KEYNOTE SPEECH: JACOB P. WALETZKY MEMORIAL AWARD RECIPIENT
Timothy P. Condon, Ph.D., Deputy Director, NIDA
Robert Malenka, M.D., Ph.D., Chair of the 2005 Jacob P. Waletzky
Memorial Award Selection Committee, SfN
Established in 2003, the Society for Neuroscience Jacob P. Waletzky Memorial Award is given for innovative research in drug addiction and alcoholism. This year’s award recipient was William A. Carlezon Jr., Ph.D.
Experience-Dependent Alterations in the Function of Brain Reward Systems:
The Role of CREB
William A. Carlezon Jr., Ph.D.
Drugs of abuse and stress each have profound effects on the NAc, including enhanced activation of CREB. We examined the consequences of altering CREB function and one of its targets (dynorphin, an endogenous opioid that acts at kappa receptors in the brain) on complex behavior, and found that elevations of CREB function within the NAc reduce the rewarding effects of cocaine, sucrose, and hypothalamic brain stimulation. Conversely, reductions in CREB activity within the NAc increase the rewarding effects of cocaine and morphine, and produce antidepressant-like effects. This pattern of behavioral effects can be attributed to changes in the expression of a single CREB-regulated protein: dynorphin.
Administration of kappa-selective agonists produces effects that are qualitatively similar to those produced by increased CREB function in the NAc. Many of these same effects are produced by microinjections of the kappa-selective agonists directly into the NAc, suggesting that dynorphin-mediated activation of kappa-receptors in this region triggers depressive-like effects. In contrast, kappa-selective antagonists produce an antidepressant-like phenotype resembling that seen in animals with disrupted CREB function in the NAc. These findings indicate that a biologically important consequence of drug- or stress-induced activation of CREB within the NAc is increased transcription of dynorphin, which triggers certain features of depression. The fact that stress and drugs trigger common molecular cascades in the NAc may contribute to the high incidence of co-morbidity of addiction and depressive conditions in humans. A better understanding of these cascades will lead to improved treatments for addiction and other psychiatric conditions.