The primary focus of this research is to better understand pharmacological mechanisms underlying the behavioral effects of cocaine that lead to its abuse, and the consequences of that abuse. The primary biological target of cocaine is the dopamine transporter (DAT), and the present research will advance basic knowledge of the behavioral pharmacology of cocaine and its abuse as mediated through the DAT. In addition, there is a large unmet medical need for medical treatments to manage cocaine addiction. In 2006, 6 million Americans age 12 and older had abused cocaine in any form, and 1.5 million had abused crack cocaine at least once in the past year. Further, another survey showed that 2.0% of 8th graders, 3.4% of 10th graders, and 5.2% of 12th graders had abused cocaine in some form. The concomitant costs to society of drug abuse in general is close to $200 billion, much of which is associated with drug-related crime. This research will ultimately lead to the discovery of new medical treatment modalities for cocaine abuse. Criminology studies show that treatment can reduce criminal activity up to 80 percent, and reduce re-arrests. Medications are an important part of treatment for many drug abusing offenders. Analogues of benztropine (BZT) also bind with high affinity to the DAT. However, the BZT analogues are distinct from cocaine in their behavioral activity. Because of these pharmacological differences, and the potential of BZT analogues to serve as medical treatments for cocaine abuse, we have extensively studied compounds from this chemical group. Previous studies of BZT analogues, have investigated off-target actions (those not mediated by the DAT) as potentially responsible for their differences from cocaine. Those studies suggested that off-target sites of action could not fully account for the differences between BZT analogs and cocaine. Instead, studies reported last year, suggest that the differences in pharmacology likely stem from fundamental differences between the manner in which they interact with the DAT. Several studies of combinations of BZT analogs with cocaine were undertaken to characterize the functional consequences of the differences in binding conformation equilibrium induced by cocaine and BZT analogs. Among BZT analogues previously studied are several N-substituted analogues with high affinity for the DAT and varying degrees of selectivity for the DAT over other targets. Several N-substituted analogs of BZT (e.g. N-allyl: AHN 2-005 and N-butyl: JHW 007) were substantially less efficacious than cocaine in stimulating locomotor activity and in producing cocaine-like subjective effects in laboratory animals. Further, JHW 007 antagonized the locomotor stimulant effects of cocaine in mice, whereas other standard DAT inhibitors, such as methylphenidate, typically shift the cocaine dose-effect curve leftward. The N-methyl analog (AHN 1-055) was more effective than the other BZT analogs, and was less selective than the others for the DAT over muscarinic M1 receptors. In studies of cocaine self administration, pretreatment with the above listed BZT analogs dose-dependently decreased cocaine self-administration. Responding of rats was maintained by cocaine (0.0321.0 mg/kg/inj) or food reinforcement under fixed-ratio 5-response schedules. Maximal rates of responding were maintained by 0.32 mg/kg/inj of cocaine, with lower rates maintained at lower and higher doses. When the BZT analogs, AHN 2-005 and JHW 007, were administered before the rats had the opportunity to self administer cocaine, the effectiveness of cocaine was substantially decreased with no changes in its potency. More specifically, increasing doses of cocaine could not surmount the antagonism produced by BZT treatment. In contrast, pretreatment with the standard dopamine uptake inhibitor, methylphenidate, potentiated the effects of cocaine, i.e. the cocaine dose-effect curve was shifted leftward. In addition, the effects of the BZT analogs on cocaine self administration were selective;the dose-dependent decrease in effectiveness of cocaine was produced by BZT analogs that had no effect on responding maintained by food reinforcement. Increases in dopamine efflux in the shell of the nucleus accumbens are closely related to the acute reinforcing effects of virtually all drugs abused by humans, and preferential effects on this brain structure are thought to underlie the abuse liability of cocaine, as well as other drugs of abuse. Therefore, we examined the effects of combinations of cocaine with a BZT analog, and compared those combinations to the effects of combinations of cocaine with a standard dopamine uptake inhibitor, WIN 35,428. Each of the drugs alone produced dose-related elevations in nucleus accumbens dopamine levels, however, in contrast to the other drugs, JHW 007 was less effective, producing maximal effects that approached 400% of control compared to the approximate 700% of control produced by cocaine and WIN 35,428. In addition the JHW 007 dose-effect curve was not as steep as those for cocaine and WIN 35,428. Combinations of cocaine with its analog, WIN 35,428, were most often greater than those predicted based on dose additivity. In contrast, combinations of cocaine with JHW 007, were most often less than additive, and at some dose combinations antagonistic. This outcome is consistent with studies suggesting that BZT analogs bind to different domains of the DAT, which can result in different DAT conformations. The conformational changes occurring with JHW 007 binding may result in functional outcomes that alter its abuse liability and its effects in combination with cocaine. These preclinical findings suggest the possibility for development of N-substituted BZT analogues as medical treatments for cocaine abuse. However, the BZT analogues would not be substantial advances in the discovery of compounds for development as medications for cocaine abuse if they have abuse liability themselves. Therefore, studies were conducted to determine whether the BZT analogs listed above would be self administered. These studies indicated no reinforcing effects (AHN 2-055, JHW 007) across a wide range of doses. Studies of a third BZT analog (AHN 1-055) indicated reinforcing effects that were substantially less than those produced by cocaine. Thus, the results with these N-substituted BZT analogues suggest the possibility for their development as medical treatments for cocaine abuse and the likelihood that the compounds themselves will have low liability for abuse. More generally, the present results confirm that the DAT can serve as an important target for the discovery of compounds with potential for development as cocaine abuse medical treatments
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