is still much to be learned about the involvement of endocannabinoids in the development of drug addiction," he says.

Although alcohol and heroin both affect the eCB system, Parsons found that each drug selectively alters different endocannabinoids. Alcohol increases the levels of 2-arachidonoylglycerol (2-AG), while causing no change in levels of anandamide (AEA). Conversely, heroin consumption significantly increases levels of AEA, while inducing a significant decrease in 2-AG. In each case, the relative change in the content of the endocannabinoid was correlated with the amount of drug taken. Cocaine consumption did not affect the levels of either AEA or 2-AG. These drug-specific changes in endocannabinoid effects may provide useful targets for the treatment of specific addictions.

For about 30 years, most research in the drug abuse field has focused on dopamine, a brain neurotransmitter involved in motivation and reward whose levels are increased by most every type of addictive drug. However, addiction treatments aimed at manipulating the dopamine system have so far not been effective and there is now substantial effort aimed at identifying other systems that may be involved in the development of drug dependence.

"It may turn out that doctors will need to take the same approach in treating drug addiction as in treating other psychiatric disorders," Parsons says. "For example, not all types of antidepressants are equally effective in all people; psychiatrists often try several drugs before finding the one to which an individual responds. So it's important to know as much as possible about all the brain systems involved in a particular disorder. While treatments aimed at the endocannabinoid system may not be a magic bullet for treating drug dependence, this target does represent a new weapon in the addiction arsenal, one that could potentially be effective in a large number of people."

Loren Parsons, Stéphanie Caillé; Lily Alvarez-Jaimes; Ilham Polis, and David Stouffer were all authors on the study, "Specific alterations of extracellular endocannabinoid levels in the nucleus accumbens by ethanol, heroin, and cocaine self-administration." See http://www.jneurosci.org/cgi/content/abstract/27/14/3695?etoc.

The work was supported by research grants from the National Institute on Alcohol and Alcoholism and the National Institute on Drug Abuse.

Send comments to: mikaono[at]scripps.edu

"While our present study highlights an endocannabinoid component in the effects of alcohol and heroin, there is still much to be learned about the involvement of endocannabinoids in the development of drug addiction," says Associate Professor Loren "Larry" Parsons.