Basic Dopamine Transporter Mechanisms Of Cocaine

National Institute On Drug Abuse

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Abstract

The primary focus of this research is to develop a better understanding of the pharmacological mechanisms underlying the behavioral effects of cocaine that lead to its abuse, and the consequences of that abuse. This better understanding will advance basic knowledge of the pharmacology of cocaine, and drug abuse. In addition, there is a large unmet medical need for cocaine addiction treatments. Recent (1999 to 2002) annual estimates of the number of individuals using cocaine range from 2 to 3.2 million in the United States alone. This research will ultimately lead to the discovery of new treatment modalities for cocaine abuse. Effective treatments for drug abuse will ultimately have a positive public health impact in curtailing drug abuse and the transmission of HIV infection. We examined the binding of atypical dopamine uptake inhibitors to dopamine (DA) transporter sites in vivo along with the behavioral effects of the drugs. Both cocaine and GBR 12909 increased locomotor activity in a dose-related manner, with the effects of GBR 12909 lasting longer than cocaine. In addition there were long lasting increases in locomotor activity produced by the atypical DA uptake inhibitors, however, maximal effects were generally lower than those produced by cocaine. Further, the stimulation produced by JHW 007 did not achieve statistical significance. The apparent rate of association for cocaine was 2.04% occupancy/min, whereas the rate of occupancy of JHW 007 was 10-fold lower. We further examined the relationship between locomotor-stimulant effects of cocaine, GBR 12909 and BZT analogues (AHN 1-055 and AHN 2-005) and their in vivo displacement of the DA transporter ligand [125I]RTI-121, by linear regression of dopamine transporter occupancy and the stimulation produced. For each of the drugs there was a significant positive correlation between occupancy and stimulation, as expected. However, for cocaine, the slope of the regression line was less than that for the other drugs. Contributing to this diminished strength of association between occupancy and effect were the effects of cocaine at early time points after injection. At these times the behavioral effect was a greater than predicted by the regression of displacement of [125I]RTI-121, and a trend for the stimulation to be less than predicted at times longer after injection. These data suggest that the on rate of occupancy of the dopamine transporter, in addition to percentage of sites occupied, contributes to the behavioral effects of cocaine. The present results suggest that among drugs that act at the DA transporter, the slower apparent rates of occupancy with the DA transporter by the BZT analogs may contribute in an important way to differences in their effectiveness. Studies described in Section III, Future Research Plans, address further tests of this hypothesis and the proposed further mechanistic studies that may account for differences in rates of association. The substantial occupancy of the dopamine transporter by JHW 007 obtained at 270 min after treatment was comparable to the occupancy obtained with cocaine at 30 min after treatment (Figure 7). Because this occupancy was sufficient to produce behavioral effects with cocaine but appeared to be inadequate for behavioral effects with JHW 007 we hypothesized that JHW 007 would function as an antagonist of cocaine. When we pretreated subjects with JHW 007 and later gave cocaine, the effects of cocaine were antagonized.