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. Several studies have indicated that the dopamine transporter (DAT) is cocaine?s primary biological target. Several classes of dopamine uptake inhibitors have been investigated as potential treatments for cocaine abuse, though most have cocaine-like indications abuse liability. However, among analogues of benztropine are compounds with high DAT affinity, and behavioral effects that are unlike those of cocaine. We have investigated the mechanism of action of these compounds in order to determine why their actions at the DAT are not transduced into cocaine-like behavioral effects. Several studies have compared cocaine?s behavioral activity to in vivo DAT binding and compared those effects to those of novel benztropine analogues. The effects of all of the drugs were dose and time dependent. Maximal occupancy of the DAT by benztropine analogues was obtained well after the 30-min time obtained with cocaine. Increases in locomotor activity produced by each of the drugs was also dose and time dependent. The stimulation of locomotor activity produced by cocaine was generally in agreement with its in vivo DAT occupancy (Fig. 2), and there was a significant correlation of DAT occupancy and amount of locomotor stimulation. However, given the established relation between DAT actions and behavioral effects, the obtained correlation was relatively poor, indicating that transporter occupancy is only one determinant of the behavioral effects of cocaine. A more detailed analysis indicated that contributing to the lower than expected correlation was a greater than predicted stimulation of behavior immediately after injection. That divergence from predicted immediately after injection suggested that rate of occupancy also influences the behavioral effects of cocaine, consistent with a recent reports relating rate of cocaine occupancy to the abuse-related subjective reports of euphoria. One BZT analogue, JHW 007, with high DAT affinity was also studied for in vivo DAT occupancy and its relation to behavior. JHW 007 effects were dose and time dependent. However, in contrast to cocaine and several other benztropine analogues, JHW 007 had an exceptionally slow in vivo apparent association with the DAT. The rate of occupancy produced by JHW 007 was ten-fold lower than that produced by cocaine injection. A previous pharmacokinetic comparison of cocaine and JHW 007 indicated that rate of CNS penetration cannot account for the slow association rate of JHW 007. In addition, JHW 007 had minimal effects on ambulatory activity over an 8-hr observation period. At doses from 2 to 24 imol/kg JHW 007 failed to produce a significant stimulation of locomotor activity throughout the 8-hr observation period despite DAT occupancy rates of about 65%. In contrast, cocaine significantly stimulated locomotor activity with DAT occupancy rates of from five to 20%. The finding of minimal stimulant effects of JHW 007, which slowly associates with the DAT, is consistent with the suggestion that rate of DAT occupancy plays an important role in the behavioral effects of DA uptake inhibitors. Occupancy without intrinsic pharmmacological effects should result in antagonist actions. Pretreatment with JHW 007 completely antagonized the effects of cocaine in mice. When administered alone JHW 007 had no significant effects on locomotor activity. This surprising result has been replicated several times. In addition, preliminary studies indicate that JHW 007 antagonizes the subjective effects of cocaine in mice In summary, JHW 007 is a novel drug that has high affinity and selectivity for the DAT in vitro. It passes the blood-brain barrier and readily penetrates the brain, slowly achieving significant levels of DAT occupancy without appreciable cocaine-like stimulant or subjective effects. Most importantly, JHW 007 antagonizes the locomotor stimulant and subjective effects of cocaine. The present results in conjunction with others suggest that the rate of DAT occupancy is a critical component of cocaine-like actions and potential abuse liability. Further, this study suggests in vivo association as a critical feature contributing to the effects of DAT ligands, and suggests that JHW 007 has the attributes necessary to serve as a lead candidate for the treatment of cocaine abuse.
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