New light shed on the causes of drug addiction

A methamphetamine epidemic rages across the United States with addicts blinded by uncontrollable desires for a drug that eventually thrusts them into a dire and catastrophic existence. Doctors don't have any effective treatments for these addicts, or for any other drug addicts; drug addiction is a disease that remains a medical mystery.

A recent study led by Pastor R. Couceyro, PhD, at Rosalind Franklin University of Medicine and Science and colleagues at Amgen sheds new light on the causes of drug addiction, and opens the possibility for new treatments in the future. These researchers have identified a brain neurotransmitter that is important for the pleasurable, and possibly addictive, effects of stimulant drugs like methamphetamine.

The study shows that highly addictive drugs, like cocaine and amphetamine, require a neurotransmitter called CART (Cocaine- and Amphetamine-Regulated Transcript) peptides to produce their maximal effects. Mice that were genetically engineered to lack CART peptides showed a dramatic insensitivity to the immediate and chronic effects of these drugs, suggesting that the pleasurable and perhaps addictive effects of cocaine, amphetamine, and other stimulants, like methamphetamine, require CART peptides. The study will appear in the Journal of Pharmacology and Experimental Therapeutics in December 2005 and is currently available online at http://jpet.aspetjournals.org/cgi/reprint/jpet.105.091678v1.

In this study, mice lacking CART peptides were created by deleting or "knocking out" the CART gene. These knockout mice were subjected to tests that measure the abuse liability of cocaine and amphetamine. The responses of CART knockout mice to these drugs were compared to those of control mice that had CART peptides. The immediate hyperactivity produced by amphetamine, as well as the dramatic hypersensitivity that results after its repeated use, were blunted in the CART knockout mice. The ability to recall the place where amphetamine was previously received was impaired in the CART knockout mice. Most significantly, voluntary intravenous cocaine intake, which resembles how addicts take many drugs, was reduced in the CART knockout mice. Both the rapid and long-term effects produced by cocaine and amphetamine were reduced when CART peptides were absent from the brain.

CART peptides were suspected to play a role in cocaine and amphetamine drug addiction more than 10 years ago after Dr. Couceyro and colleagues discovered the gene for these neuropeptides. Cocaine and amphetamine were found to increase CART gene activity within a brain area associated with addiction. The brain contains two different sized CART peptides and these are found in areas associated with addiction and emotions. Their location within these brain areas is unique among the various neurotransmitters and molecules involved in pleasure and addiction. The current study is the first to show a causal link between CART peptides and the actions of these addictive drugs. This study was funded by the Schweppe Foundation, and the National Institute on Drug Abuse/National Institutes of Health.

CART peptides may also hold promise as a therapeutic target for treating obesity. Early rodent studies showed a potent suppression of eating when CART peptides were injected directly into the brain. These studies suggested a role for CART peptides in the motivation or reason for why one eats. Interestingly, appetite suppression produced by CART peptide injections is similar to that seen with cocaine and amphetamine use. The precise mechanism by which cocaine and amphetamine decrease weight remains unknown, but CART peptides may have a role here as well. Future studies are needed to investigate the role of CART peptides in eating and obesity.

These findings point to a novel target for treating stimulant drug addiction. Selective drugs can be developed that may suppress the action of natural CART peptides to blunt the 'high' produced by addictive drugs. This may be a useful strategy for preventing drug relapse. The unique location of CART peptides within subsections of the brain involved in pleasure and emotions suggest that selective drugs may be developed with minimal side-effects. At a minimum, CART peptides represent a new strategy in the struggle to develop treatments for cocaine and amphetamine drug addiction.

These research findings are published in the manuscript "CART Peptides Modulate the Locomotor and Motivational Properties of Psychostimulants" by Pastor R. Couceyro, Charity Evans, Audra McKinzie, Darrion Mitchell, Matt Dube, Leila Hagshenas, Francis J. White, Jim Douglass, William G. Richards, and Anthony W. Bannon. Dr. Couceyro is Assistant Professor of Cellular and Molecular Pharmacology, and Dr. White is Professor of Cellular and Molecular Pharmacology at Rosalind Franklin University of Medicine and Science (RFUMS). Ms. Evans, Mr. Mitchell, Mr. Dube, and Ms. Hagshenas are students at RFUMS. Ms. McKinzie, Dr. Douglass, Dr. Richards and Dr. Bannon are collaborating researchers at Amgen Inc. The manuscript is available online at http://jpet.aspetjournals.org/cgi/reprint/jpet.105.091678v1 and will appear in the Journal of Pharmacology and Experimental Therapeutics later this year.