Synthetic local anesthetics as alleviators of cocaine inhibition of the human dopamine transporter

2005 2005

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Abstract (summary)

Cocaine addiction is a significant scientific and societal problem, which carries an enormous cost to humanity, with economic and public health ramifications. Economically, this is measured in billions of dollars. However, its social cost in terms of broken lives for both the addicts and their families cannot be easily quantified. In the United States, there are currently more than 1.7 million regular users and about 34 million people over the age of 12 years have used cocaine at least once in their lifetimes. Estimates of the prevalence of cocaine addiction range from one to three percent of the total world population. This implies that millions of people worldwide are directly affected by cocaine abuse.

Hundreds of compounds have been synthesized during the last two decades with the objective of alleviating cocaine inhibition of proteins important in nervous system function, particularly the monoamine transporters, especially cocaine's main physiological target, the dopamine transporter. Compounds that alleviate cocaine inhibition of the monoamine transporters, and that display no inhibition of these transporters have not previously been identified. In this work, I report studies of the effects of seven local anesthetics (cocaine, procaine, tetracaine, procainamide, lidocaine, prilocaine and mepivacaine) on the human dopamine transporter expressed in stably transfected HEK-293 cells. These seven compounds displaced [3H]-cocaine bound to the transporter in a concentration-dependent manner. Of these, only cocaine, procaine and tetracaine inhibited [3H]-dopamine uptake. On the other hand, procainamide, lidocaine, prilocaine and mepivacaine alleviated [3H]-dopamine uptake inhibition by 2 μM unlabeled cocaine.

In this work, I report evidence pointing at an allosteric mode of interaction between dopamine and cocaine, as well as for apparent distinct binding sites for procaine and procainamide, on the dopamine transporter. Additionally, evidence indicating multiple binding sites for cocaine on the dopamine transporter is presented. Possible structural features of the local anesthetic studied responsible for the reported properties here are discussed. A model summarizing these results is proposed.

This is the first report indicating that compounds exist that can prevent cocaine binding to the dopamine transporter with no inhibition of dopamine uptake and that are in fact capable of alleviating cocaine inhibition of this transporter.

Indexing (details)

0419: Pharmacology
0487: Biochemistry
0317: Neurology
Identifier / keyword
Health and environmental sciences; Pure sciences; Biological sciences; Anesthetics; Cocaine; Dopamine transporter
Synthetic local anesthetics as alleviators of cocaine inhibition of the human dopamine transporter
Pagan, One R.
Number of pages
Publication year
Degree date
School code
DAI-B 66/09, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
0542350599, 9780542350597
Hess, George P.
Cornell University
University location
United States -- New York
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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