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. [unreadable] AHN 1-055, a benztropine (BZT) analog, binds with high affinity to the dopamine transporter (DAT), possesses behavioral, neurochemical, and pharmacokinetic profiles distinct from cocaine. We evaluated the pharmacokinetics of AHN 1-055 in the presence of cocaine, because it, or drugs like it, if used as medications may be used with cocaine. Rats were given 5 mg/kg of AHN 1-055 and cocaine i.v. and blood and brain samples were collected over 36 h. No significant differences were found in the PK parameters of AHN 1-055, including brain-to-plasma ratios, when given alone or with cocaine. [unreadable] Several BZT analogues have affinity for histamine H1 receptors as well as the DAT. In this study, a comparative analysis was conducted of pharmacophoric features with respect to the activities of BZT analogues at the DAT and at the histamine H1 receptor. The BZT analogues showed a wide range of histamine H1 receptor (Ki = 16?37,600 nM) and DAT (Ki = 8.5?6370 nM) binding affinities. A stereoselective histamine H1-antagonist pharmacophore, using a five-point superimposition of classical antagonists on the template, cyproheptadine, was developed. A series of superimpositions and comparisons were performed with various analogues of BZT. In general, smaller substituents were well tolerated on the aromatic rings of the diphenyl methoxy group for both the DAT and H1 receptor, however, for the H1 receptor, substitution at only one of the aromatic rings was preferred. The substituents at the 2- and N-positions of the tropane ring were preferred for DAT, however, these groups seem to overlap receptor essential regions in the histamine H1 receptor. Molecular models at the DAT and the histamine H1 receptor provide further insight into the structural requirements for binding affinity and selectivity that can be implemented in future drug design.[unreadable] In a subsequent study we quantified the interactions among cocaine and classic DA uptake inhibitors or DA releasers in order to better understand how these drugs may be working when administered in combination. The DA uptake inhibitors GBR 12909, WIN 35,428, methylphenidate, indatraline, nomifensine and mazindol, and DA releasers methamphetamine, d-amphetamine, methcathinone, cathinone, fencamfamine and phentermine were examined alone and in combination with cocaine in rats trained to discriminate cocaine from saline injections. All of the DA indirect agonists dose-dependently substituted for cocaine, and shifted the cocaine dose-effect curve leftward. Isobolographic analysis indicated the interactions were generally additive, although both methamphetamine and d-amphetamine were quantitatively determined to be more potent than DA uptake inhibitors in shifting the cocaine dose-effect function to the left. The potential of d-amphetamine as an effective treatment for cocaine abuse, and negative clinical results with dopamine uptake inhibitors suggests that differences in shifts in dose-effect curves should be further examined with emerging clinical data as a predictive index of potential treatments for cocaine abuse.