Cocaine, dopamine and the endogenous opioid system

Cocaine addiction and opiate addiction are both major health problems in the United States today. Prospective studies from our Laboratory, which were able to detect the advent of the HIV-1 epidemic in parenteral drug abusers in New York City beginning around 1978, also showed that, from the beginning of the AIDS epidemic, cocaine abuse was a very important co-factor significantly increasing the risk for developing cocaine dependency. Fundamental studies from many laboratories including our own have shown that cocaine has profound effects on dopaminergic function, primarily from its well-established primary action of blocking the reuptake of dopamine from the synaptic cleft, an action of cocaine directed at the specific dopamine transporter. It has also been well-established by others that cocaine similarly blocks the reuptake of serotonin and norepinephrine. However, recent studies from our laboratory have shown that chronic cocaine administration profoundly disrupts the endogenous opioid system. Extensive studies have been conducted using an animal model which we have developed in our laboratory, the "binge" pattern cocaine administration model. Findings from these studies have led us to recognize the profound disruption of both dynorphin gene expression and kappa opioid receptor gene expression in a setting of chronic cocaine administration and, in turn, have led us to question a possible role of disruption of this system in the acquisition and persistence of cocaine addiction. These findings may have significance for the development of new pharmacotherapeutic agents which may be directed to specific components of the endogenous opioid system and, in particular, possibly the kappa opioid receptor system. Therefore, we have initiated studies to examine further the role of the dynorphin peptide-kappa opioid receptor system in normal physiologic function in humans.