Basic Dopamine Transporter Mechanisms Of Cocaine

National Institute On Drug Abuse

Investigators

Linked publications & trials

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] [unreadable] Benztropine (BZT) analogues bind with high affinity to the dopamine transporter (DAT), and have behavioral effects that are distinct from those of cocaine. We found that, in the presence of cocaine, the pharmacokinetics of BZT analogues do not differ appreciably from that obtained when the BZT analogues are administered alone. Rats were administered intravenous doses of various BZT analogues alone and with cocaine and blood and brain samples were collected over the duration of BZT action. No significant differences were found in the PK parameters of the BZT analogues with and without concurrent cocaine administration.[unreadable] [unreadable] Several BZT analogues have affinity for histamine H1 receptors as well as the DAT, which may account for their differences from cocaine in behavioral effects. A comparative analysis was conducted of the critical structural features with respect to the affinities of BZT analogues at the DAT and histamine H1 receptor binding sites. There was a wide range of binding affinities at histamine H1 receptors (Ki values from 16 to 37,600 nM) and at the DAT (Ki values from 8.5 to 6370 nM). We developed a histamine H1 pharmacophore which was stereoselective, using a five-point superimposition of classical antagonists on the template for cyproheptadine. Superimpositions and comparisons were performed with a series of BZT analogues. 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, though these groups overlap receptor-essential regions in the histamine H1 receptor. In vivo microdialysis studies indicate that several of the H1 receptor antagonists increase extracellular dopamine levels, as do the BZT analogues. Pharmacological analysis of these effects suggests that the effect on dopamine of the H1 antagonists was due to activity at the DAT. [unreadable] [unreadable] We studied the effects of combinations of the preferential M1 antagonists, TXP and TZP, on the discriminative-stimulus effects of cocaine in order to determine if selective H1 antagonists alter the effects of cocaine thereby explaining the lack of cocaine-like effects of BZT analogues. However, the preferential H1 receptor antagonists enhanced the discriminative-stimulus effects of cocaine, suggesting that the lack of cocaine-like effects of BZT analogues was not due to their preferential H1 antagonist effects.[unreadable] [unreadable] In a subsequent study we quantified the interactions among cocaine and classic DA uptake inhibitors (GBR 12909, WIN 35,428, methylphenidate, indatraline, nomifensine and mazindol) or DA releasers (methamphetamine, d-amphetamine, methcathinone, cathinone, fencamfamine and phentermine) in order to better understand how these drugs may be working when administered in combination. The drugs were examined 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. Subsequent studies have determined that the effects of typical dopamine uptake inhibitors on extracellular dopamine in the nucleus accumbens shell are additive, whereas the atypical uptake inhibitors represented by BZT analogues interacted with cocaine in a less than additive manner. The less than additive interaction suggests that the BZT analogues are inhibiting DA uptake through a mechanism(s) that is distinct from that by which cocaine inhibits uptake.