Nicotine Triggers the Same Brain Reward Circuitry as Opiates
In experiments with mice, researchers have found that nicotine triggers the same neural pathways that give opiates such as heroin their addictively rewarding properties, including associating an environment with the drug's reward. However, unlike opiates, nicotine does not directly activate the brain's opiate receptors, but activates the natural opioid reward pathway in the brain.
This research, led by Julie Blendy, PhD, of the Abramson Cancer Center of the University of Pennsylvania and Penn's Transdisciplinary Tobacco Use Research Center, suggests more effective ways that opiate blockers can be used to help smokers quit smoking.
In their experiments reported in the June 16, 2005, issue of Neuron, the researchers administered nicotine to mice and analyzed the levels of a protein called CREB, which is known to control genes involved in the reward pathway of opiates and other abused drugs. They found that CREB was not only activated in the reward regions of the nicotine-treated animal's brains, but also that the drug naloxone, which blocks the opiate receptors, blocked CREB activation as well. Also, mutant mouse strains lacking the opioid receptor did not show an increase in CREB activity when they received nicotine.
"The present results demonstrate that nicotine-associated environmental stimuli can activate the same molecular signal transduction molecules as the drug itself," said Blendy. The activation of CREB "is evident not only after acute and repeated nicotine administration, but also following exposure to an environment in which the animal has previously received nicotine."
The researchers also studied the relationship among nicotine, the environment, and this reward pathway. They conditioned mice to associate a specific test chamber with receiving nicotine, finding that the mice would prefer to stay in that chamber when given a choice. The researchers found that just placing the conditioned mice in the chamber activated CREB. They also found that naloxone blocked this conditioned increase in CREB, and that mutant mice lacking CREB or pretreated with naloxone did not show any reward response to nicotine.
The study also showed that naloxone did not block the chamber choice of mice conditioned with cocaine, suggesting that cocaine activates the brain reward pathway in a different way from nicotine and opiates.
The researchers noted that clinical studies of opioid receptor blockers to relieve cigarette cravings have produced mixed results, ranging from ineffectiveness at smoking cessation to mild reduction in the desire to smoke.
"This research suggests that the timing and context of opioid receptor antagonist administration are critical for determining the effectiveness of blocking nicotine reward," says Blendy. "Given the results reported here, clinical studies designed to evaluate administration of opioid antagonists just prior to cues associated with smoking, could lead to a more promising treatment regimen."
The researchers included Carrie L. Walters, Jessica N. Cleck, Yuo-chen Kuo, and Julie A. Blendy of the Department of Pharmacology at the University of Pennsylvania School of Medicine in Philadelphia. This research was funded by the National Cancer Institute and the National Institute on Drug Abuse and was conducted at the University of Pennsylvania Transdisciplinary Tobacco Use Research Center.
The Abramson Cancer Center of the University of Pennsylvania was established in 1973 as a center of excellence in cancer research, patient care, education and outreach. Today, the Abramson Cancer Center ranks as one of the nation's best in cancer care, according to US News and World Report, and is one of the top five in National Cancer Institute (NCI) funding. It is one of only 39 NCI-designated comprehensive cancer centers in the United States. Home to one of the largest clinical and research programs in the world, the Abramson Cancer Center of the University of Pennsylvania has 275 active cancer researchers and 250 Penn physicians involved in cancer prevention, diagnosis and treatment. More information about the Abramson Cancer Center is available at: www.pennhealth.com/cancer